TIMM22

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0030943 mitochondrion targeting sequence binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Internal targeting signals are central to TIM22-pathway substrates, but direct mitochondrion targeting sequence binding is less precise for TIMM22 itself than its pore/insertase role in the TIM22 complex. Reason: Represent TIMM22 primarily with TIM22 complex membership, membrane insertase/protein transporter activity, and protein insertion into mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md - TIM22: specializes in inserting multi-pass IMM proteins with internal targeting signals, classically metabolite carriers (the “carrier pathway”). (bogorodskiy2021roleofmitochondrial pages 4-6, ruizpesini2021molecularinsightsinto pages 12-14) file:human/TIMM22/TIMM22-deep-research-falcon.md In addition, small TIM chaperones in the IMS stabilize hydrophobic precursors after TOM passage and deliver them to the TIM22 complex.
GO:0042721 TIM22 mitochondrial import inner membrane insertion complex	IBA GO_REF:0000033	ACCEPT	Summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0045039 protein insertion into mitochondrial inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0008320 protein transmembrane transporter activity	IBA GO_REF:0000033	ACCEPT	Summary: Correct. TIMM22 contributes the pore/insertase activity of the TIM22 carrier translocase for protein transmembrane insertion. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family.
GO:0042721 TIM22 mitochondrial import inner membrane insertion complex	IEA GO_REF:0000002	ACCEPT	Summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0045039 protein insertion into mitochondrial inner membrane	IEA GO_REF:0000002	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0071806 protein transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Correct pathway family but too broad. TIMM22 is specifically a mitochondrial inner-membrane protein insertase/translocase for multi-pass carrier-pathway clients. Reason: Use protein insertion into mitochondrial inner membrane and TIM22 complex annotations rather than generic protein transmembrane transport. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
GO:0090150 establishment of protein localization to membrane	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Correct but broad. TIMM22 specifically mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Reason: Use GO:0045039 protein insertion into mitochondrial inner membrane as the specific supported process. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for TIMM22. The informative annotation is TIM22 carrier translocase complex membership and insertase/translocase function. Reason: Documented interactions with TIMM29, small TIMs, and AGK should be represented by complex/function terms rather than generic protein binding. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0032977 membrane insertase activity	IMP PMID:27554484 Tim29 is a novel subunit of the human TIM22 translocase and ...	ACCEPT	Summary: Correct and core. TIMM22 is the pore/insertase subunit of the TIM22 complex for mitochondrial inner-membrane protein insertion. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
GO:0005743 mitochondrial inner membrane	IDA PMID:32901109 Cryo-EM structure of the human mitochondrial translocase TIM...	ACCEPT	Summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family.
GO:0042721 TIM22 mitochondrial import inner membrane insertion complex	IPI PMID:32901109 Cryo-EM structure of the human mitochondrial translocase TIM...	ACCEPT	Summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0045039 protein insertion into mitochondrial inner membrane	IDA PMID:32901109 Cryo-EM structure of the human mitochondrial translocase TIM...	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0005743 mitochondrial inner membrane	EXP PMID:27265872 The presence of disulfide bonds reveals an evolutionarily co...	ACCEPT	Summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: Correct but broad. TIMM22 is specifically localized to the mitochondrial inner membrane as part of the TIM22 complex. Reason: Prefer mitochondrial inner membrane and TIM22 complex annotations over generic mitochondrion. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family.
GO:0045039 protein insertion into mitochondrial inner membrane	IMP PMID:27554484 Tim29 is a novel subunit of the human TIM22 translocase and ...	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0042721 TIM22 mitochondrial import inner membrane insertion complex	IDA PMID:28712724 Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit...	ACCEPT	Summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0042721 TIM22 mitochondrial import inner membrane insertion complex	IDA PMID:28712726 Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinas...	ACCEPT	Summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0045039 protein insertion into mitochondrial inner membrane	IDA PMID:28712724 Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit...	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0045039 protein insertion into mitochondrial inner membrane	IDA PMID:28712726 Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinas...	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0005515 protein binding	IPI PMID:27718247 TIM29 is a subunit of the human carrier translocase required...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for TIMM22. The informative annotation is TIM22 carrier translocase complex membership and insertase/translocase function. Reason: Documented interactions with TIMM29, small TIMs, and AGK should be represented by complex/function terms rather than generic protein binding. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0042721 TIM22 mitochondrial import inner membrane insertion complex	IDA PMID:27718247 TIM29 is a subunit of the human carrier translocase required...	ACCEPT	Summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. file:human/TIMM22/TIMM22-deep-research-falcon.md A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase).
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-1955380	ACCEPT	Summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family.
GO:0008320 protein transmembrane transporter activity	TAS PMID:14726512 Organization and function of the small Tim complexes acting ...	ACCEPT	Summary: Correct. TIMM22 contributes the pore/insertase activity of the TIM22 carrier translocase for protein transmembrane insertion. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
GO:0045039 protein insertion into mitochondrial inner membrane	TAS PMID:14726512 Organization and function of the small Tim complexes acting ...	ACCEPT	Summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). file:human/TIMM22/TIMM22-deep-research-falcon.md 4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
GO:0005743 mitochondrial inner membrane	TAS PMID:14726512 Organization and function of the small Tim complexes acting ...	ACCEPT	Summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase. Supporting Evidence: file:human/TIMM22/TIMM22-deep-research-falcon.md TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family.

Core Functions

TIMM22 is the pore/insertase subunit of the mitochondrial inner-membrane TIM22 carrier translocase, mediating insertion of hydrophobic multi-pass proteins such as metabolite carriers after TOM import and small-TIM chaperone delivery through the intermembrane space.

Molecular Function:

membrane insertase activity

Directly Involved In:

protein insertion into mitochondrial inner membrane

Cellular Locations:

mitochondrial inner membrane

In Complex:

TIM22 mitochondrial import inner membrane insertion complex

Supporting Evidence:

file:human/TIMM22/TIMM22-deep-research-falcon.md
TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
file:human/TIMM22/TIMM22-deep-research-falcon.md
A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
file:human/TIMM22/TIMM22-deep-research-falcon.md
4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

PMID:14726512

Organization and function of the small Tim complexes acting along the import pathway of metabolite carriers into mammalian mitochondria.

Human small Tim proteins (Tim9, Tim10a, Tim10b) form two hetero-oligomeric complexes including a 450-kDa assembly that operates along the TIM22 carrier import pathway.

"Here, we show that the human small proteins form two distinct hetero-oligomeric complexes. A 70-kDa complex that contains Tim9 and Tim10a and a Tim9-10a-10b that is part of a higher molecular weight assembly of 450 kDa."
During import the small Tim chaperones deliver carrier preproteins to human Tim22, identified as the putative insertion pore of the TIM22 translocase.

"For insertion of carrier preproteins into the inner membrane, the human small Tim proteins directly interact with human Tim22, the putative insertion pore of the TIM22 translocase."

PMID:27265872

The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly.

TIMM22 is a core inner-membrane translocase component of the Tim17/Tim22/Tim23 family that forms intramolecular disulfide bonds required for proper assembly into the TIM22 complex.

"Tim22, a membrane protein and core component of the mitochondrial translocase TIM22, forms an intramolecular disulfide bond in yeast. Tim22 belongs to the Tim17/Tim22/Tim23 family of protein translocases."
Human TIMM22 carries two intramolecular disulfide bonds (Cys69-Cys141 and Cys160-Cys179), and the Cys160-Cys179 bond is prerequisite for TIMM22 assembly into the mature TIM22 complex.

"Altogether, the biochemical analyses and transmembrane prediction for human TIMM22 indicate that one disulfide bond could be formed on the IMS side of TIMM22 between Cys69 and Cys141, and another disulfide bond that joins the TM3 and TM4 is formed between Cys160 and Cys179"
Loss of the TIMM22 disulfide bond linking Cys160-Cys179 abolishes assembly into the mature human TIM22 translocase despite retained membrane integration.

"Thus, the lack of the second disulfide bond that is present in the human TIMM22 structure renders the protein unable to assemble into the mature TIM22 complex, despite its ability for membrane integration"

PMID:27554484

Tim29 is a novel subunit of the human TIM22 translocase and is involved in complex assembly and stability.

TIM22 mediates import of hydrophobic carrier proteins into the mitochondrial inner membrane, and Tim29 (C19orf52) was identified as a metazoan-specific subunit of the human TIM22 complex.

"The TIM22 complex mediates the import of hydrophobic carrier proteins into the mitochondrial inner membrane... we identify Tim29 (C19orf52) as a novel, metazoan-specific subunit of the human TIM22 complex."
Tim29 is required for assembly and stability of the human TIM22 complex and links it to the TOM complex for transfer of hydrophobic substrates across the intermembrane space.

"Tim29 is required for the stability of the TIM22 complex and functions in the assembly of hTim22. Furthermore, Tim29 contacts the Translocase of the Outer Mitochondrial Membrane, TOM complex, enabling a mechanism for transport of hydrophobic carrier substrates across the aqueous intermembrane space."
The human TIM22 complex migrates at ~450 kDa and contains TIMM22 as the channel-forming subunit together with the small TIM chaperones hTim9, hTim10a and hTim10b.

"Like yeast, the human TIM22 complex consists of the channel-forming hTim22 protein, along with subunits of the small TIM family, hTim9, hTim10a, and hTim10b"

PMID:27718247

TIM29 is a subunit of the human carrier translocase required for protein transport.

Hydrophobic inner-membrane proteins with internal targeting signals such as metabolite carriers are inserted into the inner membrane by the TIM22 carrier translocase, and defects in this pathway are linked to neurodegenerative disorders.

"Hydrophobic inner mitochondrial membrane proteins with internal targeting signals, such as the metabolite carriers, use the carrier translocase (TIM22 complex) for transport into the inner membrane. Defects in this transport pathway have been associated with neurodegenerative disorders."
TIM29 is a 440 kDa human TIM22 complex constituent that interacts with oxidized TIMM22 and is required for structural integrity of the complex and import of carrier substrates.

"We show that TIM29 is a constituent of the 440 kDa TIM22 complex and interacts with oxidized TIM22. Our analyses demonstrate that TIM29 is required for the structural integrity of the TIM22 complex and for import of substrate proteins by the carrier translocase."
TIMM22 is the central pore-forming subunit of the carrier translocase whose human form shares ~40% identity with yeast Tim22 and is conserved across eukaryotes.

"Tim22 is the central, pore‐forming, subunit of the complex... The human TIM22 displays 40% homology with the yeast Tim22"

PMID:28712724

Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria.

AGK, the lipid kinase mutated in Sengers syndrome, was identified as a constituent of the inner-membrane TIM22 complex that assembles with TIMM22 and TIMM29 to support import of a subset of multi-spanning membrane proteins.

"Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins."
AGK's role as a TIM22 subunit is kinase-independent, linking Sengers syndrome pathogenesis to defects in TIM22-mediated mitochondrial protein biogenesis as well as phospholipid metabolism.

"The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity... The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome."

PMID:28712726

Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex.

AGK is a bona fide subunit of the human TIM22 import complex that acts kinase-independently to maintain TIM22 integrity and facilitate the import and assembly of mitochondrial carrier proteins.

"Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins."
Mitochondria from Sengers syndrome patients show a destabilized TIM22 complex and defective biogenesis of carrier substrates, linking TIM22-mediated protein import directly to disease.

"Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates."

PMID:32296183

A reference map of the human binary protein interactome.

HuRI is a proteome-wide binary protein interactome map; the cited excerpt does not directly mention TIMM22, and inclusion here provides only indirect, peripheral context for systematic PPI data that could be queried for TIMM22 interactors.

"Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies... We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions."

PMID:32901109

Cryo-EM structure of the human mitochondrial translocase TIM22 complex.

This study determined the cryo-EM structure of the human mitochondrial TIM22 carrier translocase, providing the structural framework for TIMM22-mediated insertion of multi-spanning inner-membrane proteins.

"Cryo-EM structure of the human mitochondrial translocase TIM22 complex."

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

The TIM22 complex imports metabolite carriers into the mitochondrial inner membrane and TIMM22 also inserts the precursors of TIMM23 and TIMM17A/B, with its short half-life suggesting a regulatory role in adjusting carrier import to metabolic conditions.

"The TIM22 complex is responsible for importing the large number of metabolite carriers into the inner membrane that are crucial in controlling the metabolite flux between the mitochondrial matrix and other cellular compartments... The short half-life of TIMM22 may represent a means for rapidly adjusting the import of metabolite carriers to changing metabolic conditions... TIMM22 also inserts the precursors of TIMM23 and TIMM17A/B into the inner membrane"

Reactome:R-HSA-1955380

TIMM9:TIMM10 transfers proteins to TIMM22

file:human/TIMM22/TIMM22-deep-research-falcon.md

Falcon deep research report for human TIMM22

Suggested Experiments

Experiment: Express wild-type and disease-associated TIMM22 variants in TIMM22-deficient rescue cells, then measure TIM22 complex abundance by BN-PAGE and radiolabeled import/assembly of ANT, MPC, and SFXN clients.

Hypothesis: TIMM22 disease-associated variants impair mature TIM22 complex assembly and reduce insertion of carrier-pathway clients.

Experiment: Map substrate-dependent TIMM22-TIMM29-small TIM contacts using crosslinking mass spectrometry during staged import reactions with canonical carrier and non-canonical MPC/SFXN substrates.

Hypothesis: TIMM22 acts as the core insertase while small TIM chaperones and TIMM29 tune substrate delivery specificity.

Deep Research

Falcon

(TIMM22-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2026-05-11T16:12:17.129797

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human TIMM22 (UniProt Q9Y584) functional annotation

0) Target verification (gene/protein identity)

The research target is human TIMM22 (UniProt Q9Y584), annotated as mitochondrial import inner membrane translocase subunit Tim22 (also reported synonymously in the literature as Tim22/TIMM22/TIM22 and sometimes as TEX4). TIMM22 is consistently described as a core component of the TIM22 carrier translocase of the mitochondrial inner membrane (IMM), belonging to the Tim17/Tim22/Tim23 family. This matches the UniProt description and expected domain/family context. (wrobel2016thepresenceof pages 1-2, ruizpesini2021molecularinsightsinto pages 12-14)

1) Key concepts and definitions (current understanding)

1.1 Mitochondrial protein import and the “carrier pathway”

Most mitochondrial proteins are nuclear-encoded, synthesized in the cytosol, and imported through specialized translocases. A key division is between:
- TIM23: imports presequence-containing proteins (matrix and some IMM proteins).
- TIM22: specializes in inserting multi-pass IMM proteins with internal targeting signals, classically metabolite carriers (the “carrier pathway”). (bogorodskiy2021roleofmitochondrial pages 4-6, ruizpesini2021molecularinsightsinto pages 12-14)

1.2 What TIMM22 does (molecular function)

TIMM22 is the pore/insertase subunit of the human TIM22 complex. It mediates membrane insertion of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS). (ruizpesini2021molecularinsightsinto pages 12-14, baker2022mitochondrialbiologyand pages 5-6)

1.3 TIM22 complex composition in humans

A widely cited current model describes the human TIM22 complex (~440 kDa) as comprising TIMM22, TIMM29, TIM10B, and AGK (acylglycerol kinase). (ruizpesini2021molecularinsightsinto pages 12-14)

In addition, small TIM chaperones in the IMS stabilize hydrophobic precursors after TOM passage and deliver them to the TIM22 complex. Yeast uses two hexameric small-TIM rings (Tim9/10 and Tim8/13), but in humans, the TIM9/10A ring is reported as the one detected as part of the translocase, while TIM8/TIM13 is described as dispensable for TIM22-mediated import. (ruizpesini2021molecularinsightsinto pages 12-14)

2) Mechanism, substrates, and localization

2.1 Mechanistic steps of TIM22-mediated insertion

A canonical pathway description is:
1) Precursor passes through TOM.
2) Hydrophobic precursor is stabilized in the IMS by small TIM chaperones.
3) The chaperone–precursor complex docks onto the TIM22 complex.
4) The precursor is inserted into the IMM in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)

2.2 Substrate specificity: canonical and non-canonical cargos

Canonical substrates:
- Six-transmembrane (6-TM) metabolite carriers (e.g., adenine nucleotide carriers are emphasized as core exemplars of carrier-pathway clients). (ruizpesini2021molecularinsightsinto pages 12-14, ruizpesini2021molecularinsightsinto pages 14-15)

Non-canonical / recently expanded substrate spectrum (as summarized in authoritative reviews):
- Mitochondrial pyruvate carrier (MPC) subunits, containing 2–3 predicted TM segments.
- Sideroflexins (SFXN family), containing 5 TM segments. (ruizpesini2021molecularinsightsinto pages 12-14)

In disease and functional contexts, perturbation of TIM22-pathway function has been linked to changes in the biogenesis/levels of multi-pass IMM clients including NDUFA11, NDUFC2 (complex I-related) and SFXN family members (notably SFXN4, and altered biogenesis of SFXN1/2/3). (baker2022mitochondrialbiologyand pages 5-6)

2.3 Sub-mitochondrial localization and functional positioning

Beyond generic IMM localization, the TIM22 complex is proposed to be spatially organized by interactions with structural organizers:
- MICOS is reported to interact with the TIM22 complex in human mitochondria, likely positioning TIM22 near cristae junctions and potentially near TOM to promote efficient metabolite-carrier import. (ruizpesini2021molecularinsightsinto pages 12-14, ruizpesini2021molecularinsightsinto pages 14-15)
- Yeast studies summarized in reviews report that VDAC/porin can interact with TIM22 substrates in the IMS and help recruit TIM22 for efficient insertion. (ruizpesini2021molecularinsightsinto pages 12-14)

3) Biogenesis/topology: redox-dependent maturation of human TIMM22

A distinctive and experimentally supported feature of Tim22-family proteins is oxidative folding during biogenesis.

In human cells, TIMM22 contains multiple cysteines and was experimentally shown (thiol-trapping/mutagenesis assays in mitochondria from human cell lines) to form two intramolecular disulfide bonds while retaining free thiols. Specific cysteine pairings proposed include Cys69–Cys141 and Cys160–Cys179, with evidence that the Cys160–Cys179 bond is important for assembly of the mature TIM22 complex (co-elution/interaction with native TIMM22) even if membrane insertion can still occur. (wrobel2016thepresenceof pages 9-10, wrobel2016thepresenceof pages 7-9, wrobel2016thepresenceof pages 10-12)

At the conceptual level, this oxidation is described as evolutionarily conserved across fungi and metazoa and as supporting translocase complex biogenesis by stabilizing relatively weak transmembrane regions. (wrobel2016thepresenceof pages 1-2)

4) Disease relevance: human genetics, phenotypes, and quantitative data

4.1 TIMM22 variants and combined OXPHOS deficiency (rare)

TIMM22 mutation is reported as rare, with a single patient described in the cited reviews.

Genotype:
- Compound heterozygous p.Y25* (nonsense) and p.V33L (missense) in TIMM22. (palmer2021mitochondrialproteinimport pages 10-13, baker2022mitochondrialbiologyand pages 5-6)

Clinical phenotype reported across reviews:
- Intrauterine growth retardation, hypotonia, feeding difficulties, gastroesophageal reflux, delayed myelination, and elevated lactate (and elevated creatine/creatine kinase reported in at least one review). (palmer2021mitochondrialproteinimport pages 10-13, baker2022mitochondrialbiologyand pages 5-6)

Cellular/biochemical findings:
- Marked loss of the TIM22 complex by blue-native PAGE in patient fibroblasts, rescuable by complementation.
- Reduced steady-state levels of Tim22 and Tim29, and reduced levels of a carrier client (reported as ANT3 in patient fibroblasts in one review).
- Decreased respiratory chain complex activities are reported (Complex I/II/IV in muscle in one review; Complex I/III/IV in another review), consistent with impaired carrier import impacting mitochondrial metabolism/respiration. (palmer2021mitochondrialproteinimport pages 10-13, baker2022mitochondrialbiologyand pages 5-6)

4.2 TIM22-pathway disorders via other complex components: AGK and TIMM29

AGK (acylglycerol kinase)
- AGK is described as a TIM22-complex component required for metabolite-carrier import, and AGK loss-of-function mutations cause Sengers syndrome, characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis. (ruizpesini2021molecularinsightsinto pages 14-15, baker2022mitochondrialbiologyand pages 5-6)
- Mechanistically, AGK loss is reported to destabilize the TIM22 complex and impair carrier import; it is also linked to altered cellular metabolism including TCA-cycle flux and one-carbon metabolism in patient-derived contexts. (baker2022mitochondrialbiologyand pages 5-6)

TIMM29
- A large recent cohort identified biallelic TIMM29 p.Trp172Arg as a cause of Sengers-like disease in 17 consanguineous patients. (shalata2025sengerssyndromecaused pages 1-2)
- Quantitative cohort details reported include:
- Severe infantile Sengers mortality ~86% (as summarized in the paper’s background for severe Sengers presentations).
- HyperCKemia >1000 U/L in 13/14 TIMM29 patients with available data.
- Elevated CSF lactate in 2/3 tested.
- PDH complex deficiency in 4 participants. (shalata2025sengerssyndromecaused pages 5-6)

These findings emphasize that clinical presentations linked to the “TIM22 pathway” can arise from multiple subunits, even though direct TIMM22 mutation itself is currently very rarely reported in humans. (baker2022mitochondrialbiologyand pages 5-6, shalata2025sengerssyndromecaused pages 1-2)

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2023: “Import clogging” implicates TIM22 as a site of pathologic obstruction

A major 2023 advance reframed mitochondrial disease mechanisms by showing that pathogenic mutations in a TIM22-pathway client (the carrier ANT1) can cause the mutant substrate to accumulate along the import route and physically clog TOM and TIM22, thereby obstructing broader import and driving cellular toxicity independent of ANT1’s transport activity. This was supported across yeast, mammalian cells, and mouse models (including a “super-clogger” ANT1 that produced age-dependent myopathy/neurodegeneration in mice). (coyne2023mitochondrialproteinimport pages 1-2, coyne2023mitochondrialproteinimport pages 18-19)

Implication for TIMM22 biology: TIM22 is not only an insertion machine but can become a site where disease-causing carrier variants arrest, suggesting that “carrier sequence constraints” and TIM22-associated quality control are central to mitochondrial proteostasis. (coyne2023mitochondrialproteinimport pages 18-19)

5.2 2024: Structural/interaction mapping for metazoan TIM22 assemblies (thesis evidence)

A 2024 PhD thesis focusing on the TIM22 complex reports crosslinking mass spectrometry consistent with direct physical interactions TIM22–TIM29 and TIM22–TIM10, and proposes mechanistic roles for TIM29 (docking for small TIM-delivered precursors) and AGK (dual lipid-kinase and structural role) in complex stability and function. The thesis also describes an IMS-facing TIM22 region (near residues 55–64) as a docking surface for small TIM chaperones, with the disease variant V33L near this region. (valpadashi2024structuralandfunctional pages 56-63, valpadashi2024structuralandfunctional pages 51-51)

Note: this thesis is not equivalent to peer-reviewed primary structural literature, but it provides additional mechanistic hypotheses consistent with review-level summaries and can guide targeted follow-up to peer-reviewed structural papers. (valpadashi2024structuralandfunctional pages 56-63)

6) Current applications and real-world implementations

6.1 Clinical genetics and diagnostics

TIMM22 and TIM22-pathway genes (e.g., AGK, TIMM29, small TIMs) are clinically relevant because variants can cause mitochondrial disorders. Reviews highlight that molecular diagnosis relies on genetic identification of variants plus functional corroboration in patient cells, and stress that understanding import machinery is important for developing future therapies. (heinemeyer2019underappreciatedrolesof pages 1-2, heinemeyer2019underappreciatedrolesof pages 12-13)

A practical experimental diagnostic readout used in the TIMM22 patient context is blue-native PAGE assessment of TIM22 complex abundance, coupled with steady-state abundance of key clients (e.g., ANT/ADP-ATP carrier family members) and respiratory chain functional assays. (palmer2021mitochondrialproteinimport pages 10-13)

6.2 Experimental platforms used in current research

Yeast and mammalian cell models are used to study carrier insertion and TIM22-pathway stress.
In vivo mouse models can reveal organismal phenotypes caused by import pathway disruption (e.g., ANT1 clogging model with TIM22 involvement). (coyne2023mitochondrialproteinimport pages 1-2)

6.3 Therapeutic angles (expert analysis)

Authoritative reviews argue that import-machinery knowledge is likely to be important for therapeutic development in human disease, but concrete TIMM22-directed therapies remain at an early stage. (heinemeyer2019underappreciatedrolesof pages 1-2)

Conceptually, the 2023 import-clogging findings shift the therapeutic frame from “restore transporter activity” to “prevent or resolve import obstruction / enhance proteostasis,” potentially implicating quality-control proteases and chaperone systems that act at or near TIM22. (coyne2023mitochondrialproteinimport pages 1-2, coyne2023mitochondrialproteinimport pages 18-19)

7) Figure-based evidence (mechanism schematic)

A mechanistic summary diagram of TIM22 substrate insertion—TOM passage, IMS small TIM stabilization, docking to TIM22, and sequential IMM insertion—is shown in Figure 4 of Ruiz-Pesini et al. (2021). (ruizpesini2021molecularinsightsinto media 7cda3614)

8) Summary table of key facts (evidence-linked)

The following table consolidates the key functional, disease, and recent-development findings for TIMM22 and the TIM22 pathway.

Topic	Key points (1–3 bullets)	Key evidence (paper + year)	URL/DOI
Complex	• Human TIM22 complex is an ~440-kDa inner-membrane carrier translocase containing TIMM22, TIMM29, TIM10B, and AGK. • TIMM22 is the pore/insertase subunit; TIM9/10A small TIM ring is the associated IMS chaperone in humans. • Recent structural summaries favor a single TIM22 molecule rather than an earlier twin-pore model. (ruizpesini2021molecularinsightsinto pages 12-14)	Ruiz-Pesini et al., 2021	https://doi.org/10.3390/genes12071031
Process	• Canonical substrates are multi-pass carrier proteins, especially 6-TM metabolite carriers, plus some 4-TM channel-forming TIM subunits. • Non-canonical cargos include mitochondrial pyruvate carrier (MPC) subunits with 2–3 TM segments and sideroflexins (SFXN) with 5 TM segments. • Import route: TOM passage → stabilization by small TIMs in the IMS → docking to TIM22 → sequential insertion into the inner membrane. (ruizpesini2021molecularinsightsinto pages 12-14, ruizpesini2021molecularinsightsinto media 7cda3614)	Ruiz-Pesini et al., 2021	https://doi.org/10.3390/genes12071031
Process	• TIM22 function is spatially coordinated with MICOS, which likely positions the complex at cristae junctions and near TOM for efficient carrier import. • Yeast evidence summarized in reviews indicates VDAC/porin interacts with TIM22 substrates in the IMS and helps recruit TIM22 for insertion. • These interactions support efficient precursor handover across outer and inner membrane systems. (ruizpesini2021molecularinsightsinto pages 12-14, ruizpesini2021molecularinsightsinto pages 14-15)	Ruiz-Pesini et al., 2021	https://doi.org/10.3390/genes12071031
Process	• Human TIMM22 undergoes oxidative folding with two intramolecular disulfide bonds; one reported model places bonds between Cys69–Cys141 and Cys160–Cys179. • Thiol-trapping/mutagenesis showed redox-dependent TIMM22 assembly; the C160–C179 bond is important for mature TIM22 complex assembly. • Oxidation is evolutionarily conserved and supports stable translocase biogenesis. (wrobel2016thepresenceof pages 9-10, wrobel2016thepresenceof pages 1-2, wrobel2016thepresenceof pages 7-9, wrobel2016thepresenceof pages 10-12)	Wrobel et al., 2016	https://doi.org/10.1038/srep27484
Disease	• Reported pathogenic TIMM22 variants are p.Y25* and p.V33L in a single described patient with combined OXPHOS deficiency (reported as COXPD43 in FEBS review; disease nomenclature differs across reviews). • Phenotype included intrauterine growth retardation, hypotonia, feeding difficulties, gastroesophageal reflux, delayed myelination, and elevated lactate/creatine. • Patient fibroblasts showed marked TIM22 complex loss on BN-PAGE, reduced Tim22/Tim29/ANT3, and reduced respiratory-chain activities. (palmer2021mitochondrialproteinimport pages 10-13, ruizpesini2021molecularinsightsinto pages 14-15, baker2022mitochondrialbiologyand pages 5-6)	Palmer et al., 2021; Baker et al., 2022	https://doi.org/10.1002/1873-3468.14022; https://doi.org/10.1098/rsob.220274
Disease	• AGK, a TIM22-complex component, is mutated in Sengers syndrome; reported features include congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis. • Mechanistically, AGK loss destabilizes the TIM22 complex, impairs metabolite-carrier import, and alters respiration/metabolism including one-carbon pathways. • Reviews note 12 pathogenic AGK alleles and an estimated ~40 AGK-associated Sengers cases in the later cohort paper. (palmer2021mitochondrialproteinimport pages 10-13, ruizpesini2021molecularinsightsinto pages 14-15, baker2022mitochondrialbiologyand pages 5-6, shalata2025sengerssyndromecaused pages 1-2)	Palmer et al., 2021; Ruiz-Pesini et al., 2021; Baker et al., 2022; Shalata et al., 2025	https://doi.org/10.1002/1873-3468.14022; https://doi.org/10.3390/genes12071031; https://doi.org/10.1098/rsob.220274; https://doi.org/10.1186/s40246-025-00723-y
Disease	• Biallelic TIMM29 p.Trp172Arg was reported as a new cause of severe Sengers-like disease in 17 consanguineous patients. • Quantitative cohort details: hyperCKemia >1000 U/L in 13/14 patients, elevated CSF lactate in 2/3 tested, PDHc deficiency in 4 participants, and severe infantile Sengers mortality ~86% overall in prior AGK-linked experience summarized by the paper. • Reduced ANT1 protein and abnormal mitochondria were noted, consistent with TIM22-pathway dysfunction. (shalata2025sengerssyndromecaused pages 1-2, shalata2025sengerssyndromecaused pages 5-6)	Shalata et al., 2025	https://doi.org/10.1186/s40246-025-00723-y
Recent development	• Pathogenic ANT1/Aac2 carrier mutations can physically clog mitochondrial import routes, with increased association of mutant carriers with TOM and TIM22. • This establishes import obstruction—not just loss of transport activity—as a disease mechanism relevant to the TIM22 pathway. • Mouse and cellular models support import-clogging as a cause of myopathy/neurodegeneration. (coyne2023mitochondrialproteinimport pages 1-2, coyne2023mitochondrialproteinimport pages 18-19)	Coyne et al., 2023	https://doi.org/10.7554/elife.84330
Recent development	• 2024 crosslinking/thesis work mapped direct physical contacts in the metazoan TIM22 complex, including TIM22–TIM29 and TIM22–TIM10 interactions. • TIM29 is described as a docking site for small TIM-delivered precursors and, with AGK, as important for complex stability/import function. • Crosslinks also support an IMS-facing TIM22 docking region near residues 55–64; disease variant V33L lies near this region. (valpadashi2024structuralandfunctional pages 56-63, valpadashi2024structuralandfunctional pages 51-51, valpadashi2024structuralandfunctional pages 46-46)	Valpadashi, 2024	https://doi.org/10.53846/goediss-10678

Table: This table summarizes the main functional, mechanistic, disease, and recent research points for human TIMM22 using only the cited evidence IDs. It is designed as a compact reference for a gene/protein annotation report.

9) Limitations of this evidence package

Despite targeted searching, I did not retrieve peer-reviewed 2023–2024 primary structural papers directly presenting new cryo-EM structures of the human TIM22 complex; mechanistic “structure” conclusions therefore rely on (i) 2021 review summaries of structural work and (ii) a 2024 thesis with crosslinking/interaction evidence. (ruizpesini2021molecularinsightsinto pages 12-14, valpadashi2024structuralandfunctional pages 56-63)
Direct TIMM22 human genetics currently appears sparse in the cited reviews (one reported patient), so phenotype generalization should primarily be made at the “TIM22 pathway” level (AGK, TIMM29, small TIMs) rather than assuming many undiscovered TIMM22 patients in the current literature. (baker2022mitochondrialbiologyand pages 5-6, palmer2021mitochondrialproteinimport pages 10-13)

References

(wrobel2016thepresenceof pages 1-2): Lidia Wrobel, Anna M. Sokol, Magdalena Chojnacka, and Agnieszka Chacinska. The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly. Scientific Reports, Jun 2016. URL: https://doi.org/10.1038/srep27484, doi:10.1038/srep27484. This article has 54 citations and is from a peer-reviewed journal.
(ruizpesini2021molecularinsightsinto pages 12-14): Eduardo Ruiz-Pesini, Julio Montoya, and David Pacheu-Grau. Molecular insights into mitochondrial protein translocation and human disease. Genes, 12:1031, Jul 2021. URL: https://doi.org/10.3390/genes12071031, doi:10.3390/genes12071031. This article has 4 citations.
(bogorodskiy2021roleofmitochondrial pages 4-6): Andrey Bogorodskiy, Ivan Okhrimenko, Dmitrii Burkatovskii, Philipp Jakobs, Ivan Maslov, Valentin Gordeliy, Norbert A. Dencher, Thomas Gensch, Wolfgang Voos, Joachim Altschmied, Judith Haendeler, and Valentin Borshchevskiy. Role of mitochondrial protein import in age-related neurodegenerative and cardiovascular diseases. Cells, 10:3528, Dec 2021. URL: https://doi.org/10.3390/cells10123528, doi:10.3390/cells10123528. This article has 25 citations.
(baker2022mitochondrialbiologyand pages 5-6): Megan J. Baker, Jordan J. Crameri, David R. Thorburn, Ann E. Frazier, and Diana Stojanovski. Mitochondrial biology and dysfunction in secondary mitochondrial disease. Open Biology, Dec 2022. URL: https://doi.org/10.1098/rsob.220274, doi:10.1098/rsob.220274. This article has 36 citations and is from a peer-reviewed journal.
(ruizpesini2021molecularinsightsinto pages 14-15): Eduardo Ruiz-Pesini, Julio Montoya, and David Pacheu-Grau. Molecular insights into mitochondrial protein translocation and human disease. Genes, 12:1031, Jul 2021. URL: https://doi.org/10.3390/genes12071031, doi:10.3390/genes12071031. This article has 4 citations.
(ruizpesini2021molecularinsightsinto media 7cda3614): Eduardo Ruiz-Pesini, Julio Montoya, and David Pacheu-Grau. Molecular insights into mitochondrial protein translocation and human disease. Genes, 12:1031, Jul 2021. URL: https://doi.org/10.3390/genes12071031, doi:10.3390/genes12071031. This article has 4 citations.
(wrobel2016thepresenceof pages 9-10): Lidia Wrobel, Anna M. Sokol, Magdalena Chojnacka, and Agnieszka Chacinska. The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly. Scientific Reports, Jun 2016. URL: https://doi.org/10.1038/srep27484, doi:10.1038/srep27484. This article has 54 citations and is from a peer-reviewed journal.
(wrobel2016thepresenceof pages 7-9): Lidia Wrobel, Anna M. Sokol, Magdalena Chojnacka, and Agnieszka Chacinska. The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly. Scientific Reports, Jun 2016. URL: https://doi.org/10.1038/srep27484, doi:10.1038/srep27484. This article has 54 citations and is from a peer-reviewed journal.
(wrobel2016thepresenceof pages 10-12): Lidia Wrobel, Anna M. Sokol, Magdalena Chojnacka, and Agnieszka Chacinska. The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly. Scientific Reports, Jun 2016. URL: https://doi.org/10.1038/srep27484, doi:10.1038/srep27484. This article has 54 citations and is from a peer-reviewed journal.
(palmer2021mitochondrialproteinimport pages 10-13): Catherine S. Palmer, Alexander J. Anderson, and Diana Stojanovski. Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer. FEBS Letters, 595:1107-1131, Jan 2021. URL: https://doi.org/10.1002/1873-3468.14022, doi:10.1002/1873-3468.14022. This article has 139 citations and is from a peer-reviewed journal.
(shalata2025sengerssyndromecaused pages 1-2): Adel Shalata, Ann Saada, Mohammed Mahroum, Yarin Hadid, Chaya Furman, Zaher Eldin Shalata, Robert J. Desnick, Avraham Lorber, Asaad Khoury, Adnan Higazi, Avraham Shaag, Varda Barash, Ronen Spiegel, Euvgeni Vlodavsky, Pierre Rustin, Shmuel Pietrokovski, Irena Manov, Dan Gieger, Galit Tal, Adi Salzberg, and Hanna Mandel. Sengers syndrome caused by biallelic timm29 variants and rnai silencing in drosophila orthologue recapitulates the human phenotype. Human Genomics, Feb 2025. URL: https://doi.org/10.1186/s40246-025-00723-y, doi:10.1186/s40246-025-00723-y. This article has 3 citations and is from a peer-reviewed journal.
(shalata2025sengerssyndromecaused pages 5-6): Adel Shalata, Ann Saada, Mohammed Mahroum, Yarin Hadid, Chaya Furman, Zaher Eldin Shalata, Robert J. Desnick, Avraham Lorber, Asaad Khoury, Adnan Higazi, Avraham Shaag, Varda Barash, Ronen Spiegel, Euvgeni Vlodavsky, Pierre Rustin, Shmuel Pietrokovski, Irena Manov, Dan Gieger, Galit Tal, Adi Salzberg, and Hanna Mandel. Sengers syndrome caused by biallelic timm29 variants and rnai silencing in drosophila orthologue recapitulates the human phenotype. Human Genomics, Feb 2025. URL: https://doi.org/10.1186/s40246-025-00723-y, doi:10.1186/s40246-025-00723-y. This article has 3 citations and is from a peer-reviewed journal.
(coyne2023mitochondrialproteinimport pages 1-2): Liam P. Coyne, Xiaowen Wang, Jiyao Song, Ebbing de Jong, Karin Schneider, Paul T. Massa, Frank A. Middleton, Thomas Becker, and Xin Jie Chen. Mitochondrial protein import clogging as a mechanism of disease. eLife, Sep 2023. URL: https://doi.org/10.7554/elife.84330, doi:10.7554/elife.84330. This article has 60 citations and is from a domain leading peer-reviewed journal.
(coyne2023mitochondrialproteinimport pages 18-19): Liam P. Coyne, Xiaowen Wang, Jiyao Song, Ebbing de Jong, Karin Schneider, Paul T. Massa, Frank A. Middleton, Thomas Becker, and Xin Jie Chen. Mitochondrial protein import clogging as a mechanism of disease. eLife, Sep 2023. URL: https://doi.org/10.7554/elife.84330, doi:10.7554/elife.84330. This article has 60 citations and is from a domain leading peer-reviewed journal.
(valpadashi2024structuralandfunctional pages 56-63): Anusha Valpadashi. Structural and functional characterization of TIM22 complex in the inner mitochondrial membarne. PhD thesis, University Goettingen Repository, 2024. URL: https://doi.org/10.53846/goediss-10678, doi:10.53846/goediss-10678.
(valpadashi2024structuralandfunctional pages 51-51): Anusha Valpadashi. Structural and functional characterization of TIM22 complex in the inner mitochondrial membarne. PhD thesis, University Goettingen Repository, 2024. URL: https://doi.org/10.53846/goediss-10678, doi:10.53846/goediss-10678.
(heinemeyer2019underappreciatedrolesof pages 1-2): Thea Heinemeyer, Monique Stemmet, Soraya Bardien, and Annika Neethling. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA and cell biology, 38 1:23-40, Jan 2019. URL: https://doi.org/10.1089/dna.2018.4292, doi:10.1089/dna.2018.4292. This article has 43 citations and is from a peer-reviewed journal.
(heinemeyer2019underappreciatedrolesof pages 12-13): Thea Heinemeyer, Monique Stemmet, Soraya Bardien, and Annika Neethling. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA and cell biology, 38 1:23-40, Jan 2019. URL: https://doi.org/10.1089/dna.2018.4292, doi:10.1089/dna.2018.4292. This article has 43 citations and is from a peer-reviewed journal.
(valpadashi2024structuralandfunctional pages 46-46): Anusha Valpadashi. Structural and functional characterization of TIM22 complex in the inner mitochondrial membarne. PhD thesis, University Goettingen Repository, 2024. URL: https://doi.org/10.53846/goediss-10678, doi:10.53846/goediss-10678.

Citations

ruizpesini2021molecularinsightsinto pages 12-14
baker2022mitochondrialbiologyand pages 5-6
wrobel2016thepresenceof pages 1-2
shalata2025sengerssyndromecaused pages 1-2
shalata2025sengerssyndromecaused pages 5-6
coyne2023mitochondrialproteinimport pages 18-19
valpadashi2024structuralandfunctional pages 56-63
palmer2021mitochondrialproteinimport pages 10-13
coyne2023mitochondrialproteinimport pages 1-2
heinemeyer2019underappreciatedrolesof pages 1-2
bogorodskiy2021roleofmitochondrial pages 4-6
ruizpesini2021molecularinsightsinto pages 14-15
wrobel2016thepresenceof pages 9-10
wrobel2016thepresenceof pages 7-9
wrobel2016thepresenceof pages 10-12
valpadashi2024structuralandfunctional pages 51-51
heinemeyer2019underappreciatedrolesof pages 12-13
valpadashi2024structuralandfunctional pages 46-46
https://doi.org/10.3390/genes12071031
https://doi.org/10.1038/srep27484
https://doi.org/10.1002/1873-3468.14022;
https://doi.org/10.1098/rsob.220274
https://doi.org/10.3390/genes12071031;
https://doi.org/10.1098/rsob.220274;
https://doi.org/10.1186/s40246-025-00723-y
https://doi.org/10.7554/elife.84330
https://doi.org/10.53846/goediss-10678
https://doi.org/10.1038/srep27484,
https://doi.org/10.3390/genes12071031,
https://doi.org/10.3390/cells10123528,
https://doi.org/10.1098/rsob.220274,
https://doi.org/10.1002/1873-3468.14022,
https://doi.org/10.1186/s40246-025-00723-y,
https://doi.org/10.7554/elife.84330,
https://doi.org/10.53846/goediss-10678,
https://doi.org/10.1089/dna.2018.4292,

📄 View Raw YAML

id: Q9Y584
gene_symbol: TIMM22
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: TIMM22 encodes the pore/insertase subunit of the mitochondrial inner-membrane TIM22 carrier translocase. The human TIM22 complex inserts hydrophobic multi-pass inner-membrane proteins, especially metabolite carrier proteins with internal targeting signals, after TOM passage and small-TIM chaperone delivery through the intermembrane space.
existing_annotations:
- term:
    id: GO:0030943
    label: mitochondrion targeting sequence binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Internal targeting signals are central to TIM22-pathway substrates, but direct mitochondrion targeting sequence binding is less precise for TIMM22 itself than its pore/insertase role in the TIM22 complex.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    reason: Represent TIMM22 primarily with TIM22 complex membership, membrane insertase/protein transporter activity, and protein insertion into mitochondrial inner membrane.
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: '- **TIM22**: specializes in **inserting multi-pass IMM proteins with internal targeting signals**, classically metabolite carriers (the “carrier pathway”). (bogorodskiy2021roleofmitochondrial pages 4-6, ruizpesini2021molecularinsightsinto pages 12-14)'
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: In addition, **small TIM chaperones** in the IMS stabilize hydrophobic precursors after TOM passage and deliver them to the TIM22 complex.
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct. TIMM22 contributes the pore/insertase activity of the TIM22 carrier translocase for protein transmembrane insertion.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0071806
    label: protein transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Correct pathway family but too broad. TIMM22 is specifically a mitochondrial inner-membrane protein insertase/translocase for multi-pass carrier-pathway clients.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    reason: Use protein insertion into mitochondrial inner membrane and TIM22 complex annotations rather than generic protein transmembrane transport.
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
- term:
    id: GO:0090150
    label: establishment of protein localization to membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Correct but broad. TIMM22 specifically mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    reason: Use GO:0045039 protein insertion into mitochondrial inner membrane as the specific supported process.
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Protein binding is too generic for TIMM22. The informative annotation is TIM22 carrier translocase complex membership and insertase/translocase function.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    reason: Documented interactions with TIMM29, small TIMs, and AGK should be represented by complex/function terms rather than generic protein binding.
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IMP
  original_reference_id: PMID:27554484
  review:
    summary: Correct and core. TIMM22 is the pore/insertase subunit of the TIM22 complex for mitochondrial inner-membrane protein insertion.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:32901109
  review:
    summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IPI
  original_reference_id: PMID:32901109
  review:
    summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:32901109
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:27265872
  review:
    summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: Correct but broad. TIMM22 is specifically localized to the mitochondrial inner membrane as part of the TIM22 complex.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    reason: Prefer mitochondrial inner membrane and TIM22 complex annotations over generic mitochondrion.
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IMP
  original_reference_id: PMID:27554484
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IDA
  original_reference_id: PMID:28712724
  review:
    summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IDA
  original_reference_id: PMID:28712726
  review:
    summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28712724
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28712726
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27718247
  review:
    summary: Protein binding is too generic for TIMM22. The informative annotation is TIM22 carrier translocase complex membership and insertase/translocase function.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    reason: Documented interactions with TIMM29, small TIMs, and AGK should be represented by complex/function terms rather than generic protein binding.
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IDA
  original_reference_id: PMID:27718247
  review:
    summary: Correct. TIMM22 is a core component of the human TIM22 carrier translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1955380
  review:
    summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: PMID:14726512
  review:
    summary: Correct. TIMM22 contributes the pore/insertase activity of the TIM22 carrier translocase for protein transmembrane insertion.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: PMID:14726512
  review:
    summary: Correct and core. TIMM22 mediates insertion of hydrophobic multi-pass proteins into the mitochondrial inner membrane.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: PMID:14726512
  review:
    summary: Correct. TIMM22 is a mitochondrial inner-membrane component of the TIM22 carrier translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TIMM22/TIMM22-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
      supporting_text: TIMM22 is consistently described as a core component of the **TIM22 carrier translocase** of the **mitochondrial inner membrane (IMM)**, belonging to the **Tim17/Tim22/Tim23 family**.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: PMID:14726512
  title: Organization and function of the small Tim complexes acting along the import pathway of metabolite carriers into mammalian mitochondria.
  findings:
  - statement: Human small Tim proteins (Tim9, Tim10a, Tim10b) form two hetero-oligomeric complexes including a 450-kDa assembly that operates along the TIM22 carrier import pathway.
    supporting_text: >-
      Here, we show that the human small  proteins form two distinct hetero-oligomeric complexes. A 70-kDa complex that  contains Tim9 and Tim10a and a Tim9-10a-10b that is part of a higher molecular  weight assembly of 450 kDa.
    reference_section_type: ABSTRACT
  - statement: During import the small Tim chaperones deliver carrier preproteins to human Tim22, identified as the putative insertion pore of the TIM22 translocase.
    supporting_text: >-
      For  insertion of carrier preproteins into the inner membrane, the human small Tim  proteins directly interact with human Tim22, the putative insertion pore of the  TIM22 translocase.
    reference_section_type: ABSTRACT
- id: PMID:27265872
  title: The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly.
  findings:
  - statement: TIMM22 is a core inner-membrane translocase component of the Tim17/Tim22/Tim23 family that forms intramolecular disulfide bonds required for proper assembly into the TIM22 complex.
    supporting_text: >-
      Tim22, a membrane protein  and core component of the mitochondrial translocase TIM22, forms an  intramolecular disulfide bond in yeast. Tim22 belongs to the Tim17/Tim22/Tim23  family of protein translocases.
    reference_section_type: ABSTRACT
  - statement: Human TIMM22 carries two intramolecular disulfide bonds (Cys69-Cys141 and Cys160-Cys179), and the Cys160-Cys179 bond is prerequisite for TIMM22 assembly into the mature TIM22 complex.
    supporting_text: >-
      Altogether, the biochemical analyses and transmembrane prediction for human TIMM22 indicate that one disulfide bond could be formed on the IMS side of TIMM22 between Cys69 and Cys141, and another disulfide bond that joins the TM3 and TM4 is formed between Cys160 and Cys179
    reference_section_type: RESULTS
  - statement: Loss of the TIMM22 disulfide bond linking Cys160-Cys179 abolishes assembly into the mature human TIM22 translocase despite retained membrane integration.
    supporting_text: >-
      Thus, the lack of the second disulfide bond that is present in the human TIMM22 structure renders the protein unable to assemble into the mature TIM22 complex, despite its ability for membrane integration
    reference_section_type: RESULTS
- id: PMID:27554484
  title: Tim29 is a novel subunit of the human TIM22 translocase and is involved in complex assembly and stability.
  findings:
  - statement: TIM22 mediates import of hydrophobic carrier proteins into the mitochondrial inner membrane, and Tim29 (C19orf52) was identified as a metazoan-specific subunit of the human TIM22 complex.
    supporting_text: >-
      The TIM22 complex mediates the import of hydrophobic carrier proteins into the  mitochondrial inner membrane... we  identify Tim29 (C19orf52) as a novel, metazoan-specific subunit of the human  TIM22 complex.
    reference_section_type: ABSTRACT
  - statement: Tim29 is required for assembly and stability of the human TIM22 complex and links it to the TOM complex for transfer of hydrophobic substrates across the intermembrane space.
    supporting_text: >-
      Tim29 is required for  the stability of the TIM22 complex and functions in the assembly of hTim22.  Furthermore, Tim29 contacts the Translocase of the Outer Mitochondrial Membrane,  TOM complex, enabling a mechanism for transport of hydrophobic carrier  substrates across the aqueous intermembrane space.
    reference_section_type: ABSTRACT
  - statement: The human TIM22 complex migrates at ~450 kDa and contains TIMM22 as the channel-forming subunit together with the small TIM chaperones hTim9, hTim10a and hTim10b.
    supporting_text: >-
      Like yeast, the human TIM22 complex consists of the channel-forming hTim22 protein, along with subunits of the small TIM family, hTim9, hTim10a, and hTim10b
    reference_section_type: INTRODUCTION
- id: PMID:27718247
  title: TIM29 is a subunit of the human carrier translocase required for protein transport.
  findings:
  - statement: Hydrophobic inner-membrane proteins with internal targeting signals such as metabolite carriers are inserted into the inner membrane by the TIM22 carrier translocase, and defects in this pathway are linked to neurodegenerative disorders.
    supporting_text: >-
      Hydrophobic inner mitochondrial membrane proteins with internal targeting  signals, such as the metabolite carriers, use the carrier translocase (TIM22  complex) for transport into the inner membrane. Defects in this transport  pathway have been associated with neurodegenerative disorders.
    reference_section_type: ABSTRACT
  - statement: TIM29 is a 440 kDa human TIM22 complex constituent that interacts with oxidized TIMM22 and is required for structural integrity of the complex and import of carrier substrates.
    supporting_text: >-
      We show that TIM29 is a constituent of the 440 kDa TIM22 complex and interacts with oxidized TIM22. Our analyses  demonstrate that TIM29 is required for the structural integrity of the TIM22  complex and for import of substrate proteins by the carrier translocase.
    reference_section_type: ABSTRACT
  - statement: TIMM22 is the central pore-forming subunit of the carrier translocase whose human form shares ~40% identity with yeast Tim22 and is conserved across eukaryotes.
    supporting_text: >-
      Tim22 is the central, pore‐forming, subunit of the complex... The human TIM22 displays 40% homology with the yeast Tim22
    reference_section_type: INTRODUCTION
- id: PMID:28712724
  title: Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria.
  findings:
  - statement: AGK, the lipid kinase mutated in Sengers syndrome, was identified as a constituent of the inner-membrane TIM22 complex that assembles with TIMM22 and TIMM29 to support import of a subset of multi-spanning membrane proteins.
    supporting_text: >-
      Determining its mitochondrial interactome, we have identified  AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane.  AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of  multi-spanning membrane proteins.
    reference_section_type: ABSTRACT
  - statement: AGK's role as a TIM22 subunit is kinase-independent, linking Sengers syndrome pathogenesis to defects in TIM22-mediated mitochondrial protein biogenesis as well as phospholipid metabolism.
    supporting_text: >-
      The function of AGK as a subunit of the TIM22  complex does not depend on its kinase activity... The dual function of AGK as lipid kinase and  constituent of the TIM22 complex reveals that disturbances in both phospholipid  metabolism and mitochondrial protein biogenesis contribute to the pathogenesis  of Sengers syndrome.
    reference_section_type: ABSTRACT
- id: PMID:28712726
  title: Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex.
  findings:
  - statement: AGK is a bona fide subunit of the human TIM22 import complex that acts kinase-independently to maintain TIM22 integrity and facilitate the import and assembly of mitochondrial carrier proteins.
    supporting_text: >-
      Here we identified  AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that  AGK functions in a kinase-independent manner to maintain the integrity of the  TIM22 complex, where it facilitates the import and assembly of mitochondrial  carrier proteins.
    reference_section_type: ABSTRACT
  - statement: Mitochondria from Sengers syndrome patients show a destabilized TIM22 complex and defective biogenesis of carrier substrates, linking TIM22-mediated protein import directly to disease.
    supporting_text: >-
      Mitochondria isolated from Sengers syndrome patient cells and  tissues show a destabilized TIM22 complex and defects in the biogenesis of  carrier substrates.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: HuRI is a proteome-wide binary protein interactome map; the cited excerpt does not directly mention TIMM22, and inclusion here provides only indirect, peripheral context for systematic PPI data that could be queried for TIMM22 interactors.
    supporting_text: >-
      Here we present a human 'all-by-all'  reference interactome map of human binary protein interactions, or 'HuRI'. With  approximately 53,000 protein-protein interactions, HuRI has approximately four  times as many such interactions as there are high-quality curated interactions  from small-scale studies... We demonstrate the utility of  HuRI in identifying the specific subcellular roles of protein-protein  interactions.
    reference_section_type: ABSTRACT
- id: PMID:32901109
  title: Cryo-EM structure of the human mitochondrial translocase TIM22 complex.
  findings:
  - statement: This study determined the cryo-EM structure of the human mitochondrial TIM22 carrier translocase, providing the structural framework for TIMM22-mediated insertion of multi-spanning inner-membrane proteins.
    supporting_text: >-
      Cryo-EM structure of the human mitochondrial translocase TIM22 complex.
    full_text_unavailable: true
    reference_section_type: ABSTRACT
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings:
  - statement: The TIM22 complex imports metabolite carriers into the mitochondrial inner membrane and TIMM22 also inserts the precursors of TIMM23 and TIMM17A/B, with its short half-life suggesting a regulatory role in adjusting carrier import to metabolic conditions.
    supporting_text: >-
      The TIM22 complex is responsible for importing the large number of metabolite carriers into the inner membrane that are crucial in controlling the metabolite flux between the mitochondrial matrix and other cellular compartments... The short half-life of TIMM22 may represent a means for rapidly adjusting the import of metabolite carriers to changing metabolic conditions... TIMM22 also inserts the precursors of TIMM23 and TIMM17A/B into the inner membrane
    reference_section_type: DISCUSSION
- id: Reactome:R-HSA-1955380
  title: TIMM9:TIMM10 transfers proteins to TIMM22
  findings: []
- id: file:human/TIMM22/TIMM22-deep-research-falcon.md
  title: Falcon deep research report for human TIMM22
  findings: []
core_functions:
- description: TIMM22 is the pore/insertase subunit of the mitochondrial inner-membrane TIM22 carrier translocase, mediating insertion of hydrophobic multi-pass proteins such as metabolite carriers after TOM import and small-TIM chaperone delivery through the intermembrane space.
  supported_by:
  - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
    supporting_text: TIMM22 is the **pore/insertase subunit** of the human TIM22 complex. It mediates **membrane insertion** of hydrophobic, multi-pass inner membrane proteins after their passage through the TOM complex and chaperoning through the intermembrane space (IMS).
  - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
    supporting_text: A widely cited current model describes the **human TIM22 complex (~440 kDa)** as comprising **TIMM22**, **TIMM29**, **TIM10B**, and **AGK** (acylglycerol kinase).
  - reference_id: file:human/TIMM22/TIMM22-deep-research-falcon.md
    supporting_text: 4) The precursor is inserted into the **IMM** in a sequential manner. (ruizpesini2021molecularinsightsinto pages 14-15, ruizpesini2021molecularinsightsinto media 7cda3614)
  molecular_function:
    id: GO:0032977
    label: membrane insertase activity
  directly_involved_in:
  - id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
proposed_new_terms: []
suggested_questions:
- question: Which non-canonical human TIM22 clients beyond metabolite carriers depend directly on TIMM22 versus accessory subunits such as TIMM29 or AGK?
  experts: []
- question: How do TIMM22 disease variants alter substrate docking, redox-dependent assembly, and pore/insertase function separately?
  experts: []
suggested_experiments:
- hypothesis: TIMM22 disease-associated variants impair mature TIM22 complex assembly and reduce insertion of carrier-pathway clients.
  description: Express wild-type and disease-associated TIMM22 variants in TIMM22-deficient rescue cells, then measure TIM22 complex abundance by BN-PAGE and radiolabeled import/assembly of ANT, MPC, and SFXN clients.
- hypothesis: TIMM22 acts as the core insertase while small TIM chaperones and TIMM29 tune substrate delivery specificity.
  description: Map substrate-dependent TIMM22-TIMM29-small TIM contacts using crosslinking mass spectrometry during staged import reactions with canonical carrier and non-canonical MPC/SFXN substrates.

Gene Description

Existing Annotations Review

Core Functions

TIMM22 is the pore/insertase subunit of the mitochondrial inner-membrane TIM22 carrier translocase, mediating insertion of hydrophobic multi-pass proteins such as metabolite carriers after TOM import and small-TIM chaperone delivery through the intermembrane space.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human TIMM22 (UniProt Q9Y584) functional annotation

0) Target verification (gene/protein identity)

1) Key concepts and definitions (current understanding)

1.1 Mitochondrial protein import and the “carrier pathway”

1.2 What TIMM22 does (molecular function)

1.3 TIM22 complex composition in humans

2) Mechanism, substrates, and localization

2.1 Mechanistic steps of TIM22-mediated insertion

2.2 Substrate specificity: canonical and non-canonical cargos

2.3 Sub-mitochondrial localization and functional positioning

3) Biogenesis/topology: redox-dependent maturation of human TIMM22

4) Disease relevance: human genetics, phenotypes, and quantitative data

4.1 TIMM22 variants and combined OXPHOS deficiency (rare)

4.2 TIM22-pathway disorders via other complex components: AGK and TIMM29

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2023: “Import clogging” implicates TIM22 as a site of pathologic obstruction

5.2 2024: Structural/interaction mapping for metazoan TIM22 assemblies (thesis evidence)

6) Current applications and real-world implementations

6.1 Clinical genetics and diagnostics

6.2 Experimental platforms used in current research

6.3 Therapeutic angles (expert analysis)

7) Figure-based evidence (mechanism schematic)

8) Summary table of key facts (evidence-linked)

9) Limitations of this evidence package

Citations

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