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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030943 mitochondrion targeting sequence binding | IBA GO_REF:0000033 | MODIFY | 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 Reason: GO:0030943 (mitochondrion targeting sequence binding) is obsolete in the current GO release (consider GO:0140436 / GO:0008320). TIMM22 is the carrier-pathway channel/insertase, not a targeting-signal receptor, so the receptor MF GO:0140436 does not apply; its response to internal targeting signals is part of its protein-conducting channel activity, as shown for yeast Tim22 (PMID:11864609, a signal-gated channel that responds to internal targeting signals). This IBA descends from the same PANTHER node as yeast TIM22's (PTN000364156, seeded by SGD:S000002376, whose own IDA from PMID:11864609 is also remapped to GO:0008320), and is remapped the same way (MODIFY to GO:0008320). This folds the row into the GO:0008320 IBA TIMM22 already carries and asserts nothing new. Represent TIMM22 primarily with TIM22 complex membership, membrane insertase/protein transporter activity, and protein insertion into mitochondrial inner membrane. Proposed replacements: transmembrane protein transporter activity 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**. |
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Download this section (compressed HTML)Q: Which non-canonical human TIM22 clients beyond metabolite carriers depend directly on TIMM22 versus accessory subunits such as TIMM29 or AGK?
Q: How do TIMM22 disease variants alter substrate docking, redox-dependent assembly, and pore/insertase function separately?
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.
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