Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005745 m-AAA complex	IBA GO_REF:0000033	ACCEPT	Summary: SPG-7 is a well-established component of the m-AAA protease complex based on phylogenetic analysis (IBA from PAINT) and conserved domain architecture with mammalian AFG3L2. UniProt explicitly notes SPG-7 is an ortholog of human AFG3L2 and yeast AFG3, both core m-AAA complex subunits. Deep research confirms conserved m-AAA domain architecture (file:worm/spg-7/spg-7-deep-research-falcon.md). Reason: The IBA annotation is well-supported by phylogenetic conservation and domain analysis. SPG-7 contains characteristic m-AAA protease domains: AAA+ ATPase (IPR003593) and peptidase M41 (IPR000642). This is a core localization for the protein. Supporting Evidence: UniProt:Q9N3T5 Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins file:worm/spg-7/spg-7-deep-research-falcon.md spg-7 is inferred to encode an ATP-dependent, zinc metalloprotease that assembles into the m-AAA complex on the matrix side of the inner mitochondrial membrane
GO:0004222 metalloendopeptidase activity	IBA GO_REF:0000033	ACCEPT	Summary: SPG-7 contains a conserved M41 peptidase domain with the HExxH zinc-binding motif characteristic of metalloendopeptidases. The IBA annotation from PAINT is phylogenetically well-supported across m-AAA protease family members. Reason: Core molecular function of SPG-7 is metalloendopeptidase activity. The protein has conserved zinc-binding sites and an active site based on UniProt annotations. This activity is essential for its role in mitochondrial protein processing. Supporting Evidence: UniProt:Q9N3T5 Binds 1 zinc ion per subunit
GO:0034982 mitochondrial protein processing	IBA GO_REF:0000033	ACCEPT	Summary: Mitochondrial protein processing is a core function of m-AAA proteases across eukaryotes. This IBA annotation is well-supported by phylogenetic conservation and is consistent with experimental evidence in C. elegans (PMID:22700657, PMID:25274306, PMID:25773600). Reason: Core biological process for SPG-7. The m-AAA protease processes imported mitochondrial proteins and degrades misfolded proteins. This is directly supported by C. elegans experimental data showing spg-7 RNAi affects mitochondrial function and activates compensatory stress responses. Supporting Evidence: UniProt:Q9N3T5 Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: SPG-7 contains an AAA+ ATPase domain with Walker A and Walker B motifs. The IEA annotation from UniProt keyword mapping is correct but overly general. Reason: While accurate, this term is too general. SPG-7 specifically binds and hydrolyzes ATP as part of its ATPase activity. The more specific term GO:0005524 (ATP binding) is already annotated and better captures the function. Proposed replacements: ATP binding
GO:0004176 ATP-dependent peptidase activity	IEA GO_REF:0000002	ACCEPT	Summary: SPG-7 functions as an ATP-dependent peptidase. The AAA+ ATPase domain powers substrate unfolding and translocation into the proteolytic chamber, where the M41 peptidase domain degrades substrates. This is a defining feature of m-AAA proteases. Reason: This term accurately describes SPG-7's integrated molecular function combining ATPase and peptidase activities. The InterPro-based IEA annotation is well-supported by domain architecture. Supporting Evidence: UniProt:Q9N3T5 In the N-terminal section; belongs to the AAA ATPase family
GO:0004222 metalloendopeptidase activity	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of the IBA annotation for metalloendopeptidase activity. The IEA from InterPro mapping is consistent with the IBA phylogenetic annotation. Reason: Both the IEA (InterPro) and IBA (PAINT) annotations support this core molecular function. Keeping both evidence types is appropriate as they represent independent lines of evidence. Supporting Evidence: UniProt:Q9N3T5 In the C-terminal section; belongs to the peptidase M41 family
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: SPG-7 has a well-characterized ATP-binding site in its AAA+ ATPase domain. ATP binding is essential for m-AAA protease function. Reason: Core molecular function for SPG-7. The AAA+ ATPase domain requires ATP binding for substrate engagement, unfolding, and translocation. Well-supported by domain analysis. Supporting Evidence: UniProt:Q9N3T5 In the N-terminal section; belongs to the AAA ATPase family
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: SPG-7 is a mitochondrial inner membrane protein with two transmembrane helices. The protein is anchored in the inner membrane with catalytic domains facing the matrix. Reason: Core cellular localization for SPG-7. UniProt annotation indicates multi-pass membrane protein topology with matrix-facing catalytic domains, consistent with m-AAA protease architecture. Supporting Evidence: UniProt:Q9N3T5 Mitochondrion inner membrane
GO:0006508 proteolysis	IEA GO_REF:0000120	ACCEPT	Summary: SPG-7 performs proteolysis as part of the m-AAA protease complex. This is the general parent term for its peptidase activity. Reason: While more specific terms exist (e.g., mitochondrial protein processing), this general proteolysis annotation is not incorrect and captures the core enzymatic activity. The IEA annotation is well-supported. Supporting Evidence: UniProt:Q9N3T5 Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins
GO:0008233 peptidase activity	IEA GO_REF:0000043	ACCEPT	Summary: General peptidase activity term. SPG-7 is indeed a peptidase, specifically a metalloendopeptidase (GO:0004222). Reason: Broad but accurate term. More specific terms (metalloendopeptidase activity, ATP-dependent peptidase activity) are also annotated, which is appropriate. Supporting Evidence: UniProt:Q9N3T5 In the C-terminal section; belongs to the peptidase M41 family
GO:0008237 metallopeptidase activity	IEA GO_REF:0000043	ACCEPT	Summary: SPG-7 is a metallopeptidase containing a zinc-dependent catalytic site. This is a parent term of metalloendopeptidase activity. Reason: Accurate intermediate-level term. SPG-7 uses zinc for catalysis. Supporting Evidence: UniProt:Q9N3T5 Binds 1 zinc ion per subunit
GO:0008270 zinc ion binding	IEA GO_REF:0000002	ACCEPT	Summary: SPG-7 binds zinc as a catalytic cofactor. UniProt identifies zinc-binding residues that coordinate the catalytic zinc ion. Reason: Correct annotation. Zinc binding is essential for SPG-7's metallopeptidase activity. The zinc ion is required for catalysis at the active site. Supporting Evidence: UniProt:Q9N3T5 Binds 1 zinc ion per subunit
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: Very general term indicating membrane localization. SPG-7 is specifically located in the mitochondrial inner membrane. Reason: Not incorrect but very general. The more specific term GO:0005743 (mitochondrial inner membrane) is also annotated, which provides better precision. Supporting Evidence: UniProt:Q9N3T5 Multi-pass membrane protein
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: Very general term. SPG-7 has both peptidase (protein hydrolase) and ATPase (nucleotide hydrolase) activities. Reason: Accurate high-level classification. More specific terms are also annotated.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: SPG-7's AAA+ ATPase domain hydrolyzes ATP to power substrate engagement and translocation. This is essential for m-AAA protease function. Reason: Core molecular function. ATP hydrolysis drives the mechanical work of unfolding substrates and translocating them into the proteolytic chamber. Supporting Evidence: UniProt:Q9N3T5 In the N-terminal section; belongs to the AAA ATPase family
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: General term for metal binding. SPG-7 specifically binds zinc. Reason: Accurate but general. More specific term (zinc ion binding, GO:0008270) is also annotated.
GO:0051604 protein maturation	IEA GO_REF:0000117	ACCEPT	Summary: SPG-7 participates in protein maturation through processing of imported mitochondrial proteins. This ARBA machine learning annotation is consistent with m-AAA protease function. Reason: Appropriate annotation. m-AAA proteases process and mature mitochondrial proteins after import, contributing to their functional maturation. Supporting Evidence: UniProt:Q9N3T5 Functions both in post-translational assembly and in the turnover of mistranslated or misfolded polypeptides
GO:0110039 positive regulation of nematode male tail tip morphogenesis	IMP PMID:21408209 A bow-tie genetic architecture for morphogenesis suggested b...	KEEP AS NON CORE	Summary: In a genome-wide RNAi screen for male tail tip morphogenesis genes, spg-7 RNAi resulted in a "Lep" (leptoderan) phenotype - retention of the pointed larval tail tip. This was identified alongside 211 other genes. The annotation represents a high-throughput screen hit rather than focused investigation of spg-7's role. Reason: This annotation is technically valid - spg-7 RNAi does cause a male tail tip morphogenesis defect. However, this is likely a pleiotropic consequence of general mitochondrial dysfunction rather than a direct role in morphogenesis. The paper identified spg-7 as one of 41 suppressors of let-7 lethality with morphogenesis phenotypes, suggesting this reflects general cellular fitness rather than a specific role in tail tip development. This should be kept but marked as non-core function. Supporting Evidence: PMID:21408209 Of the 41 suppressors of let-7 lethality identified by Ding et al. [44], six were positives in our screen. RNAi knockdown of two (pri-2, npp-6) resulted in the Ore phenotype, of two others (spg-7, smo-1) in the Lep phenotype
GO:0034982 mitochondrial protein processing	IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon...	ACCEPT	Summary: Nargund et al. (2012) showed that spg-7(RNAi) causes mitochondrial stress that activates the UPRmt via ATFS-1. This demonstrates that SPG-7 is required for normal mitochondrial protein handling, and its loss leads to accumulation of misfolded proteins. Reason: Direct experimental evidence for spg-7 function in mitochondrial protein processing. Loss of spg-7 function causes nuclear accumulation of ATFS-1 and activation of UPRmt, indicating impaired mitochondrial proteostasis. Supporting Evidence: PMID:22700657 However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus UniProt:Q9N3T5 RNAi- mediated knockdown induces nuclear and mitochondrial transcription of mitochondrial protective genes including chaperone hsp-60 as part of the mitochondrial unfolded protein response
GO:0034982 mitochondrial protein processing	IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	ACCEPT	Summary: Pellegrino et al. (2014) used spg-7(RNAi) as a tool to induce mitochondrial stress and activate the UPRmt. The paper confirms spg-7's role in mitochondrial protein quality control. Reason: Independent experimental confirmation of spg-7's role in mitochondrial protein processing. The study uses spg-7 knockdown to model mitochondrial dysfunction. Supporting Evidence: UniProt:Q9N3T5 Functions both in post-translational assembly and in the turnover of mistranslated or misfolded polypeptides
GO:0010629 negative regulation of gene expression	IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	MODIFY	Summary: When SPG-7 is functional, it suppresses expression of stress-response genes by maintaining mitochondrial proteostasis. Loss of spg-7 leads to upregulation of UPRmt target genes and innate immune genes via ATFS-1. Reason: The annotation is technically accurate but captures an indirect effect. SPG-7 does not directly regulate gene expression - rather, its proteolytic activity maintains mitochondrial health, which in turn keeps ATFS-1 in mitochondria where it is degraded. A more appropriate annotation would be to the upstream process (mitochondrial protein processing) or the regulatory pathway. Proposed replacements: mitochondrial unfolded protein response Supporting Evidence: PMID:22700657 However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus
GO:0010468 regulation of gene expression	IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	MODIFY	Summary: The IGI annotation with atfs-1 indicates genetic interaction - spg-7 and atfs-1 together regulate gene expression. The paper shows that spg-7(RNAi) effects on gene expression require atfs-1. Reason: Similar to the IMP annotation above, this captures an indirect effect. SPG-7 does not directly regulate gene expression but rather maintains mitochondrial proteostasis. The effects on gene expression are mediated by ATFS-1 when mitochondrial stress occurs. A more specific term would better capture the mechanism. Proposed replacements: mitochondrial unfolded protein response Supporting Evidence: UniProt:Q9N3T5 RNAi-mediated knockdown abolishes transcription up- regulation in an atfs-1 (tm4919) mutant background
GO:0050829 defense response to Gram-negative bacterium	IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	KEEP AS NON CORE	Summary: Pellegrino et al. (2014) showed that spg-7(RNAi) pre-treatment activates the UPRmt, which in turn induces innate immune genes (abf-2, lys-2, clec-4, clec-65). This provides resistance to P. aeruginosa infection. The immune response is ATFS-1 dependent and represents a coupling of mitochondrial stress to innate immunity. Reason: This annotation reflects a downstream consequence of SPG-7 dysfunction rather than a direct role in immunity. When SPG-7 is lost, mitochondrial stress activates ATFS-1-dependent innate immune genes. While experimentally valid, this represents a stress response pathway activation rather than a core immune function of SPG-7. The core function is mitochondrial protein processing; immune activation is a consequence of its loss. Supporting Evidence: UniProt:Q9N3T5 RNAi-mediated knockdown also induces the transcription of innate immunity-related genes such as lys-2, abf-2, clec-65 and clec-4 which results in resistance to P.aeruginosa-mediated infection
GO:0050829 defense response to Gram-negative bacterium	IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista...	KEEP AS NON CORE	Summary: Multiple IGI annotations exist for this term, indicating genetic interactions with various innate immunity components. These all reflect the ATFS-1-dependent coupling of mitochondrial stress to immune gene induction. Reason: Same rationale as above - the immune response is a downstream consequence of mitochondrial stress caused by loss of SPG-7 function. The core function remains mitochondrial protein processing. Supporting Evidence: UniProt:Q9N3T5 RNAi-mediated knockdown also induces the transcription of innate immunity-related genes such as lys-2, abf-2, clec-65 and clec-4 which results in resistance to P.aeruginosa-mediated infection
GO:0004222 metalloendopeptidase activity	ISS PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: ISS annotation based on similarity to human AFG3L2. The Yoneda et al. (2004) paper established spg-7 as encoding a mitochondrial protease in C. elegans, demonstrating that RNAi knockdown activates the UPRmt. Reason: The ISS annotation is well-supported. SPG-7 has conserved metalloprotease domains and sequence similarity to characterized m-AAA proteases. This annotation provides additional evidence type for the core molecular function. Supporting Evidence: UniProt:Q9N3T5 In the C-terminal section; belongs to the peptidase M41 family
GO:0005739 mitochondrion	ISS PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: ISS annotation based on similarity to mouse Afg3l2. Mitochondrial localization is well-established for m-AAA proteases. Reason: Correct cellular component annotation. While more specific terms exist (mitochondrial inner membrane), this general mitochondrial localization is accurate and useful. Supporting Evidence: UniProt:Q9N3T5 Mitochondrion inner membrane
GO:0065003 protein-containing complex assembly	IMP PMID:15280428 Compartment-specific perturbation of protein handling activa...	MODIFY	Summary: Yoneda et al. (2004) showed that RNAi of spg-7 and other mitochondrial proteases/ chaperones activates the UPRmt. This indicates a role in assembly of multi-subunit mitochondrial complexes. Reason: While the annotation reflects an indirect function, the term is too general. SPG-7's role is specifically in mitochondrial respiratory chain complex assembly and mitochondrial protein complex maturation. A more specific term would be more informative. Proposed replacements: mitochondrial respiratory chain complex assembly Supporting Evidence: UniProt:Q9N3T5 The complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes
GO:0034514 mitochondrial unfolded protein response	IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon...	NEW	Summary: SPG-7 is a key activator of the UPRmt when its function is compromised. Loss of spg-7 function leads to mitochondrial stress and activation of the UPRmt pathway via ATFS-1. This is one of the best-characterized UPRmt triggers in C. elegans. Reason: This is a well-established function of spg-7 in C. elegans not currently annotated. Multiple papers (PMID:22700657, PMID:25274306, PMID:15280428) demonstrate that spg-7(RNAi) activates the UPRmt. While SPG-7 does not directly signal in the UPRmt pathway, its loss triggers the response, making it involved in the process. Supporting Evidence: PMID:22700657 However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus UniProt:Q9N3T5 RNAi- mediated knockdown induces nuclear and mitochondrial transcription of mitochondrial protective genes including chaperone hsp-60 as part of the mitochondrial unfolded protein response
GO:0033108 mitochondrial respiratory chain complex assembly	ISS PMID:15280428 Compartment-specific perturbation of protein handling activa...	NEW	Summary: m-AAA proteases are required for assembly of mitochondrial respiratory chain complexes. This function is well-established in yeast and mammals and is conserved in C. elegans based on domain architecture and phenotypic effects. Reason: This core function is implicit in UniProt annotation but not currently in GO. UniProt states the m-AAA protease complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes. PMID:25773600 shows spg-7(RNAi) reduces oxygen consumption, indicating respiratory defects. Supporting Evidence: UniProt:Q9N3T5 The complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes UniProt:Q9N3T5 RNAi-mediated knockdown reduces oxygen consumption

Core Functions

ATP-dependent zinc metalloendopeptidase that degrades misfolded and unassembled mitochondrial inner membrane proteins. The proteolytic chamber is formed by the M41 peptidase domain and requires zinc for catalysis.

Molecular Function:

ATP-dependent peptidase activity

Directly Involved In:

mitochondrial protein processing

Cellular Locations:

mitochondrial inner membrane

In Complex:

m-AAA complex

Supporting Evidence:

UniProt:Q9N3T5
Acts as a component of the m-AAA protease complex which is an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial inner membrane proteins

Processes imported mitochondrial proteins and is required for assembly of mitochondrial respiratory chain and ATPase complexes. Loss of function leads to respiratory deficiency with reduced oxygen consumption.

Molecular Function:

metalloendopeptidase activity

Directly Involved In:

mitochondrial respiratory chain complex assembly protein maturation

Cellular Locations:

mitochondrial inner membrane

In Complex:

m-AAA complex

Supporting Evidence:

UniProt:Q9N3T5
The complex is necessary for the assembly of mitochondrial respiratory chain and ATPase complexes
UniProt:Q9N3T5
RNAi-mediated knockdown reduces oxygen consumption

Maintains mitochondrial proteostasis; loss of function activates the mitochondrial unfolded protein response (UPRmt) via ATFS-1 nuclear accumulation and transcriptional upregulation of mitochondrial chaperones.

Molecular Function:

ATP-dependent peptidase activity

Directly Involved In:

mitochondrial unfolded protein response

Cellular Locations:

mitochondrial inner membrane

In Complex:

m-AAA complex

Supporting Evidence:

PMID:22700657
However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

InterPro domains IPR000642, IPR003593, IPR003959 support molecular function annotations

GO_REF:0000033

Annotation inferences using phylogenetic trees

PAINT IBA annotations from phylogenetic analysis of m-AAA protease family

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

Keyword mappings support general molecular function terms

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

Subcellular location annotation supports mitochondrial inner membrane localization

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

ARBA prediction for protein maturation involvement

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Combined IEA methods support ATP binding, proteolysis annotations

PMID:15280428

Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones

Established that spg-7 RNAi activates UPRmt hsp-6 and hsp-60 induction

"hsp-6 and hsp-60 induction was specific to perturbed mitochondrial protein handling, as neither heat-shock nor endoplasmic reticulum stress nor manipulations that impair mitochondrial steps in intermediary metabolism or ATP synthesis activated the mitochondrial chaperone genes"

PMID:21408209

A bow-tie genetic architecture for morphogenesis suggested by a genome-wide RNAi screen in Caenorhabditis elegans

spg-7 identified as one of 212 genes affecting male tail tip morphogenesis

"Of the 41 suppressors of let-7 lethality identified by Ding et al. [44], six were positives in our screen. RNAi knockdown of two (pri-2, npp-6) resulted in the Ore phenotype, of two others (spg-7, smo-1) in the Lep phenotype"
spg-7 RNAi causes Lep leptoderan phenotype

"RNAi knockdown of two (pri-2, npp-6) resulted in the Ore phenotype, of two others (spg-7, smo-1) in the Lep phenotype"

PMID:22700657

Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation

spg-7 RNAi causes mitochondrial stress leading to ATFS-1 nuclear accumulation

"However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus"
Established ATFS-1 import efficiency model for UPRmt regulation

"However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus"

PMID:25274306

Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection

spg-7 RNAi activates UPRmt and innate immune genes via ATFS-1

"a number of transcripts induced during mitochondrial stress caused by inhibition of the mitochondrial protease SPG-7 encode innate immunity proteins"
UPRmt pre-activation provides resistance to P. aeruginosa

"UPRmt pre-activation dramatically reduced the intestinal accumulation of P. aeruginosa expressing GFP"

PMID:25773600

Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).

spg-7 RNAi reduces oxygen consumption indicating respiratory defects

"balanced ATFS-1 accumulation promoted OXPHOS complex assembly and function"
ATFS-1 regulates OXPHOS gene expression during mitochondrial stress

"atfs-1 was required to limit the accumulation of OXPHOS transcripts during mitochondrial stress"

file:worm/spg-7/spg-7-deep-research-falcon.md

Falcon Research Report on spg-7 (worm)

SPG-7 encodes conserved m-AAA metalloprotease subunit with AAA+ ATPase and M41 peptidase domains
m-AAA proteases maintain protein quality, support mitochondrial ribosomal biogenesis and OXPHOS component maturation

Suggested Experiments

Experiment: Proteomic identification of SPG-7 substrates using substrate-trapping mutants

Hypothesis: SPG-7 has specific substrates among misfolded or unassembled inner membrane proteins

Type: Proteomics

Experiment: Co-immunoprecipitation to determine SPG-7 and PPGN-1 complex composition

Hypothesis: SPG-7 forms hetero-oligomeric complexes with PPGN-1 in vivo

Type: Biochemistry

Experiment: Measurement of individual respiratory chain complex activities in spg-7 mutants

Hypothesis: Loss of SPG-7 leads to specific defects in respiratory chain complex assembly

Type: Enzymology

Experiment: Live imaging of mitochondrial dynamics in spg-7 mutants

Hypothesis: SPG-7 deficiency alters mitochondrial morphology and network dynamics

Type: Microscopy

📚 Additional Documentation

Deep Research Falcon

(spg-7-deep-research-falcon.md)

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organism: worm
gene_id: spg-7
gene_symbol: spg-7
uniprot_accession: Q9N3T5
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{ECO:0000250|UniProtKB:Q9Y4W6};'
gene_info: Name=spg-7 {ECO:0000312|WormBase:Y47G6A.10}; ORFNames=Y47G6A.10 {ECO:0000312|WormBase:Y47G6A.10};
organism_full: Caenorhabditis elegans.
protein_family: In the C-terminal section; belongs to the peptidase M41
protein_domains: AAA+_ATPase. (IPR003593); AAA_lid_3. (IPR041569); ATP-dep_Zn_Metalloprotease.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9N3T5
Protein Description: RecName: Full=AFG3-like protein spg-7 {ECO:0000305}; EC=3.4.24.- {ECO:0000250|UniProtKB:Q9Y4W6};
Gene Information: Name=spg-7 {ECO:0000312|WormBase:Y47G6A.10}; ORFNames=Y47G6A.10 {ECO:0000312|WormBase:Y47G6A.10};
Organism (full): Caenorhabditis elegans.
Protein Family: In the C-terminal section; belongs to the peptidase M41
Key Domains: AAA+_ATPase. (IPR003593); AAA_lid_3. (IPR041569); ATP-dep_Zn_Metalloprotease. (IPR050928); ATPase_AAA_core. (IPR003959); ATPase_AAA_CS. (IPR003960)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "spg-7" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'spg-7' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene spg-7 (gene ID: spg-7, UniProt: Q9N3T5) in worm.

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.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9N3T5
Protein Description: RecName: Full=AFG3-like protein spg-7 {ECO:0000305}; EC=3.4.24.- {ECO:0000250|UniProtKB:Q9Y4W6};
Gene Information: Name=spg-7 {ECO:0000312|WormBase:Y47G6A.10}; ORFNames=Y47G6A.10 {ECO:0000312|WormBase:Y47G6A.10};
Organism (full): Caenorhabditis elegans.
Protein Family: In the C-terminal section; belongs to the peptidase M41
Key Domains: AAA+_ATPase. (IPR003593); AAA_lid_3. (IPR041569); ATP-dep_Zn_Metalloprotease. (IPR050928); ATPase_AAA_core. (IPR003959); ATPase_AAA_CS. (IPR003960)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "spg-7" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene spg-7 (gene ID: spg-7, UniProt: Q9N3T5) in worm.

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.

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.

Plan: We verified identity and domains, then gathered recent (2023–2024) authoritative reviews on mitochondrial AAA proteases to anchor function/localization and mechanistic roles. Direct, recent C. elegans spg-7 primary data proved limited in the retrieved evidence set; therefore, we clearly distinguish conserved-mechanism inferences from explicitly demonstrated findings in other systems.

Aspect	Expected per prompt	Evidence/Notes	Source (URL)	Year
Gene symbol	spg-7 (Y47G6A.10)	Ortholog of mammalian SPG7/paraplegin within the mitochondrial m-AAA protease family	https://doi.org/10.1007/s12035-023-03768-z (dastidar2024multifacetedrolesof pages 2-5)	2024
Organism	Caenorhabditis elegans	Conserved m-AAA protease family members include SPG7; analysis maps worm spg-7 to m-AAA subunits	https://doi.org/10.1089/ars.2022.0124 (khalimonchuk2023moleculardeterminantsof pages 17-18)	2023
Protein family	Peptidase M41 (m-AAA metalloprotease)	m-AAA defined as an inner-mitochondrial-membrane zinc metalloprotease with an AAA+ ATPase module	https://doi.org/10.1089/ars.2022.0124 (khalimonchuk2023moleculardeterminantsof pages 17-18)	2023
Key domains	AAA+ ATPase (Walker A/B, SRH); Zn metalloprotease HExxH motif	AFG3L2 domain architecture (ATPase + Zn metalloprotease) generalized to m-AAA subunits supports expected spg-7 domains	https://doi.org/10.1007/s12035-023-03768-z (dastidar2024multifacetedrolesof pages 2-5)	2024
Subcellular localization	Inner mitochondrial membrane, catalytic sites facing matrix	m-AAA proteases are IMM-anchored with proteolytic/chaperone activity on the matrix-facing side (roles in OXPHOS assembly and PQC)	https://doi.org/10.1089/ars.2022.0124 (khalimonchuk2023moleculardeterminantsof pages 6-8)	2023

Table: Table summarizing verification of C. elegans spg-7 (UniProt Q9N3T5) identity, expected domains/family, and canonical mitochondrial localization, with primary review sources cited for each assertion.

Executive summary
spg-7 (UniProt Q9N3T5) in Caenorhabditis elegans encodes a conserved mitochondrial inner-membrane m-AAA metalloprotease subunit (peptidase M41 family) bearing an AAA+ ATPase module and a zinc-dependent protease domain. By strong conservation with mammalian AFG3L2/SPG7 complexes, spg-7 is expected to assemble into hexameric m-AAA protease complexes on the matrix side of the inner membrane to drive ATP-dependent protein processing and degradation central to mitochondrial protein quality control, biogenesis, and oxidative phosphorylation (OXPHOS) complex assembly. Contemporary reviews (2023–2024) synthesize mechanistic roles of m-AAA proteases in processing OXPHOS subunits, ribosomal factors, and elements of the mitochondrial calcium uniporter machinery, linking activity to mitochondrial dynamics and stress signaling. Where C. elegans-specific experimental data are not directly available in our retrieved corpus, we explicitly indicate inference from orthologs. (khalimonchuk2023moleculardeterminantsof pages 6-8, dastidar2024multifacetedrolesof pages 2-5, dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9)

1) Key concepts and definitions (current understanding)
- Identity and family: spg-7 encodes an m-AAA protease subunit (peptidase M41) with an N-terminal transmembrane region, AAA+ ATPase domain (Walker A/B and SRH motifs), and a C-terminal zinc metalloprotease active site (HExxH/HxxEH motif variants), characteristic of inner-mitochondrial-membrane AAA proteases that face the matrix. This architecture underpins ATP-driven substrate engagement and threading into the proteolytic chamber for processing. (dastidar2024multifacetedrolesof pages 2-5)
- Subcellular localization: m-AAA proteases (including SPG7 orthologs) reside in the inner mitochondrial membrane with catalytic activity on the matrix side, executing proteolysis and chaperone-like processing that maintain mitochondrial proteostasis and support biogenesis. (khalimonchuk2023moleculardeterminantsof pages 6-8)
- Assembly and mechanism: m-AAA proteases function as homo- or hetero-hexamers; in mammals, AFG3L2 forms homo-oligomers or hetero-oligomers with SPG7 (paraplegin). Substrate handling involves ATPase-mediated capture via pore loops, translocation, and proteolysis at the zinc-active site. Autocatalytic maturation and MPP processing are part of biogenesis. These principles inform spg-7 function in worm by conservation. (dastidar2024multifacetedrolesof pages 2-5)
- Biological roles: m-AAA proteases maintain protein quality, support mitochondrial ribosomal biogenesis (e.g., bL32m/MrpL32 processing) and co-/post-translational maturation of OXPHOS components, and contribute to mitochondrial DNA stability, respiratory chain assembly, and regulation of mitochondrial Ca2+ handling via uniporter complex components such as EMRE/MCU. (khalimonchuk2023moleculardeterminantsof pages 6-8, dastidar2024multifacetedrolesof pages 7-9)

2) Recent developments and latest research (2023–2024 focus)
- Integrated mechanism and disease linkage (2024): A comprehensive review details AFG3L2/SPG7 structure-function, stepwise substrate processing by the AAA+ module and protease, and roles in OXPHOS assembly and proteostasis. It highlights that loss of m-AAA activity destabilizes mitochondrial-encoded OXPHOS subunits (e.g., COX1, COX3, CYTB) and impairs respirasome formation, integrating proteostasis with respiratory competence. These mechanistic insights strongly support analogous roles for C. elegans spg-7. (dastidar2024multifacetedrolesof pages 2-5, dastidar2024multifacetedrolesof pages 7-9)
- PQC and calcium homeostasis (2023): A recent review emphasizes m-AAA protease participation in maturation of EMRE and modulation of MCU activity, linking SPG7/m-AAA function to mitochondrial Ca2+ influx and organelle stress responses—mechanisms likely conserved across metazoans, including nematodes. (khalimonchuk2023moleculardeterminantsof pages 6-8)
- UPRmt intersection (2024): Reviews synthesize that m-AAA defects provoke mitochondrial proteostatic stress and fragmentation via OMA1/OPA1 processing, thereby engaging mitochondrial stress axes. Although transcriptional induction patterns can differ across species and cell types, the mechanistic coupling of m-AAA function to mitochondrial stress and dynamics is well supported. (dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9)

3) Current applications and implementations
- Research models: m-AAA perturbations (AFG3L2/SPG7) in vertebrate systems are used to model OXPHOS assembly defects, proteotoxic stress, and mitochondrial fragmentation for disease-relevant studies (ataxias, optic atrophy). These paradigms guide use of spg-7 perturbations in C. elegans to induce mitochondrial stress and probe UPRmt and proteostasis pathways, by conservation. (dastidar2024multifacetedrolesof pages 7-9, khalimonchuk2023moleculardeterminantsof pages 6-8)
- Mechanistic reconstitution: Subunit composition determines substrate preferences of m-AAA complexes; this is applied experimentally to dissect processing of dynamin-like GTPases (e.g., OPA1) and OXPHOS subunits in model systems, informing expected substrate classes for spg-7 in worm. (dastidar2024multifacetedrolesof pages 7-9)

4) Expert opinions and authoritative analysis
- m-AAA as central proteostasis hubs: Contemporary expert reviews frame AFG3L2/SPG7 m-AAA proteases as multifunctional hubs that coordinate mitochondrial proteostasis, respiratory chain assembly, and stress signaling. They argue that defects lead to selective instability of mitochondrial-encoded subunits and trigger OMA1 activation with fragmentation, providing a unifying mechanism for diverse phenotypes. (dastidar2024multifacetedrolesof pages 7-9)
- Calcium uniporter regulation: Reviews highlight SPG7/m-AAA involvement in EMRE maturation and MCU complex regulation, proposing that m-AAA activity restrains excessive Ca2+ influx and associated mitochondrial damage, a concept with implications for neuronal and metabolic resilience. (khalimonchuk2023moleculardeterminantsof pages 6-8)

5) Relevant statistics and quantitative data
- Respiratory biogenesis dependency: Loss of AFG3L2 reduces mitochondrial-encoded respiratory subunits (COX1, COX3, CYTB, ND2) relative to nuclear-encoded components and impairs respirasome assembly; while the review consolidates multiple primary measurements, specific percentages vary by experimental system and are not enumerated in the extracted sections. Nevertheless, the qualitative direction and selectivity of effects are clear. (dastidar2024multifacetedrolesof pages 7-9)
- Stress-axis coupling: Reviews summarize increased OMA1 activity and OPA1 cleavage under m-AAA deficiency, with consequent mitochondrial fragmentation and decreased membrane potential/respiration in cellular and animal models. Quantitative magnitudes depend on model and mutation, but the mechanistic linkage is robust across studies. (dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9)

Function, substrates, and pathways (integrated narrative)
- Molecular function: spg-7 is inferred to encode an ATP-dependent, zinc metalloprotease that assembles into the m-AAA complex on the matrix side of the inner mitochondrial membrane. It uses its AAA+ module to recognize and unfold substrates and its protease domain to cleave them, thereby executing quality control and specific maturation steps. This is based on conserved m-AAA domain architecture and mechanism. (dastidar2024multifacetedrolesof pages 2-5, khalimonchuk2023moleculardeterminantsof pages 6-8)
- Substrate specificity (inferred by conservation): Classes include (i) co-/post-translationally inserted OXPHOS subunits that require surveillance and processing; (ii) mitochondrial ribosomal proteins essential for translation (e.g., bL32m/MrpL32); and (iii) elements of the uniporter complex (EMRE), collectively linking spg-7 to respiration, translation capacity, and Ca2+ handling. Direct worm substrates were not delineated in the retrieved texts; the substrate classes follow conserved m-AAA biology. (khalimonchuk2023moleculardeterminantsof pages 6-8, dastidar2024multifacetedrolesof pages 7-9)
- Localization and site of action: Inner mitochondrial membrane, matrix-facing active site, enabling surveillance of matrix-exposed membrane proteins and soluble matrix proteins near the membrane. (khalimonchuk2023moleculardeterminantsof pages 6-8)
- Pathway context: spg-7 is positioned within mitochondrial protein quality control, OXPHOS assembly, and mitochondrial dynamics regulation via OMA1/OPA1 balance, with downstream consequences for mitochondrial unfolded protein response signaling when proteostasis is perturbed. (dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9, khalimonchuk2023moleculardeterminantsof pages 6-8)

Phenotypes upon loss or perturbation (interpretation for C. elegans)
- By conservation with vertebrate models, spg-7 loss-of-function is expected to impair mitochondrial respiration (reduced membrane potential, oxygen consumption), fragment mitochondrial networks via OMA1 activation, and destabilize mitochondrial-encoded respiratory subunits, thereby triggering stress responses. Direct C. elegans RNAi or mutant quantitative data were not captured in the retrieved 2023–2024 sources used here; thus, these predictions are labeled as inference from orthologs. (dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9)

Limitations of the current evidence set
- The sources retrieved and analyzed here are recent, authoritative reviews that robustly define m-AAA protease biology. However, we did not retrieve C. elegans spg-7-specific primary experiments with quantitative phenotypes in 2023–2024 within this evidence set. Consequently, we clearly demarcate conserved-mechanism inferences from directly demonstrated worm data. (khalimonchuk2023moleculardeterminantsof pages 6-8, dastidar2024multifacetedrolesof pages 2-5)

Citations (URLs and publication dates)
- Khalimonchuk O, Becker DF. Molecular determinants of mitochondrial shape and function and their role in glaucoma. Antioxidants & Redox Signaling. Published May 2023. URL: https://doi.org/10.1089/ars.2022.0124 (khalimonchuk2023moleculardeterminantsof pages 6-8)
- Dastidar RG, Banerjee S, Lal PB, Dastidar SG. Multifaceted roles of AFG3L2, a mitochondrial ATPase in relation to neurological disorders. Molecular Neurobiology. Published November 2024. URL: https://doi.org/10.1007/s12035-023-03768-z (dastidar2024multifacetedrolesof pages 2-5, dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9)

Conclusion
The C. elegans gene spg-7 (Q9N3T5) encodes a conserved m-AAA protease subunit with AAA+ ATPase and M41 metalloprotease domains, localized to the matrix face of the inner mitochondrial membrane. By strong conservation with AFG3L2/SPG7 biology, spg-7 is expected to mediate ATP-dependent proteolysis and maturation of key mitochondrial proteins, sustaining OXPHOS assembly, mitochondrial translation capacity, and Ca2+ homeostasis, and to interface with mitochondrial stress signaling when proteostasis is challenged. Recent (2023–2024) expert reviews integrate these roles into a coherent view linking m-AAA proteases to respiratory biogenesis, membrane dynamics, and disease mechanisms, providing a robust framework for interpreting spg-7 function in worm and prioritizing targets for experimental validation. (khalimonchuk2023moleculardeterminantsof pages 6-8, dastidar2024multifacetedrolesof pages 2-5, dastidar2024multifacetedrolesof pages 5-7, dastidar2024multifacetedrolesof pages 7-9)

References

(dastidar2024multifacetedrolesof pages 2-5): Ranita Ghosh Dastidar, Saradindu Banerjee, Piyush Behari Lal, and Somasish Ghosh Dastidar. Multifaceted roles of afg3l2, a mitochondrial atpase in relation to neurological disorders. Molecular Neurobiology, 61:3788-3808, Nov 2024. URL: https://doi.org/10.1007/s12035-023-03768-z, doi:10.1007/s12035-023-03768-z. This article has 9 citations and is from a peer-reviewed journal.
(khalimonchuk2023moleculardeterminantsof pages 17-18): Oleh Khalimonchuk and Donald F. Becker. Molecular determinants of mitochondrial shape and function and their role in glaucoma. Antioxidants & Redox Signaling, 38:896-919, May 2023. URL: https://doi.org/10.1089/ars.2022.0124, doi:10.1089/ars.2022.0124. This article has 6 citations and is from a domain leading peer-reviewed journal.
(khalimonchuk2023moleculardeterminantsof pages 6-8): Oleh Khalimonchuk and Donald F. Becker. Molecular determinants of mitochondrial shape and function and their role in glaucoma. Antioxidants & Redox Signaling, 38:896-919, May 2023. URL: https://doi.org/10.1089/ars.2022.0124, doi:10.1089/ars.2022.0124. This article has 6 citations and is from a domain leading peer-reviewed journal.
(dastidar2024multifacetedrolesof pages 5-7): Ranita Ghosh Dastidar, Saradindu Banerjee, Piyush Behari Lal, and Somasish Ghosh Dastidar. Multifaceted roles of afg3l2, a mitochondrial atpase in relation to neurological disorders. Molecular Neurobiology, 61:3788-3808, Nov 2024. URL: https://doi.org/10.1007/s12035-023-03768-z, doi:10.1007/s12035-023-03768-z. This article has 9 citations and is from a peer-reviewed journal.
(dastidar2024multifacetedrolesof pages 7-9): Ranita Ghosh Dastidar, Saradindu Banerjee, Piyush Behari Lal, and Somasish Ghosh Dastidar. Multifaceted roles of afg3l2, a mitochondrial atpase in relation to neurological disorders. Molecular Neurobiology, 61:3788-3808, Nov 2024. URL: https://doi.org/10.1007/s12035-023-03768-z, doi:10.1007/s12035-023-03768-z. This article has 9 citations and is from a peer-reviewed journal.

Citations

dastidar2024multifacetedrolesof pages 2-5
khalimonchuk2023moleculardeterminantsof pages 17-18
khalimonchuk2023moleculardeterminantsof pages 6-8
dastidar2024multifacetedrolesof pages 7-9
dastidar2024multifacetedrolesof pages 5-7
https://doi.org/10.1007/s12035-023-03768-z
https://doi.org/10.1089/ars.2022.0124
https://doi.org/10.1007/s12035-023-03768-z,
https://doi.org/10.1089/ars.2022.0124,

📄 View Raw YAML

id: Q9N3T5
gene_symbol: spg-7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: SPG-7 is the C. elegans ortholog of human AFG3L2 (not SPG7/paraplegin
  as the gene name might suggest; the true SPG7 ortholog is ppgn-1). It encodes a
  subunit of the mitochondrial m-AAA protease complex, an ATP-dependent zinc metalloprotease
  localized to the matrix-facing surface of the mitochondrial inner membrane. SPG-7
  functions in mitochondrial protein quality control by degrading misfolded or unassembled
  inner membrane proteins and processing newly imported mitochondrial proteins. Loss
  of SPG-7 function causes mitochondrial stress that activates the mitochondrial unfolded
  protein response (UPRmt) via the transcription factor ATFS-1, leading to transcriptional
  upregulation of mitochondrial chaperones (hsp-6, hsp-60) and innate immune genes.
  SPG-7 is essential for normal mitochondrial respiratory function and morphology.
existing_annotations:
- term:
    id: GO:0005745
    label: m-AAA complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SPG-7 is a well-established component of the m-AAA protease complex based
      on phylogenetic analysis (IBA from PAINT) and conserved domain architecture
      with mammalian AFG3L2. UniProt explicitly notes SPG-7 is an ortholog of human
      AFG3L2 and yeast AFG3, both core m-AAA complex subunits. Deep research confirms
      conserved m-AAA domain architecture (file:worm/spg-7/spg-7-deep-research-falcon.md).
    action: ACCEPT
    reason: 'The IBA annotation is well-supported by phylogenetic conservation and
      domain analysis. SPG-7 contains characteristic m-AAA protease domains: AAA+
      ATPase (IPR003593) and peptidase M41 (IPR000642). This is a core localization
      for the protein.'
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Acts as a component of the m-AAA protease complex which is
        an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial
        inner membrane proteins
    - reference_id: file:worm/spg-7/spg-7-deep-research-falcon.md
      supporting_text: spg-7 is inferred to encode an ATP-dependent, zinc metalloprotease
        that assembles into the m-AAA complex on the matrix side of the inner mitochondrial
        membrane
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SPG-7 contains a conserved M41 peptidase domain with the HExxH zinc-binding
      motif characteristic of metalloendopeptidases. The IBA annotation from PAINT
      is phylogenetically well-supported across m-AAA protease family members.
    action: ACCEPT
    reason: Core molecular function of SPG-7 is metalloendopeptidase activity. The
      protein has conserved zinc-binding sites and an active site based on UniProt
      annotations. This activity is essential for its role in mitochondrial protein
      processing.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Binds 1 zinc ion per subunit
- term:
    id: GO:0034982
    label: mitochondrial protein processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Mitochondrial protein processing is a core function of m-AAA proteases
      across eukaryotes. This IBA annotation is well-supported by phylogenetic conservation
      and is consistent with experimental evidence in C. elegans (PMID:22700657, PMID:25274306,
      PMID:25773600).
    action: ACCEPT
    reason: Core biological process for SPG-7. The m-AAA protease processes imported
      mitochondrial proteins and degrades misfolded proteins. This is directly supported
      by C. elegans experimental data showing spg-7 RNAi affects mitochondrial function
      and activates compensatory stress responses.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Acts as a component of the m-AAA protease complex which is
        an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial
        inner membrane proteins
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SPG-7 contains an AAA+ ATPase domain with Walker A and Walker B motifs.
      The IEA annotation from UniProt keyword mapping is correct but overly general.
    action: MODIFY
    reason: While accurate, this term is too general. SPG-7 specifically binds and
      hydrolyzes ATP as part of its ATPase activity. The more specific term GO:0005524
      (ATP binding) is already annotated and better captures the function.
    proposed_replacement_terms:
    - id: GO:0005524
      label: ATP binding
- term:
    id: GO:0004176
    label: ATP-dependent peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: SPG-7 functions as an ATP-dependent peptidase. The AAA+ ATPase domain
      powers substrate unfolding and translocation into the proteolytic chamber, where
      the M41 peptidase domain degrades substrates. This is a defining feature of
      m-AAA proteases.
    action: ACCEPT
    reason: This term accurately describes SPG-7's integrated molecular function combining
      ATPase and peptidase activities. The InterPro-based IEA annotation is well-supported
      by domain architecture.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: In the N-terminal section; belongs to the AAA ATPase family
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate of the IBA annotation for metalloendopeptidase activity. The
      IEA from InterPro mapping is consistent with the IBA phylogenetic annotation.
    action: ACCEPT
    reason: Both the IEA (InterPro) and IBA (PAINT) annotations support this core
      molecular function. Keeping both evidence types is appropriate as they represent
      independent lines of evidence.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: In the C-terminal section; belongs to the peptidase M41 family
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SPG-7 has a well-characterized ATP-binding site in its AAA+ ATPase domain.
      ATP binding is essential for m-AAA protease function.
    action: ACCEPT
    reason: Core molecular function for SPG-7. The AAA+ ATPase domain requires ATP
      binding for substrate engagement, unfolding, and translocation. Well-supported
      by domain analysis.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: In the N-terminal section; belongs to the AAA ATPase family
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SPG-7 is a mitochondrial inner membrane protein with two transmembrane
      helices. The protein is anchored in the inner membrane with catalytic domains
      facing the matrix.
    action: ACCEPT
    reason: Core cellular localization for SPG-7. UniProt annotation indicates multi-pass
      membrane protein topology with matrix-facing catalytic domains, consistent with
      m-AAA protease architecture.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SPG-7 performs proteolysis as part of the m-AAA protease complex. This
      is the general parent term for its peptidase activity.
    action: ACCEPT
    reason: While more specific terms exist (e.g., mitochondrial protein processing),
      this general proteolysis annotation is not incorrect and captures the core enzymatic
      activity. The IEA annotation is well-supported.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Acts as a component of the m-AAA protease complex which is
        an ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial
        inner membrane proteins
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: General peptidase activity term. SPG-7 is indeed a peptidase, specifically
      a metalloendopeptidase (GO:0004222).
    action: ACCEPT
    reason: Broad but accurate term. More specific terms (metalloendopeptidase activity,
      ATP-dependent peptidase activity) are also annotated, which is appropriate.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: In the C-terminal section; belongs to the peptidase M41 family
- term:
    id: GO:0008237
    label: metallopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SPG-7 is a metallopeptidase containing a zinc-dependent catalytic site.
      This is a parent term of metalloendopeptidase activity.
    action: ACCEPT
    reason: Accurate intermediate-level term. SPG-7 uses zinc for catalysis.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Binds 1 zinc ion per subunit
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: SPG-7 binds zinc as a catalytic cofactor. UniProt identifies zinc-binding
      residues that coordinate the catalytic zinc ion.
    action: ACCEPT
    reason: Correct annotation. Zinc binding is essential for SPG-7's metallopeptidase
      activity. The zinc ion is required for catalysis at the active site.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Binds 1 zinc ion per subunit
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Very general term indicating membrane localization. SPG-7 is specifically
      located in the mitochondrial inner membrane.
    action: ACCEPT
    reason: Not incorrect but very general. The more specific term GO:0005743 (mitochondrial
      inner membrane) is also annotated, which provides better precision.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Very general term. SPG-7 has both peptidase (protein hydrolase) and ATPase
      (nucleotide hydrolase) activities.
    action: ACCEPT
    reason: Accurate high-level classification. More specific terms are also annotated.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: SPG-7's AAA+ ATPase domain hydrolyzes ATP to power substrate engagement
      and translocation. This is essential for m-AAA protease function.
    action: ACCEPT
    reason: Core molecular function. ATP hydrolysis drives the mechanical work of
      unfolding substrates and translocating them into the proteolytic chamber.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: In the N-terminal section; belongs to the AAA ATPase family
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: General term for metal binding. SPG-7 specifically binds zinc.
    action: ACCEPT
    reason: Accurate but general. More specific term (zinc ion binding, GO:0008270)
      is also annotated.
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: SPG-7 participates in protein maturation through processing of imported
      mitochondrial proteins. This ARBA machine learning annotation is consistent
      with m-AAA protease function.
    action: ACCEPT
    reason: Appropriate annotation. m-AAA proteases process and mature mitochondrial
      proteins after import, contributing to their functional maturation.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Functions both in post-translational assembly and in the turnover
        of mistranslated or misfolded polypeptides
- term:
    id: GO:0110039
    label: positive regulation of nematode male tail tip morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:21408209
  review:
    summary: In a genome-wide RNAi screen for male tail tip morphogenesis genes, spg-7
      RNAi resulted in a "Lep" (leptoderan) phenotype - retention of the pointed larval
      tail tip. This was identified alongside 211 other genes. The annotation represents
      a high-throughput screen hit rather than focused investigation of spg-7's role.
    action: KEEP_AS_NON_CORE
    reason: This annotation is technically valid - spg-7 RNAi does cause a male tail
      tip morphogenesis defect. However, this is likely a pleiotropic consequence
      of general mitochondrial dysfunction rather than a direct role in morphogenesis.
      The paper identified spg-7 as one of 41 suppressors of let-7 lethality with
      morphogenesis phenotypes, suggesting this reflects general cellular fitness
      rather than a specific role in tail tip development. This should be kept but
      marked as non-core function.
    supported_by:
    - reference_id: PMID:21408209
      supporting_text: Of the 41 suppressors of let-7 lethality identified by Ding
        et al. [44], six were positives in our screen. RNAi knockdown of two (pri-2,
        npp-6) resulted in the Ore phenotype, of two others (spg-7, smo-1) in the
        Lep phenotype
- term:
    id: GO:0034982
    label: mitochondrial protein processing
  evidence_type: IMP
  original_reference_id: PMID:22700657
  review:
    summary: Nargund et al. (2012) showed that spg-7(RNAi) causes mitochondrial stress
      that activates the UPRmt via ATFS-1. This demonstrates that SPG-7 is required
      for normal mitochondrial protein handling, and its loss leads to accumulation
      of misfolded proteins.
    action: ACCEPT
    reason: Direct experimental evidence for spg-7 function in mitochondrial protein
      processing. Loss of spg-7 function causes nuclear accumulation of ATFS-1 and
      activation of UPRmt, indicating impaired mitochondrial proteostasis.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: However, during mitochondrial stress, we found that import
        efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the
        cytosol and traffic to the nucleus
    - reference_id: UniProt:Q9N3T5
      supporting_text: RNAi- mediated knockdown induces nuclear and mitochondrial
        transcription of mitochondrial protective genes including chaperone hsp-60
        as part of the mitochondrial unfolded protein response
- term:
    id: GO:0034982
    label: mitochondrial protein processing
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: Pellegrino et al. (2014) used spg-7(RNAi) as a tool to induce mitochondrial
      stress and activate the UPRmt. The paper confirms spg-7's role in mitochondrial
      protein quality control.
    action: ACCEPT
    reason: Independent experimental confirmation of spg-7's role in mitochondrial
      protein processing. The study uses spg-7 knockdown to model mitochondrial dysfunction.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Functions both in post-translational assembly and in the turnover
        of mistranslated or misfolded polypeptides
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: When SPG-7 is functional, it suppresses expression of stress-response
      genes by maintaining mitochondrial proteostasis. Loss of spg-7 leads to upregulation
      of UPRmt target genes and innate immune genes via ATFS-1.
    action: MODIFY
    reason: The annotation is technically accurate but captures an indirect effect.
      SPG-7 does not directly regulate gene expression - rather, its proteolytic activity
      maintains mitochondrial health, which in turn keeps ATFS-1 in mitochondria where
      it is degraded. A more appropriate annotation would be to the upstream process
      (mitochondrial protein processing) or the regulatory pathway.
    proposed_replacement_terms:
    - id: GO:0034514
      label: mitochondrial unfolded protein response
    additional_reference_ids:
    - PMID:22700657
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: However, during mitochondrial stress, we found that import
        efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the
        cytosol and traffic to the nucleus
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:25274306
  review:
    summary: The IGI annotation with atfs-1 indicates genetic interaction - spg-7
      and atfs-1 together regulate gene expression. The paper shows that spg-7(RNAi)
      effects on gene expression require atfs-1.
    action: MODIFY
    reason: Similar to the IMP annotation above, this captures an indirect effect.
      SPG-7 does not directly regulate gene expression but rather maintains mitochondrial
      proteostasis. The effects on gene expression are mediated by ATFS-1 when mitochondrial
      stress occurs. A more specific term would better capture the mechanism.
    proposed_replacement_terms:
    - id: GO:0034514
      label: mitochondrial unfolded protein response
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: RNAi-mediated knockdown abolishes transcription up- regulation
        in an atfs-1 (tm4919) mutant background
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: Pellegrino et al. (2014) showed that spg-7(RNAi) pre-treatment activates
      the UPRmt, which in turn induces innate immune genes (abf-2, lys-2, clec-4,
      clec-65). This provides resistance to P. aeruginosa infection. The immune response
      is ATFS-1 dependent and represents a coupling of mitochondrial stress to innate
      immunity.
    action: KEEP_AS_NON_CORE
    reason: This annotation reflects a downstream consequence of SPG-7 dysfunction
      rather than a direct role in immunity. When SPG-7 is lost, mitochondrial stress
      activates ATFS-1-dependent innate immune genes. While experimentally valid,
      this represents a stress response pathway activation rather than a core immune
      function of SPG-7. The core function is mitochondrial protein processing; immune
      activation is a consequence of its loss.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: RNAi-mediated knockdown also induces the transcription of innate
        immunity-related genes such as lys-2, abf-2, clec-65 and clec-4 which results
        in resistance to P.aeruginosa-mediated infection
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IGI
  original_reference_id: PMID:25274306
  review:
    summary: Multiple IGI annotations exist for this term, indicating genetic interactions
      with various innate immunity components. These all reflect the ATFS-1-dependent
      coupling of mitochondrial stress to immune gene induction.
    action: KEEP_AS_NON_CORE
    reason: Same rationale as above - the immune response is a downstream consequence
      of mitochondrial stress caused by loss of SPG-7 function. The core function
      remains mitochondrial protein processing.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: RNAi-mediated knockdown also induces the transcription of innate
        immunity-related genes such as lys-2, abf-2, clec-65 and clec-4 which results
        in resistance to P.aeruginosa-mediated infection
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: ISS
  original_reference_id: PMID:15280428
  review:
    summary: ISS annotation based on similarity to human AFG3L2. The Yoneda et al.
      (2004) paper established spg-7 as encoding a mitochondrial protease in C. elegans,
      demonstrating that RNAi knockdown activates the UPRmt.
    action: ACCEPT
    reason: The ISS annotation is well-supported. SPG-7 has conserved metalloprotease
      domains and sequence similarity to characterized m-AAA proteases. This annotation
      provides additional evidence type for the core molecular function.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: In the C-terminal section; belongs to the peptidase M41 family
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: PMID:15280428
  review:
    summary: ISS annotation based on similarity to mouse Afg3l2. Mitochondrial localization
      is well-established for m-AAA proteases.
    action: ACCEPT
    reason: Correct cellular component annotation. While more specific terms exist
      (mitochondrial inner membrane), this general mitochondrial localization is accurate
      and useful.
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: IMP
  original_reference_id: PMID:15280428
  review:
    summary: Yoneda et al. (2004) showed that RNAi of spg-7 and other mitochondrial
      proteases/ chaperones activates the UPRmt. This indicates a role in assembly
      of multi-subunit mitochondrial complexes.
    action: MODIFY
    reason: While the annotation reflects an indirect function, the term is too general.
      SPG-7's role is specifically in mitochondrial respiratory chain complex assembly
      and mitochondrial protein complex maturation. A more specific term would be
      more informative.
    proposed_replacement_terms:
    - id: GO:0033108
      label: mitochondrial respiratory chain complex assembly
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: The complex is necessary for the assembly of mitochondrial
        respiratory chain and ATPase complexes
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:22700657
  review:
    summary: SPG-7 is a key activator of the UPRmt when its function is compromised.
      Loss of spg-7 function leads to mitochondrial stress and activation of the UPRmt
      pathway via ATFS-1. This is one of the best-characterized UPRmt triggers in
      C. elegans.
    action: NEW
    reason: This is a well-established function of spg-7 in C. elegans not currently
      annotated. Multiple papers (PMID:22700657, PMID:25274306, PMID:15280428) demonstrate
      that spg-7(RNAi) activates the UPRmt. While SPG-7 does not directly signal in
      the UPRmt pathway, its loss triggers the response, making it involved in the
      process.
    additional_reference_ids:
    - PMID:25274306
    - PMID:15280428
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: However, during mitochondrial stress, we found that import
        efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the
        cytosol and traffic to the nucleus
    - reference_id: UniProt:Q9N3T5
      supporting_text: RNAi- mediated knockdown induces nuclear and mitochondrial
        transcription of mitochondrial protective genes including chaperone hsp-60
        as part of the mitochondrial unfolded protein response
- term:
    id: GO:0033108
    label: mitochondrial respiratory chain complex assembly
  evidence_type: ISS
  original_reference_id: PMID:15280428
  review:
    summary: m-AAA proteases are required for assembly of mitochondrial respiratory
      chain complexes. This function is well-established in yeast and mammals and
      is conserved in C. elegans based on domain architecture and phenotypic effects.
    action: NEW
    reason: This core function is implicit in UniProt annotation but not currently
      in GO. UniProt states the m-AAA protease complex is necessary for the assembly
      of mitochondrial respiratory chain and ATPase complexes. PMID:25773600 shows
      spg-7(RNAi) reduces oxygen consumption, indicating respiratory defects.
    additional_reference_ids:
    - PMID:25773600
    supported_by:
    - reference_id: UniProt:Q9N3T5
      supporting_text: The complex is necessary for the assembly of mitochondrial
        respiratory chain and ATPase complexes
    - reference_id: UniProt:Q9N3T5
      supporting_text: RNAi-mediated knockdown reduces oxygen consumption
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings:
  - statement: InterPro domains IPR000642, IPR003593, IPR003959 support molecular
      function annotations
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: PAINT IBA annotations from phylogenetic analysis of m-AAA protease
      family
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: Keyword mappings support general molecular function terms
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping
  findings:
  - statement: Subcellular location annotation supports mitochondrial inner membrane
      localization
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings:
  - statement: ARBA prediction for protein maturation involvement
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: Combined IEA methods support ATP binding, proteolysis annotations
- id: PMID:15280428
  title: Compartment-specific perturbation of protein handling activates genes encoding
    mitochondrial chaperones
  findings:
  - statement: Established that spg-7 RNAi activates UPRmt hsp-6 and hsp-60 induction
    supporting_text: hsp-6 and hsp-60 induction was specific to perturbed mitochondrial
      protein handling, as neither heat-shock nor endoplasmic reticulum stress nor
      manipulations that impair mitochondrial steps in intermediary metabolism or
      ATP synthesis activated the mitochondrial chaperone genes
    reference_section_type: ABSTRACT
- id: PMID:21408209
  title: A bow-tie genetic architecture for morphogenesis suggested by a genome-wide
    RNAi screen in Caenorhabditis elegans
  findings:
  - statement: spg-7 identified as one of 212 genes affecting male tail tip morphogenesis
    supporting_text: Of the 41 suppressors of let-7 lethality identified by Ding et
      al. [44], six were positives in our screen. RNAi knockdown of two (pri-2, npp-6)
      resulted in the Ore phenotype, of two others (spg-7, smo-1) in the Lep phenotype
    reference_section_type: RESULTS
  - statement: spg-7 RNAi causes Lep leptoderan phenotype
    supporting_text: RNAi knockdown of two (pri-2, npp-6) resulted in the Ore phenotype,
      of two others (spg-7, smo-1) in the Lep phenotype
    reference_section_type: RESULTS
- id: PMID:22700657
  title: Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation
  findings:
  - statement: spg-7 RNAi causes mitochondrial stress leading to ATFS-1 nuclear accumulation
    supporting_text: However, during mitochondrial stress, we found that import efficiency
      was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and
      traffic to the nucleus
    reference_section_type: RESULTS
  - statement: Established ATFS-1 import efficiency model for UPRmt regulation
    supporting_text: However, during mitochondrial stress, we found that import efficiency
      was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and
      traffic to the nucleus
    reference_section_type: RESULTS
- id: PMID:25274306
  title: Mitochondrial UPR-regulated innate immunity provides resistance to pathogen
    infection
  findings:
  - statement: spg-7 RNAi activates UPRmt and innate immune genes via ATFS-1
    supporting_text: a number of transcripts induced during mitochondrial stress caused
      by inhibition of the mitochondrial protease SPG-7 encode innate immunity proteins
    reference_section_type: RESULTS
  - statement: UPRmt pre-activation provides resistance to P. aeruginosa
    supporting_text: UPRmt pre-activation dramatically reduced the intestinal accumulation
      of P. aeruginosa expressing GFP
    reference_section_type: RESULTS
- id: PMID:25773600
  title: Mitochondrial and nuclear accumulation of the transcription factor ATFS-1
    promotes OXPHOS recovery during the UPR(mt).
  findings:
  - statement: spg-7 RNAi reduces oxygen consumption indicating respiratory defects
    supporting_text: balanced ATFS-1 accumulation promoted OXPHOS complex assembly
      and function
    reference_section_type: ABSTRACT
  - statement: ATFS-1 regulates OXPHOS gene expression during mitochondrial stress
    supporting_text: atfs-1 was required to limit the accumulation of OXPHOS transcripts
      during mitochondrial stress
    reference_section_type: ABSTRACT
- id: file:worm/spg-7/spg-7-deep-research-falcon.md
  title: Falcon Research Report on spg-7 (worm)
  findings:
  - statement: SPG-7 encodes conserved m-AAA metalloprotease subunit with AAA+ ATPase
      and M41 peptidase domains
  - statement: m-AAA proteases maintain protein quality, support mitochondrial ribosomal
      biogenesis and OXPHOS component maturation
core_functions:
- description: ATP-dependent zinc metalloendopeptidase that degrades misfolded and
    unassembled mitochondrial inner membrane proteins. The proteolytic chamber is
    formed by the M41 peptidase domain and requires zinc for catalysis.
  molecular_function:
    id: GO:0004176
    label: ATP-dependent peptidase activity
  directly_involved_in:
  - id: GO:0034982
    label: mitochondrial protein processing
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0005745
    label: m-AAA complex
  supported_by:
  - reference_id: UniProt:Q9N3T5
    supporting_text: Acts as a component of the m-AAA protease complex which is an
      ATP-dependent metalloprotease mediating degradation of non-assembled mitochondrial
      inner membrane proteins
- description: Processes imported mitochondrial proteins and is required for assembly
    of mitochondrial respiratory chain and ATPase complexes. Loss of function leads
    to respiratory deficiency with reduced oxygen consumption.
  molecular_function:
    id: GO:0004222
    label: metalloendopeptidase activity
  directly_involved_in:
  - id: GO:0033108
    label: mitochondrial respiratory chain complex assembly
  - id: GO:0051604
    label: protein maturation
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0005745
    label: m-AAA complex
  supported_by:
  - reference_id: UniProt:Q9N3T5
    supporting_text: The complex is necessary for the assembly of mitochondrial respiratory
      chain and ATPase complexes
  - reference_id: UniProt:Q9N3T5
    supporting_text: RNAi-mediated knockdown reduces oxygen consumption
- description: Maintains mitochondrial proteostasis; loss of function activates the
    mitochondrial unfolded protein response (UPRmt) via ATFS-1 nuclear accumulation
    and transcriptional upregulation of mitochondrial chaperones.
  molecular_function:
    id: GO:0004176
    label: ATP-dependent peptidase activity
  directly_involved_in:
  - id: GO:0034514
    label: mitochondrial unfolded protein response
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0005745
    label: m-AAA complex
  supported_by:
  - reference_id: PMID:22700657
    supporting_text: However, during mitochondrial stress, we found that import efficiency
      was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and
      traffic to the nucleus
proposed_new_terms: []
suggested_questions:
- question: What are the specific substrates of SPG-7 m-AAA protease in C. elegans
    mitochondria?
  experts: []
- question: Does SPG-7 form homo-oligomers or hetero-oligomers with PPGN-1 the true
    SPG7 ortholog?
  experts: []
- question: What is the relative contribution of SPG-7 vs PPGN-1 to m-AAA protease
    activity?
  experts: []
- question: How does SPG-7 deficiency affect specific respiratory chain complexes?
  experts: []
suggested_experiments:
- description: Proteomic identification of SPG-7 substrates using substrate-trapping
    mutants
  experiment_type: Proteomics
  hypothesis: SPG-7 has specific substrates among misfolded or unassembled inner membrane
    proteins
- description: Co-immunoprecipitation to determine SPG-7 and PPGN-1 complex composition
  experiment_type: Biochemistry
  hypothesis: SPG-7 forms hetero-oligomeric complexes with PPGN-1 in vivo
- description: Measurement of individual respiratory chain complex activities in spg-7
    mutants
  experiment_type: Enzymology
  hypothesis: Loss of SPG-7 leads to specific defects in respiratory chain complex
    assembly
- description: Live imaging of mitochondrial dynamics in spg-7 mutants
  experiment_type: Microscopy
  hypothesis: SPG-7 deficiency alters mitochondrial morphology and network dynamics
tags:
- caeel-mitophagy

spg-7

Gene Description

Existing Annotations Review

Core Functions

ATP-dependent zinc metalloendopeptidase that degrades misfolded and unassembled mitochondrial inner membrane proteins. The proteolytic chamber is formed by the M41 peptidase domain and requires zinc for catalysis.

Processes imported mitochondrial proteins and is required for assembly of mitochondrial respiratory chain and ATPase complexes. Loss of function leads to respiratory deficiency with reduced oxygen consumption.

Maintains mitochondrial proteostasis; loss of function activates the mitochondrial unfolded protein response (UPRmt) via ATFS-1 nuclear accumulation and transcriptional upregulation of mitochondrial chaperones.

References

Suggested Questions for Experts

Suggested Experiments

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📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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