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