isp-1 encodes the Rieske iron-sulfur protein (ISP), the [2Fe-2S]-cluster-bearing catalytic subunit of mitochondrial respiratory complex III (the cytochrome bc1 / ubiquinol-cytochrome c oxidoreductase complex, EC 7.1.1.8). Anchored in the mitochondrial inner membrane, its mobile Rieske head domain accepts an electron from ubiquinol at the complex III Qo site and delivers it to cytochrome c1, performing the electron-transfer step of the protonmotive Q-cycle and thereby feeding electrons into the respiratory chain. In C. elegans the partial loss-of-function allele isp-1(qm150) is a classic mitochondrial ("Mit") longevity mutant: it lowers oxygen consumption and extends lifespan, with the lifespan extension driven by an elevated mitochondrial superoxide signal rather than by reduced oxidative damage.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016491 oxidoreductase activity | IBA GO_REF:0000033 | MODIFY | Summary: Correct but uninformatively general. ISP-1's specific molecular function is electron transfer through its Rieske [2Fe-2S] cluster; the complex-level oxidoreductase reaction is captured more precisely by GO:0008121. Reason: oxidoreductase activity is a high-level parent. The subunit-specific activity of the Rieske protein is electron transfer (GO:0009055), enabled via its 2Fe-2S cluster; complex III's overall reaction is quinol-cytochrome-c reductase activity (GO:0008121), already separately annotated. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000015358 · Rieske / complex III oxidoreductase node IBA propagates the broad parent oxidoreductase activity; the correct subunit-level term is electron transfer activity (GO:0009055). Proposed replacements: electron transfer activity Supporting Evidence: PMID:26504246 encodes the Rieske iron-sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain) |
| GO:0045275 respiratory chain complex III | IBA GO_REF:0000033 | ACCEPT | Summary: Core annotation. ISP-1 is the Rieske iron-sulfur subunit of respiratory chain complex III (cytochrome bc1). Reason: Well established across eukaryotes and in C. elegans; ISP-1 is an integral catalytic subunit of complex III. Supporting Evidence: PMID:21151885 subunits of complex I and III of the mitochondrial respiratory chain PMID:26504246 complex III of the electron transport chain |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. Within complex III, ISP-1 transfers electrons from ubiquinol to cytochrome c1 (and onward to cytochrome c). Reason: This is the pathway step complex III performs and to which the Rieske subunit is central; phylogenetically well supported and consistent with the experimental worm data. Supporting Evidence: PMID:21151885 Partial loss-of-function mutations in these genes decrease electron transport file:worm/isp-1/isp-1-deep-research-falcon.md transfers electrons from ubiquinol to cytochrome c1 |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Core localization. Complex III, including the Rieske subunit, resides in the mitochondrial inner membrane. Reason: UniProt subcellular location; ISP-1 has a single-pass inner-membrane anchor with its Rieske head projecting to the intermembrane-space side. Supporting Evidence: file:worm/isp-1/isp-1-uniprot.txt C:mitochondrial inner membrane; IEA:UniProtKB-SubCell |
| GO:0008121 quinol-cytochrome-c reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Complex III catalytic activity (EC 7.1.1.8) to which ISP-1 contributes the essential electron-transfer step. Retained as a core molecular function of the subunit in the context of the assembled complex. Reason: ISP-1 is a catalytic subunit of ubiquinol-cytochrome c oxidoreductase; the Rieske cluster carries out the electron-transfer half of this reaction. Best represented in core_functions as contributes_to (a complex-level activity). Supporting Evidence: file:worm/isp-1/isp-1-uniprot.txt EC=7.1.1.8 PMID:26504246 subunit of cytochrome c oxidoreductase |
| GO:0016020 membrane | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Uninformative general parent, redundant with the specific and correct mitochondrial inner membrane annotation (GO:0005743). Reason: "membrane" adds no information beyond the more precise GO:0005743 already assigned; it is an over-general IEA byproduct. |
| GO:0051537 2 iron, 2 sulfur cluster binding | IEA GO_REF:0000002 | ACCEPT | Summary: Core molecular function. The defining feature of the Rieske protein: it coordinates a high-potential [2Fe-2S] cluster, the redox center used for electron transfer. Reason: UniProt cofactor annotation and Rieske-family conservation; one [2Fe-2S] cluster is bound per subunit. Supporting Evidence: file:worm/isp-1/isp-1-uniprot.txt Binds 1 [2Fe-2S] cluster per subunit file:worm/isp-1/isp-1-uniprot.txt The Rieske protein is a high potential 2Fe-2S protein |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Complex III couples electron transfer to proton translocation across the inner membrane via the Q-cycle. This is a complex-level chemiosmotic outcome, not ISP-1's direct molecular function (electron transfer); retained as non-core. Reason: Proton translocation is an emergent property of the intact Q-cycle to which ISP-1 contributes, rather than an activity ISP-1 performs on its own. Correct to retain, but the subunit's core function is electron transfer. |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | IMP PMID:16920626 Mitochondrial complex I function modulates volatile anesthet... | ACCEPT | Summary: Experimentally supported in C. elegans. The isp-1 complex III mutant shows impaired mitochondrial respiration/oxidative phosphorylation, directly implicating isp-1 in mitochondrial electron transport. Reason: Falk et al. measured respiration in the isp-1 (complex III) mutant and found diminished complex II-dependent oxidative phosphorylation, consistent with a defect in the ubiquinol-to-cytochrome c step; core process, experimentally anchored. |
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Download this section (compressed HTML)What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular mechanism by which the isp-1(qm150) Rieske substitution is converted into the pro-longevity retrograde signal is undetermined. It is established that qm150 elevates mitochondrial superoxide and that this elevation is necessary and sufficient for the lifespan extension, but the causal chain from the specific perturbation of ISP-1 head/tether dynamics, through altered Qo-site electron transfer and superoxide production, to the downstream transcriptional longevity program has not been resolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Firmly established: isp-1 encodes the Rieske [2Fe-2S] subunit of complex III; qm150 is a partial loss-of-function allele that lowers oxygen consumption and extends lifespan; the longevity requires elevated mitochondrial superoxide (abolished by antioxidants, phenocopied by paraquat); and intragenic suppressors that restore function map to a conserved six-residue tether region ("spring-loaded" model). What is unresolved is the signal-generating step itself.
Significance: isp-1(qm150) is a canonical mitohormesis / Mit longevity model. Defining the signal-generating step would connect a specific electron-transport-chain lesion to a conserved lifespan-extension program with relevance to mitochondrial disease and aging.
What would resolve it: Structure-guided electron-transfer and superoxide measurements on qm150 and its intragenic tether-region suppressors, combined with epistasis to the retrograde transcriptional effectors, to identify the step that generates the superoxide longevity signal.
Provenance (the field's own admissions):
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