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.
|
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):
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.
Gene: isp-1 | UniProt: O44512 | Organism: Caenorhabditis elegans | Protein: Cytochrome b-c1 complex subunit Rieske, mitochondrial | EC: 7.1.1.8
The isp-1 gene (locus F42G8.12) in C. elegans encodes the Rieske iron-sulfur protein (ISP), a catalytic subunit of mitochondrial Complex III (ubiquinol:cytochrome c oxidoreductase, also known as the cytochrome bc1 complex) (jafari2016newfunctionaland pages 1-4). ISP-1 belongs to the highly conserved Rieske iron-sulfur protein family, with orthologs including UQCRFS1 in mammals (osz2025mutationsofthe pages 4-6). The protein contains characteristic domains including a Rieske 2Fe-2S cluster domain (IPR017941), a Rieske 2Fe-2S superfamily domain (IPR036922), a Rieske Fe-S protein domain (IPR014349), and a bc1 Rieske transmembrane superfamily domain (IPR037008), all consistent with its function as a catalytic electron transfer component within the Q-cycle of Complex III.
ISP-1 comprises three structurally and functionally distinct domains that are essential for its role in the Q-cycle mechanism of Complex III:
| Domain/Feature | Description | Function |
|---|---|---|
| Transmembrane helix (anchor) | Single N-terminal transmembrane α-helix that anchors ISP-1 in the mitochondrial inner membrane as a core subunit of Complex III/cytochrome bc1. The membrane anchor remains relatively static while the catalytic domain moves. (jafari2016newfunctionaland pages 1-4, yang2012rieskeiron–sulfurprotein pages 1-3) | Positions ISP-1 within Complex III and maintains the spatial framework needed for electron transfer between quinol oxidation and cytochrome c1 reduction. (jafari2016newfunctionaland pages 1-4, yang2012rieskeiron–sulfurprotein pages 1-3) |
| Tether domain (spring mechanism) | Flexible linker connecting the membrane anchor to the extrinsic catalytic head. In mechanistic models it behaves as a chemical “spring,” alternating between extended and relaxed/helical conformations during catalysis; the qm150 Pro→Ser mutation lies in this region. (jafari2016newfunctionaland pages 1-4, jafari2016newfunctionaland pages 10-16, jafari2016newfunctionaland pages 6-8, jafari2016newfunctionaland pages 4-6) | Enables controlled movement of the head domain between the Qo site and cytochrome c1, thereby regulating enzyme-substrate complex formation, electron flux through the Q-cycle, and ROS propensity. (jafari2016newfunctionaland pages 10-16, jafari2016newfunctionaland pages 6-8, jafari2016newfunctionaland pages 4-6) |
| Head domain with 2Fe-2S cluster | Extrinsic/mobile catalytic head domain containing the Rieske 2Fe-2S cluster with distinctive histidine coordination and relatively high redox potential. This domain projects to the P side/intermembrane-space side of the membrane. (jafari2016newfunctionaland pages 1-4, schmidt2004rieskeiron–sulfurproteins pages 1-2) | Accepts an electron from ubiquinol at the Qo site and later donates that electron to heme c1; its mobility and redox chemistry are central to Complex III catalysis. (jafari2016newfunctionaland pages 1-4, jafari2016newfunctionaland pages 10-16, schmidt2004rieskeiron–sulfurproteins pages 1-2) |
| Qo site interaction | ISP-1 docks at the quinol oxidation (Qo) site near cytochrome b, where oxidized ISP interacts with ubiquinol (QH2). The first electron-transfer step reduces the 2Fe-2S cluster and generates a semiquinone intermediate. (jafari2016newfunctionaland pages 10-16, jafari2016newfunctionaland pages 6-8) | Executes the initial oxidation of QH2 and bifurcates electron flow in the Q-cycle, a key energy-conserving step in Complex III. (jafari2016newfunctionaland pages 10-16, jafari2016newfunctionaland pages 6-8, gurung2005theironsulfurcluster pages 1-1) |
| Cytochrome c1 interaction | After reduction at the Qo site, the ISP-1 head swings toward cytochrome c1 into the c1-state conformation, where the reduced 2Fe-2S center transfers its electron to heme c1. (jafari2016newfunctionaland pages 1-4, jafari2016newfunctionaland pages 10-16, yang2012rieskeiron–sulfurprotein pages 1-3, crofts1999physicochemicalaspectsof pages 11-12) | Couples quinol oxidation to reduction of cytochrome c1 and ultimately cytochrome c, supporting downstream electron flow to Complex IV. (jafari2016newfunctionaland pages 1-4, yang2012rieskeiron–sulfurprotein pages 1-3) |
| Proton-exiting gate role | Experimental disruption of the Rieske 2Fe-2S center creates a proton leak, supporting the model that the cluster/head region acts as a proton-exiting gate in cytochrome bc1. (gurung2005theironsulfurcluster pages 1-1, gurung2005theironsulfurcluster pages 5-5) | Prevents nonspecific proton leakage and helps couple electron transfer to proton translocation, preserving the proton motive force used for ATP synthesis. (gurung2005theironsulfurcluster pages 1-1, gurung2005theironsulfurcluster pages 5-5) |
| Overall Q-cycle reaction (EC 7.1.1.8; ubiquinol:ferricytochrome-c reductase) | ISP-1 is a catalytic subunit of Complex III/ubiquinol:cytochrome c oxidoreductase. In the Q-cycle, it transfers electrons from ubiquinol to cytochrome c1 while coordinating with the Qo and Qi sites to couple redox chemistry to proton translocation across the inner membrane. (jafari2016newfunctionaland pages 1-4, jafari2016newfunctionaland pages 10-16, gurung2005theironsulfurcluster pages 1-1, yang2012rieskeiron–sulfurprotein pages 1-3) | Contributes to the net reaction of ubiquinol oxidation and cytochrome c reduction while generating the proton gradient required for oxidative phosphorylation and ATP production. (jafari2016newfunctionaland pages 1-4, jafari2016newfunctionaland pages 10-16, yang2012rieskeiron–sulfurprotein pages 1-3) |
Table: This table summarizes the major structural features of the C. elegans ISP-1/Rieske iron-sulfur protein and links each feature to its role in Complex III catalysis. It is useful for connecting protein architecture to the Q-cycle mechanism and the gene’s primary biochemical function.
Transmembrane anchor. A single N-terminal transmembrane α-helix anchors ISP-1 in the mitochondrial inner membrane, positioning it as a core subunit of the cytochrome bc1 complex (jafari2016newfunctionaland pages 1-4, yang2012rieskeiron–sulfurprotein pages 1-3). This anchor remains relatively static during catalysis.
Tether domain. A flexible linker region connects the membrane anchor to the catalytic head domain. This tether operates as a chemical "spring," alternating between extended and relaxed (helical) conformations to enable the large-scale domain movement required for catalysis (jafari2016newfunctionaland pages 1-4, jafari2016newfunctionaland pages 10-16). The tether contains conserved amino acids critical for mediating interactions between cytochrome b and the ISP head domain (jafari2016newfunctionaland pages 6-8). Notably, the well-characterized isp-1(qm150) mutation—a proline-to-serine substitution—maps to this tether region and profoundly affects protein function (jafari2016newfunctionaland pages 6-8, jafari2016newfunctionaland pages 4-6).
Extrinsic head domain with 2Fe-2S cluster. The catalytic head domain projects into the intermembrane space (P-side) and harbors the Rieske [2Fe-2S] cluster with distinctive histidine-coordinated nitrogen ligands, conferring a relatively high redox potential compared to other iron-sulfur centers (schmidt2004rieskeiron–sulfurproteins pages 1-2). This domain undergoes large-scale movement of approximately 16–22 Å between the Qo site on cytochrome b and cytochrome c1, with root-mean-square displacement occurring in less than 25 nanoseconds (crofts1999physicochemicalaspectsof pages 11-12).
ISP-1 functions as a catalytic subunit of Complex III, which catalyzes the oxidation of ubiquinol (coenzyme QH₂) coupled to the reduction of cytochrome c and the translocation of protons across the mitochondrial inner membrane (EC 7.1.1.8) (jafari2016newfunctionaland pages 1-4, gurung2005theironsulfurcluster pages 1-1). The specific role of ISP-1 within the Q-cycle is as follows:
Step 1 — Ubiquinol oxidation at the Qo site. The oxidized 2Fe-2S cluster (ISP_ox) of the head domain docks at the Qo site (quinol oxidation site) near cytochrome b, where it accepts one electron from bound ubiquinol (QH₂). This first electron transfer reduces ISP_ox to ISP_H and generates a transient semiquinone intermediate (SQo) (jafari2016newfunctionaland pages 10-16).
Step 2 — Electron shuttle to cytochrome c1. The reduced ISP head dissociates from the Qo site and swings on its tether to dock at cytochrome c1, where the electron is transferred from the reduced 2Fe-2S cluster to heme c1, coupled with release of a proton to the P-phase (intermembrane space). This constitutes the "high-potential chain" of electron flow, ultimately reducing soluble cytochrome c (jafari2016newfunctionaland pages 10-16, yang2012rieskeiron–sulfurprotein pages 1-3).
Step 3 — Bifurcation of electron flow. The second electron from ubiquinol oxidation follows the separate "low-potential chain" through heme b_L and heme b_H of cytochrome b to the Qi site (quinone reduction site), where ubiquinone is reduced to ubiquinol. This bifurcated electron transfer is fundamental to the Q-cycle's proton-translocation stoichiometry of 2H⁺/e⁻ (jafari2016newfunctionaland pages 10-16, osz2025mutationsofthe pages 19-21, gurung2005theironsulfurcluster pages 1-1).
Proton-exiting gate function. Experimental work has demonstrated that the 2Fe-2S cluster also serves as a proton-exiting gate: destruction or genetic elimination of the cluster creates a proton-leaking channel in the bc1 complex, abolishing proton-pumping activity. This indicates the ISP head domain is critical for maintaining the integrity of proton translocation coupled to electron transfer (gurung2005theironsulfurcluster pages 1-1, gurung2005theironsulfurcluster pages 5-5).
ISP-1 is localized to the mitochondrial inner membrane, where it functions as an integral component of the energy-conserving electron transport chain (jafari2016newfunctionaland pages 1-4, yang2012rieskeiron–sulfurprotein pages 1-3, gurung2005theironsulfurcluster pages 1-1). The protein's topology places the transmembrane anchor within the lipid bilayer while the catalytic head domain with the 2Fe-2S cluster extends into the intermembrane space (P-side) (jafari2016newfunctionaland pages 1-4, yang2012rieskeiron–sulfurprotein pages 1-3). ISP-1 also plays a structural role in stabilizing higher-order respiratory supercomplexes (I:III:IV respirasomes), which are proposed to increase electron transport chain efficiency and reduce ROS production (osz2025mutationsofthe pages 19-21).
The best-characterized allele of isp-1 is qm150, a proline-to-serine substitution in the tether domain that inhibits electron flux into the Qo site by interfering with formation of the enzyme-substrate complex between QH₂ and ISP_ox (jafari2016newfunctionaland pages 6-8, jafari2016newfunctionaland pages 4-6). This mutation results in drastically diminished respiratory function and causes pleiotropic phenotypes including:
Intragenic suppressor mutations identified in the tether region partially restore electron transfer rates and suppress some pleiotropic phenotypes, but at the cost of increased ROS production, demonstrating the intimate relationship between tether mechanics and Q-cycle gating (jafari2016newfunctionaland pages 4-6, jafari2016newfunctionaland pages 6-8).
Mild mitochondrial dysfunction caused by isp-1 mutation activates multiple conserved stress response and longevity-promoting signaling pathways. The central upstream signal appears to be elevated mitochondrial ROS, which triggers several downstream transcriptional programs.
| Pathway/Transcription Factor | Role in isp-1 Longevity | Key Evidence | Key Reference |
|---|---|---|---|
| HIF-1 | Required for lifespan extension | isp-1(qm150) elevates ROS and increases HIF-1 target gene expression; loss of hif-1 or aha-1 shortens the extended lifespan of isp-1 mutants, indicating HIF-1 is a key mediator of mitochondrial retrograde longevity signaling. (lee2010inhibitionofrespiration pages 2-3, lee2010inhibitionofrespiration pages 4-4, lee2010inhibitionofrespiration pages 2-2) | Lee et al., 2010 (lee2010inhibitionofrespiration pages 2-3, lee2010inhibitionofrespiration pages 4-4, lee2010inhibitionofrespiration pages 2-2) |
| DAF-16/FOXO | Required for full lifespan extension | DAF-16 target genes are enriched among transcripts upregulated in isp-1 mutants; DAF-16 shows increased nuclear localization, and daf-16 loss markedly suppresses isp-1 longevity. ROS appears to be an upstream activator, with IMB-2, CST-1/2, BAR-1, and MATH-33 supporting DAF-16-dependent longevity. (senchuk2018activationofdaf16foxo pages 4-6, senchuk2018activationofdaf16foxo pages 9-11, senchuk2018activationofdaf16foxo pages 15-17, senchuk2018activationofdaf16foxo pages 1-2) | Senchuk et al., 2018 (senchuk2018activationofdaf16foxo pages 4-6, senchuk2018activationofdaf16foxo pages 9-11, senchuk2018activationofdaf16foxo pages 15-17, senchuk2018activationofdaf16foxo pages 1-2) |
| SKN-1/Nrf2 | Required for lifespan extension | SKN-1 target genes are activated in isp-1 mutants, and SKN-1 is required for the increased longevity of mitochondrial mutants including isp-1, supporting a ROS-responsive oxidative stress program downstream of ETC dysfunction. (senchuk2018activationofdaf16foxo pages 17-18) | Senchuk et al., 2018 (senchuk2018activationofdaf16foxo pages 17-18) |
| ATFS-1/mitoUPR | Dispensable for adult lifespan extension; required for development in isp-1 background | ATFS-1 is necessary for induction of mitoUPR reporters and target genes in isp-1 mutants, but adult-only atfs-1 knockdown does not reduce isp-1 lifespan. In contrast, loss of ATFS-1 during development causes developmental arrest or prevents isp-1 animals from reaching adulthood, indicating a stage-specific requirement. (bennett2014activationofthe pages 1-2, bennett2014activationofthe pages 7-8, wu2018mitochondrialunfoldedprotein pages 2-5, wu2018mitochondrialunfoldedprotein pages 1-2, wu2018mitochondrialunfoldedprotein pages 10-13) | Bennett et al., 2014; Wu et al., 2018 (bennett2014activationofthe pages 1-2, bennett2014activationofthe pages 7-8, wu2018mitochondrialunfoldedprotein pages 2-5, wu2018mitochondrialunfoldedprotein pages 1-2, wu2018mitochondrialunfoldedprotein pages 10-13) |
| Developmental timing (L3/L4 window) | Required for establishment of lifespan extension | ETC inhibition including isp-1 RNAi extends lifespan only when imposed during larval development, especially by late L3/early L4; similar perturbation in adults fails to produce longevity, indicating a developmentally programmed mitochondrial checkpoint or signaling window. (rea2007relationshipbetweenmitochondrial pages 1-2, rea2007relationshipbetweenmitochondrial pages 7-8, rea2007relationshipbetweenmitochondrial pages 2-3, rea2007relationshipbetweenmitochondrial pages 6-7) | Rea et al., 2007 (rea2007relationshipbetweenmitochondrial pages 1-2, rea2007relationshipbetweenmitochondrial pages 7-8, rea2007relationshipbetweenmitochondrial pages 2-3, rea2007relationshipbetweenmitochondrial pages 6-7) |
Table: This table summarizes the major signaling pathways and timing requirements linked to isp-1-mediated mitochondrial dysfunction in C. elegans. It distinguishes pathways needed for lifespan extension from those primarily required for development.
Lee, Hwang, and Kenyon (2010) demonstrated that isp-1(qm150) mutants exhibit increased expression of HIF-1-dependent target genes, including nhr-57 and F22B5.4 (lee2010inhibitionofrespiration pages 4-4, lee2010inhibitionofrespiration pages 2-2). Loss of hif-1 or RNAi knockdown of aha-1 (HIF-1β) significantly shortened the extended lifespan of isp-1 mutants, establishing HIF-1 as a key mediator of mitochondrial retrograde longevity signaling (lee2010inhibitionofrespiration pages 2-3, lee2010inhibitionofrespiration pages 2-2). Epistasis experiments showed that isp-1 mutations do not further extend lifespan in vhl-1 or egl-9 mutants (which constitutively stabilize HIF-1), consistent with isp-1 acting upstream of or through the HIF-1 pathway (lee2010inhibitionofrespiration pages 2-2).
Senchuk et al. (2018) found that DAF-16 target genes are significantly enriched among transcripts upregulated in isp-1 mutants, with approximately 50% overlap with genes upregulated in the long-lived insulin/IGF-1 pathway mutant daf-2 (senchuk2018activationofdaf16foxo pages 4-6). DAF-16 shows increased nuclear localization in isp-1 worms, and genetic disruption of daf-16 markedly reduces the lifespan extension (from ~72% to ~19% increase over wild-type) (senchuk2018activationofdaf16foxo pages 9-11). Multiple DAF-16-interacting proteins—including MATH-33, IMB-2 (transportin-1 homolog), CST-1/CST-2 (protein kinases), and BAR-1 (β-catenin homolog)—are required for the full longevity of isp-1 mutants, indicating a complex regulatory network downstream of ROS-mediated DAF-16 activation (senchuk2018activationofdaf16foxo pages 15-17, senchuk2018activationofdaf16foxo pages 1-2).
SKN-1 target genes are also activated in isp-1 mutants, and SKN-1 is required for the increased longevity observed in these animals (senchuk2018activationofdaf16foxo pages 17-18). This indicates that the oxidative stress response mediated by SKN-1/Nrf2 constitutes an additional arm of the mitochondrial retrograde signaling network.
The role of ATFS-1 and the mitoUPR in isp-1 biology is nuanced and somewhat debated. isp-1 mutants exhibit ATFS-1-dependent activation of the mitoUPR, as evidenced by upregulation of the hsp-6p::GFP reporter and endogenous target genes (wu2018mitochondrialunfoldedprotein pages 2-5, bennett2014activationofthe pages 6-6). However, Bennett et al. (2014) demonstrated that knockdown of atfs-1 did not prevent lifespan extension in isp-1(qm150) mutants, leading to the conclusion that the mitoUPR is neither necessary nor sufficient for longevity (bennett2014activationofthe pages 1-2, bennett2014activationofthe pages 7-8). Wu et al. (2018) provided additional resolution by showing that while ATFS-1 is dispensable for adult lifespan maintenance, it is absolutely essential during development—loss of atfs-1 during early development prevents isp-1 worms from reaching adulthood (wu2018mitochondrialunfoldedprotein pages 2-5, wu2018mitochondrialunfoldedprotein pages 1-2). This indicates a stage-specific requirement for mitoUPR activation.
A critical finding from Rea, Ventura, and Johnson (2007) established that mitochondrial dysfunction-dependent life extension requires perturbation during the L3/L4 larval stage, which coincides with the last somatic cell divisions and massive mitochondrial DNA expansion in C. elegans (rea2007relationshipbetweenmitochondrial pages 1-2, rea2007relationshipbetweenmitochondrial pages 7-8, rea2007relationshipbetweenmitochondrial pages 2-3). When isp-1 RNAi or other ETC inhibition is applied only during adulthood, lifespan is not extended, indicating that a developmental signal initiated during the proliferative larval period is essential for programming the longevity phenotype (rea2007relationshipbetweenmitochondrial pages 6-7).
Knowlton et al. (2017) identified isp-1 as one of a select subset of electron transport chain genes required for axon regeneration in C. elegans mechanosensory neurons. isp-1(qm150) mutants showed normal axonal development and growth cone formation after laser axotomy but were impaired in subsequent axon extension (knowlton2017aselectsubset pages 1-2). Critically, pan-neuronal overexpression of isp-1 was sufficient to enhance axon regrowth above wild-type levels, indicating that ISP-1-dependent mitochondrial function is rate-limiting for axon regeneration (knowlton2017aselectsubset pages 12-13, knowlton2017aselectsubset pages 9-11). Loss of isp-1 was epistatic to enhanced calcium signaling (egl-19 gain-of-function) and elevated MAP kinase signaling (DLK-1 overexpression), positioning mitochondrial function downstream of or in parallel with these injury response pathways (knowlton2017aselectsubset pages 8-9, knowlton2017aselectsubset pages 7-8).
Recent work by Rathor et al. (2024) demonstrated that isp-1 knockdown specifically in GABAergic neurons extends organismal lifespan and enhances stress resistance through non-cell autonomous mechanisms (rathor2024mitochondrialstressin pages 10-13, rathor2024mitochondrialstressin pages 40-43). DAF-16/FoxO is essential for mediating these systemic effects on lifespan, stress tolerance, mitochondrial homeostasis, and reproductive capacity. The neuropeptide FLP-13, expressed in GABAergic neurons, was identified as a mediator of this non-cell autonomous aging regulation, with isp-1 knockdown and loss of GABA function operating through the same pathway (rathor2024mitochondrialstressin pages 10-13).
ISP-1 serves as a stabilizer of higher-order respiratory supercomplex assemblies (I:III:IV respirasomes). The isp-1(qm150) mutation disrupts supercomplex formation, thereby impairing not only Complex III activity but also complex I function, and potentially increasing ROS production rates (osz2025mutationsofthe pages 19-21).
isp-1 belongs to a group of C. elegans mitochondrial mutants—alongside clk-1 (ubiquinone biosynthesis), nuo-6 (Complex I subunit), and others—that share the paradoxical property of extending lifespan despite compromised mitochondrial function. Both clk-1 and isp-1 mutants show elevated ROS and require HIF-1 for longevity, though they differ mechanistically: isp-1(qm150) reduces oxygen consumption rate while clk-1(qm30) does not (lee2010inhibitionofrespiration pages 2-3, lee2010inhibitionofrespiration pages 4-4). All three long-lived mitochondrial mutants (clk-1, isp-1, nuo-6) exhibit overlapping transcriptional responses including upregulation of DAF-16 target genes (senchuk2018activationofdaf16foxo pages 1-2).
The isp-1 gene encodes the Rieske iron-sulfur protein, a catalytic subunit of mitochondrial Complex III that is essential for the Q-cycle mechanism of ubiquinol:cytochrome c oxidoreduction. The protein is anchored in the mitochondrial inner membrane by a single transmembrane helix and operates through a "spring-loaded" tether mechanism that enables its 2Fe-2S cluster-containing head domain to shuttle electrons from ubiquinol at the Qo site to cytochrome c1, while simultaneously functioning as a proton-exiting gate. Partial loss of ISP-1 function, as exemplified by the qm150 allele, reduces electron flux through Complex III and triggers a cascade of compensatory mitochondrial retrograde signaling through HIF-1, DAF-16/FOXO, SKN-1/Nrf2, and ATFS-1/mitoUPR pathways—primarily driven by elevated mitochondrial ROS. This signaling, when initiated during a critical developmental window at the L3/L4 larval stage, programs the organism for extended lifespan. Beyond aging, ISP-1 function is rate-limiting for axon regeneration and participates in non-cell autonomous inter-tissue signaling from GABAergic neurons to regulate systemic stress resistance and longevity.
References
(jafari2016newfunctionaland pages 1-4): Gholamali Jafari, Brian M. Wasko, Matt Kaeberlein, and Antony R. Crofts. New functional and biophysical insights into the mitochondrial rieske iron-sulfur protein from genetic suppressor analysis in c. elegans. Worm, 5:6157, Apr 2016. URL: https://doi.org/10.1080/21624054.2016.1174803, doi:10.1080/21624054.2016.1174803. This article has 13 citations.
(osz2025mutationsofthe pages 4-6): Fanni Ősz, Aamir Nazir, Krisztina Takács-Vellai, and Zsolt Farkas. Mutations of the electron transport chain affect lifespan and ros levels in c. elegans. Antioxidants, 14:76, Jan 2025. URL: https://doi.org/10.3390/antiox14010076, doi:10.3390/antiox14010076. This article has 16 citations.
(yang2012rieskeiron–sulfurprotein pages 1-3): Wen‐Chao Yang, Hui Li, Fu Wang, Xiao‐Lei Zhu, and Guang‐Fu Yang. Rieske iron–sulfur protein of the cytochrome bc1 complex: a potential target for fungicide discovery. ChemBioChem, 13:1542-1551, Jul 2012. URL: https://doi.org/10.1002/cbic.201200295, doi:10.1002/cbic.201200295. This article has 28 citations and is from a peer-reviewed journal.
(jafari2016newfunctionaland pages 10-16): Gholamali Jafari, Brian M. Wasko, Matt Kaeberlein, and Antony R. Crofts. New functional and biophysical insights into the mitochondrial rieske iron-sulfur protein from genetic suppressor analysis in c. elegans. Worm, 5:6157, Apr 2016. URL: https://doi.org/10.1080/21624054.2016.1174803, doi:10.1080/21624054.2016.1174803. This article has 13 citations.
(jafari2016newfunctionaland pages 6-8): Gholamali Jafari, Brian M. Wasko, Matt Kaeberlein, and Antony R. Crofts. New functional and biophysical insights into the mitochondrial rieske iron-sulfur protein from genetic suppressor analysis in c. elegans. Worm, 5:6157, Apr 2016. URL: https://doi.org/10.1080/21624054.2016.1174803, doi:10.1080/21624054.2016.1174803. This article has 13 citations.
(jafari2016newfunctionaland pages 4-6): Gholamali Jafari, Brian M. Wasko, Matt Kaeberlein, and Antony R. Crofts. New functional and biophysical insights into the mitochondrial rieske iron-sulfur protein from genetic suppressor analysis in c. elegans. Worm, 5:6157, Apr 2016. URL: https://doi.org/10.1080/21624054.2016.1174803, doi:10.1080/21624054.2016.1174803. This article has 13 citations.
(schmidt2004rieskeiron–sulfurproteins pages 1-2): C. L. Schmidt. Rieske iron–sulfur proteins from extremophilic organisms. Journal of Bioenergetics and Biomembranes, 36:107-113, Feb 2004. URL: https://doi.org/10.1023/b:jobb.0000019602.96578.78, doi:10.1023/b:jobb.0000019602.96578.78. This article has 15 citations and is from a peer-reviewed journal.
(gurung2005theironsulfurcluster pages 1-1): Buddha Gurung, Linda P. C. Yu, D. Xia, and Chang-an Yu. The iron-sulfur cluster of the rieske iron-sulfur protein functions as a proton-exiting gate in the cytochrome bc1 complex*. Journal of Biological Chemistry, 280:24895-24902, Jul 2005. URL: https://doi.org/10.1074/jbc.m503319200, doi:10.1074/jbc.m503319200. This article has 36 citations and is from a domain leading peer-reviewed journal.
(crofts1999physicochemicalaspectsof pages 11-12): Antony R. Crofts, Sangjin Hong, Zhaolei Zhang, and Edward A. Berry. Physicochemical aspects of the movement of the rieske iron sulfur protein during quinol oxidation by the bc(1) complex from mitochondria and photosynthetic bacteria. Biochemistry, 38 48:15827-39, Nov 1999. URL: https://doi.org/10.1021/bi990963e, doi:10.1021/bi990963e. This article has 77 citations and is from a peer-reviewed journal.
(gurung2005theironsulfurcluster pages 5-5): Buddha Gurung, Linda P. C. Yu, D. Xia, and Chang-an Yu. The iron-sulfur cluster of the rieske iron-sulfur protein functions as a proton-exiting gate in the cytochrome bc1 complex*. Journal of Biological Chemistry, 280:24895-24902, Jul 2005. URL: https://doi.org/10.1074/jbc.m503319200, doi:10.1074/jbc.m503319200. This article has 36 citations and is from a domain leading peer-reviewed journal.
(osz2025mutationsofthe pages 19-21): Fanni Ősz, Aamir Nazir, Krisztina Takács-Vellai, and Zsolt Farkas. Mutations of the electron transport chain affect lifespan and ros levels in c. elegans. Antioxidants, 14:76, Jan 2025. URL: https://doi.org/10.3390/antiox14010076, doi:10.3390/antiox14010076. This article has 16 citations.
(lee2010inhibitionofrespiration pages 2-3): Seung-Jae Lee, Ara B. Hwang, and Cynthia Kenyon. Inhibition of respiration extends c. elegans life span via reactive oxygen species that increase hif-1 activity. Current Biology, 20:2131-2136, Dec 2010. URL: https://doi.org/10.1016/j.cub.2010.10.057, doi:10.1016/j.cub.2010.10.057. This article has 614 citations and is from a highest quality peer-reviewed journal.
(lee2010inhibitionofrespiration pages 4-5): Seung-Jae Lee, Ara B. Hwang, and Cynthia Kenyon. Inhibition of respiration extends c. elegans life span via reactive oxygen species that increase hif-1 activity. Current Biology, 20:2131-2136, Dec 2010. URL: https://doi.org/10.1016/j.cub.2010.10.057, doi:10.1016/j.cub.2010.10.057. This article has 614 citations and is from a highest quality peer-reviewed journal.
(lee2010inhibitionofrespiration pages 4-4): Seung-Jae Lee, Ara B. Hwang, and Cynthia Kenyon. Inhibition of respiration extends c. elegans life span via reactive oxygen species that increase hif-1 activity. Current Biology, 20:2131-2136, Dec 2010. URL: https://doi.org/10.1016/j.cub.2010.10.057, doi:10.1016/j.cub.2010.10.057. This article has 614 citations and is from a highest quality peer-reviewed journal.
(lee2010inhibitionofrespiration pages 2-2): Seung-Jae Lee, Ara B. Hwang, and Cynthia Kenyon. Inhibition of respiration extends c. elegans life span via reactive oxygen species that increase hif-1 activity. Current Biology, 20:2131-2136, Dec 2010. URL: https://doi.org/10.1016/j.cub.2010.10.057, doi:10.1016/j.cub.2010.10.057. This article has 614 citations and is from a highest quality peer-reviewed journal.
(senchuk2018activationofdaf16foxo pages 4-6): Megan M. Senchuk, Dylan J. Dues, Claire E. Schaar, Benjamin K. Johnson, Zachary B. Madaj, Megan J. Bowman, Mary E. Winn, and Jeremy M. Van Raamsdonk. Activation of daf-16/foxo by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in caenorhabditis elegans. PLOS Genetics, 14:e1007268, Mar 2018. URL: https://doi.org/10.1371/journal.pgen.1007268, doi:10.1371/journal.pgen.1007268. This article has 187 citations and is from a domain leading peer-reviewed journal.
(senchuk2018activationofdaf16foxo pages 9-11): Megan M. Senchuk, Dylan J. Dues, Claire E. Schaar, Benjamin K. Johnson, Zachary B. Madaj, Megan J. Bowman, Mary E. Winn, and Jeremy M. Van Raamsdonk. Activation of daf-16/foxo by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in caenorhabditis elegans. PLOS Genetics, 14:e1007268, Mar 2018. URL: https://doi.org/10.1371/journal.pgen.1007268, doi:10.1371/journal.pgen.1007268. This article has 187 citations and is from a domain leading peer-reviewed journal.
(senchuk2018activationofdaf16foxo pages 15-17): Megan M. Senchuk, Dylan J. Dues, Claire E. Schaar, Benjamin K. Johnson, Zachary B. Madaj, Megan J. Bowman, Mary E. Winn, and Jeremy M. Van Raamsdonk. Activation of daf-16/foxo by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in caenorhabditis elegans. PLOS Genetics, 14:e1007268, Mar 2018. URL: https://doi.org/10.1371/journal.pgen.1007268, doi:10.1371/journal.pgen.1007268. This article has 187 citations and is from a domain leading peer-reviewed journal.
(senchuk2018activationofdaf16foxo pages 1-2): Megan M. Senchuk, Dylan J. Dues, Claire E. Schaar, Benjamin K. Johnson, Zachary B. Madaj, Megan J. Bowman, Mary E. Winn, and Jeremy M. Van Raamsdonk. Activation of daf-16/foxo by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in caenorhabditis elegans. PLOS Genetics, 14:e1007268, Mar 2018. URL: https://doi.org/10.1371/journal.pgen.1007268, doi:10.1371/journal.pgen.1007268. This article has 187 citations and is from a domain leading peer-reviewed journal.
(senchuk2018activationofdaf16foxo pages 17-18): Megan M. Senchuk, Dylan J. Dues, Claire E. Schaar, Benjamin K. Johnson, Zachary B. Madaj, Megan J. Bowman, Mary E. Winn, and Jeremy M. Van Raamsdonk. Activation of daf-16/foxo by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in caenorhabditis elegans. PLOS Genetics, 14:e1007268, Mar 2018. URL: https://doi.org/10.1371/journal.pgen.1007268, doi:10.1371/journal.pgen.1007268. This article has 187 citations and is from a domain leading peer-reviewed journal.
(bennett2014activationofthe pages 1-2): Christopher F. Bennett, Helen Vander Wende, Marissa Simko, Shannon Klum, Sarah Barfield, Haeri Choi, Victor V. Pineda, and Matt Kaeberlein. Activation of the mitochondrial unfolded protein response does not predict longevity in caenorhabditis elegans. Nature communications, 5:3483-3483, Mar 2014. URL: https://doi.org/10.1038/ncomms4483, doi:10.1038/ncomms4483. This article has 272 citations and is from a highest quality peer-reviewed journal.
(bennett2014activationofthe pages 7-8): Christopher F. Bennett, Helen Vander Wende, Marissa Simko, Shannon Klum, Sarah Barfield, Haeri Choi, Victor V. Pineda, and Matt Kaeberlein. Activation of the mitochondrial unfolded protein response does not predict longevity in caenorhabditis elegans. Nature communications, 5:3483-3483, Mar 2014. URL: https://doi.org/10.1038/ncomms4483, doi:10.1038/ncomms4483. This article has 272 citations and is from a highest quality peer-reviewed journal.
(wu2018mitochondrialunfoldedprotein pages 2-5): Ziyun Wu, Megan M. Senchuk, Dylan J. Dues, Benjamin K. Johnson, Jason F. Cooper, Leira Lew, Emily Machiela, Claire E. Schaar, Heather DeJonge, T. Keith Blackwell, and Jeremy M. Van Raamsdonk. Mitochondrial unfolded protein response transcription factor atfs-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biology, Dec 2018. URL: https://doi.org/10.1186/s12915-018-0615-3, doi:10.1186/s12915-018-0615-3. This article has 140 citations and is from a domain leading peer-reviewed journal.
(wu2018mitochondrialunfoldedprotein pages 1-2): Ziyun Wu, Megan M. Senchuk, Dylan J. Dues, Benjamin K. Johnson, Jason F. Cooper, Leira Lew, Emily Machiela, Claire E. Schaar, Heather DeJonge, T. Keith Blackwell, and Jeremy M. Van Raamsdonk. Mitochondrial unfolded protein response transcription factor atfs-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biology, Dec 2018. URL: https://doi.org/10.1186/s12915-018-0615-3, doi:10.1186/s12915-018-0615-3. This article has 140 citations and is from a domain leading peer-reviewed journal.
(wu2018mitochondrialunfoldedprotein pages 10-13): Ziyun Wu, Megan M. Senchuk, Dylan J. Dues, Benjamin K. Johnson, Jason F. Cooper, Leira Lew, Emily Machiela, Claire E. Schaar, Heather DeJonge, T. Keith Blackwell, and Jeremy M. Van Raamsdonk. Mitochondrial unfolded protein response transcription factor atfs-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biology, Dec 2018. URL: https://doi.org/10.1186/s12915-018-0615-3, doi:10.1186/s12915-018-0615-3. This article has 140 citations and is from a domain leading peer-reviewed journal.
(rea2007relationshipbetweenmitochondrial pages 1-2): Shane L Rea, Natascia Ventura, and Thomas E Johnson. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in caenorhabditis elegans. PLoS Biology, 5:e259, Oct 2007. URL: https://doi.org/10.1371/journal.pbio.0050259, doi:10.1371/journal.pbio.0050259. This article has 475 citations and is from a highest quality peer-reviewed journal.
(rea2007relationshipbetweenmitochondrial pages 7-8): Shane L Rea, Natascia Ventura, and Thomas E Johnson. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in caenorhabditis elegans. PLoS Biology, 5:e259, Oct 2007. URL: https://doi.org/10.1371/journal.pbio.0050259, doi:10.1371/journal.pbio.0050259. This article has 475 citations and is from a highest quality peer-reviewed journal.
(rea2007relationshipbetweenmitochondrial pages 2-3): Shane L Rea, Natascia Ventura, and Thomas E Johnson. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in caenorhabditis elegans. PLoS Biology, 5:e259, Oct 2007. URL: https://doi.org/10.1371/journal.pbio.0050259, doi:10.1371/journal.pbio.0050259. This article has 475 citations and is from a highest quality peer-reviewed journal.
(rea2007relationshipbetweenmitochondrial pages 6-7): Shane L Rea, Natascia Ventura, and Thomas E Johnson. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in caenorhabditis elegans. PLoS Biology, 5:e259, Oct 2007. URL: https://doi.org/10.1371/journal.pbio.0050259, doi:10.1371/journal.pbio.0050259. This article has 475 citations and is from a highest quality peer-reviewed journal.
(bennett2014activationofthe pages 6-6): Christopher F. Bennett, Helen Vander Wende, Marissa Simko, Shannon Klum, Sarah Barfield, Haeri Choi, Victor V. Pineda, and Matt Kaeberlein. Activation of the mitochondrial unfolded protein response does not predict longevity in caenorhabditis elegans. Nature communications, 5:3483-3483, Mar 2014. URL: https://doi.org/10.1038/ncomms4483, doi:10.1038/ncomms4483. This article has 272 citations and is from a highest quality peer-reviewed journal.
(knowlton2017aselectsubset pages 1-2): Wendy M. Knowlton, Thomas Hubert, Zilu Wu, Andrew D. Chisholm, and Yishi Jin. A select subset of electron transport chain genes associated with optic atrophy link mitochondria to axon regeneration in caenorhabditis elegans. Frontiers in Neuroscience, May 2017. URL: https://doi.org/10.3389/fnins.2017.00263, doi:10.3389/fnins.2017.00263. This article has 26 citations and is from a peer-reviewed journal.
(knowlton2017aselectsubset pages 12-13): Wendy M. Knowlton, Thomas Hubert, Zilu Wu, Andrew D. Chisholm, and Yishi Jin. A select subset of electron transport chain genes associated with optic atrophy link mitochondria to axon regeneration in caenorhabditis elegans. Frontiers in Neuroscience, May 2017. URL: https://doi.org/10.3389/fnins.2017.00263, doi:10.3389/fnins.2017.00263. This article has 26 citations and is from a peer-reviewed journal.
(knowlton2017aselectsubset pages 9-11): Wendy M. Knowlton, Thomas Hubert, Zilu Wu, Andrew D. Chisholm, and Yishi Jin. A select subset of electron transport chain genes associated with optic atrophy link mitochondria to axon regeneration in caenorhabditis elegans. Frontiers in Neuroscience, May 2017. URL: https://doi.org/10.3389/fnins.2017.00263, doi:10.3389/fnins.2017.00263. This article has 26 citations and is from a peer-reviewed journal.
(knowlton2017aselectsubset pages 8-9): Wendy M. Knowlton, Thomas Hubert, Zilu Wu, Andrew D. Chisholm, and Yishi Jin. A select subset of electron transport chain genes associated with optic atrophy link mitochondria to axon regeneration in caenorhabditis elegans. Frontiers in Neuroscience, May 2017. URL: https://doi.org/10.3389/fnins.2017.00263, doi:10.3389/fnins.2017.00263. This article has 26 citations and is from a peer-reviewed journal.
(knowlton2017aselectsubset pages 7-8): Wendy M. Knowlton, Thomas Hubert, Zilu Wu, Andrew D. Chisholm, and Yishi Jin. A select subset of electron transport chain genes associated with optic atrophy link mitochondria to axon regeneration in caenorhabditis elegans. Frontiers in Neuroscience, May 2017. URL: https://doi.org/10.3389/fnins.2017.00263, doi:10.3389/fnins.2017.00263. This article has 26 citations and is from a peer-reviewed journal.
(rathor2024mitochondrialstressin pages 10-13): Laxmi Rathor, Shayla Curry, Youngyong Park, Taylor McElroy, Briana Robles, Yi Sheng, Wei-Wen Chen, Kisuk Min, Rui Xiao, Myon Hee Lee, and Sung Min Han. Mitochondrial stress in gabaergic neurons non-cell autonomously regulates organismal health and aging. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.20.585932, doi:10.1101/2024.03.20.585932. This article has 5 citations.
(rathor2024mitochondrialstressin pages 40-43): Laxmi Rathor, Shayla Curry, Youngyong Park, Taylor McElroy, Briana Robles, Yi Sheng, Wei-Wen Chen, Kisuk Min, Rui Xiao, Myon Hee Lee, and Sung Min Han. Mitochondrial stress in gabaergic neurons non-cell autonomously regulates organismal health and aging. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.20.585932, doi:10.1101/2024.03.20.585932. This article has 5 citations.
UniProt: O44512 (O44512_CAEEL) · WormBase: WBGene00002162 / F42G8.12 · NCBI Gene: 177609
Locus: Chromosome IV · Protein: 276 aa · EC 7.1.1.8
isp-1 encodes the Rieske iron-sulfur protein (ISP), the [2Fe-2S]-cluster-bearing
subunit of mitochondrial respiratory complex III (cytochrome bc1 / ubiquinol–cytochrome
c oxidoreductase). Within complex III it accepts electrons from ubiquinol at the Qo site and
passes them to cytochrome c1, as part of the protonmotive Q-cycle.
isp-1-uniprot.txt, RuleBase RU004494/RU004495).interpro/panther/PTHR10134/).isp-1-uniprot.txt: CATALYTIC ACTIVITY, COFACTOR, MISCELLANEOUS "The Rieske protein is aisp-1(qm150) reduces mitochondrial respiration: it shows impairedisp-1(qm150) is a partial (hypomorphic) loss-of-function missense allele. Phenotypes:qm150 substitution in ISP-1 is converted into the elevated-superoxide signal that| # | Term | Evid | Action | Rationale |
|---|---|---|---|---|
| 1 | GO:0016491 oxidoreductase activity | IBA | MODIFY→GO:0009055 | correct but over-general; subunit MF is electron transfer |
| 2 | GO:0045275 respiratory chain complex III | IBA | ACCEPT | core CC (complex membership) |
| 3 | GO:0006122 mito electron transport ubiquinol→cyt c | IBA | ACCEPT | core BP |
| 4 | GO:0005743 mitochondrial inner membrane | IEA | ACCEPT | core CC |
| 5 | GO:0008121 quinol-cytochrome-c reductase activity | IEA | ACCEPT | complex-level MF ISP-1 contributes to (core) |
| 6 | GO:0016020 membrane | IEA | MARK_AS_OVER_ANNOTATED | uninformative; subsumed by GO:0005743 |
| 7 | GO:0051537 2 iron, 2 sulfur cluster binding | IEA | ACCEPT | core MF (defining Rieske cofactor) |
| 8 | GO:1902600 proton transmembrane transport | IEA | KEEP_AS_NON_CORE | Q-cycle proton translocation is a complex-level consequence, not ISP-1's direct MF |
| 9 | GO:0006122 (IMP, PMID:16920626) | IMP | ACCEPT | experimentally supported in worm (complex III respiration defect) |
No aging/longevity/behavioral GO annotations are present in the GOA (they are mutant phenotypes,
not curated normal roles), so none need down-weighting there; the longevity biology is captured
in description and knowledge_gaps only.
id: O44512
gene_symbol: isp-1
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: >-
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.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:16920626
title: Mitochondrial complex I function modulates volatile anesthetic sensitivity
in C. elegans.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Primarily a complex I / volatile anesthetic study, but includes direct
respirometry on the complex III mutant isp-1: it shows diminished
complex II-dependent oxidative phosphorylation, supporting isp-1's role in
mitochondrial respiration. Source of the WormBase IMP annotation to
GO:0006122. PMID and content verified against PubMed and cached full text.
- id: PMID:11709184
title: Mitochondrial electron transport is a key determinant of life span in Caenorhabditis
elegans.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Feng, Bussiere & Hekimi 2001 (Dev Cell). Discovery paper for isp-1(qm150):
identifies the mutation in the C. elegans iron-sulfur protein of complex III
and establishes low oxygen consumption, decreased ROS sensitivity, and
increased lifespan. PubMed-verified (note: an initially mis-recollected PMID,
11740940, is a different Drosophila paper; corrected to 11709184).
- id: PMID:21151885
title: A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis
elegans.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Yang & Hekimi 2010 (PLoS Biol). Establishes that isp-1 (and nuo-6) are
complex III/I subunits whose partial loss decreases electron transport, and
that an elevated mitochondrial superoxide signal is necessary and sufficient
for the longevity. PubMed-verified; full text cached.
- id: PMID:20346072
title: Two modes of mitochondrial dysfunction lead independently to lifespan extension
in Caenorhabditis elegans.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Yang & Hekimi 2010 (Aging Cell). Shows the isp-1(qm150) genomic mutation and
isp-1(RNAi) extend lifespan by distinct, separable mechanisms, and reiterates
the "partial loss-of-function of a complex III subunit" framing. PubMed-verified.
- id: PMID:26504246
title: Tether mutations that restore function and suppress pleiotropic phenotypes
of the C. elegans isp-1(qm150) Rieske iron-sulfur protein.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Jafari et al. 2015 (PNAS, Kaeberlein lab). Structure-function of ISP-1:
intragenic suppressors of qm150 map to a conserved six-residue tether region,
and the authors propose a "spring-loaded" gating model linking a single Rieske
subunit to pleiotropic phenotypes including longevity. Key source for the
knowledge gap. PubMed-verified.
- id: file:worm/isp-1/isp-1-uniprot.txt
title: UniProtKB O44512 (isp-1, C. elegans) - Cytochrome b-c1 complex subunit Rieske,
mitochondrial
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
UniProt entry establishing the Rieske family assignment, EC 7.1.1.8, the
[2Fe-2S] cofactor (one per subunit), and mitochondrion inner membrane
localization used to anchor the cofactor and localization annotations.
- id: file:worm/isp-1/isp-1-deep-research-falcon.md
title: Falcon (Edison) deep research report for C. elegans isp-1
findings: []
reference_review:
relevance: LOW
correctness: UNVERIFIED
review_notes: >-
Machine-generated deep-research narrative used only as a background pointer;
no load-bearing claim in this review depends on it. All substantive claims are
anchored to PubMed-verified primary literature or the UniProt record.
existing_annotations:
- term:
id: GO:0016491
label: oxidoreductase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
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.
action: MODIFY
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.
proposed_replacement_terms:
- id: GO:0009055
label: electron transfer activity
propagation_review:
root_cause: TERM_SCOPING_PROBLEM
failure_modes:
- GRANULARITY_MISMATCH
source_entities:
- source_id: PANTHER:PTN000015358
source_label: Rieske / complex III oxidoreductase node
comment: >-
IBA propagates the broad parent oxidoreductase activity; the correct
subunit-level term is electron transfer activity (GO:0009055).
supported_by:
- reference_id: PMID:26504246
supporting_text: >-
encodes the Rieske iron-sulfur protein subunit of cytochrome c
oxidoreductase (complex III of the electron transport chain)
- term:
id: GO:0045275
label: respiratory chain complex III
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: >-
Core annotation. ISP-1 is the Rieske iron-sulfur subunit of respiratory chain
complex III (cytochrome bc1).
action: ACCEPT
reason: >-
Well established across eukaryotes and in C. elegans; ISP-1 is an integral
catalytic subunit of complex III.
supported_by:
- reference_id: PMID:21151885
supporting_text: subunits of complex I and III of the mitochondrial respiratory
chain
- reference_id: PMID:26504246
supporting_text: complex III of the electron transport chain
- term:
id: GO:0006122
label: mitochondrial electron transport, ubiquinol to cytochrome c
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: >-
Core biological process. Within complex III, ISP-1 transfers electrons from
ubiquinol to cytochrome c1 (and onward to cytochrome c).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:21151885
supporting_text: Partial loss-of-function mutations in these genes decrease
electron transport
- reference_id: file:worm/isp-1/isp-1-deep-research-falcon.md
supporting_text: transfers electrons from ubiquinol to cytochrome c1
- term:
id: GO:0005743
label: mitochondrial inner membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: >-
Core localization. Complex III, including the Rieske subunit, resides in the
mitochondrial inner membrane.
action: ACCEPT
reason: >-
UniProt subcellular location; ISP-1 has a single-pass inner-membrane anchor
with its Rieske head projecting to the intermembrane-space side.
supported_by:
- reference_id: file:worm/isp-1/isp-1-uniprot.txt
supporting_text: "C:mitochondrial inner membrane; IEA:UniProtKB-SubCell"
- term:
id: GO:0008121
label: quinol-cytochrome-c reductase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
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.
action: ACCEPT
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).
supported_by:
- reference_id: file:worm/isp-1/isp-1-uniprot.txt
supporting_text: EC=7.1.1.8
- reference_id: PMID:26504246
supporting_text: subunit of cytochrome c oxidoreductase
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
Uninformative general parent, redundant with the specific and correct
mitochondrial inner membrane annotation (GO:0005743).
action: MARK_AS_OVER_ANNOTATED
reason: >-
"membrane" adds no information beyond the more precise GO:0005743 already
assigned; it is an over-general IEA byproduct.
- term:
id: GO:0051537
label: 2 iron, 2 sulfur cluster binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
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.
action: ACCEPT
reason: >-
UniProt cofactor annotation and Rieske-family conservation; one [2Fe-2S]
cluster is bound per subunit.
supported_by:
- reference_id: file:worm/isp-1/isp-1-uniprot.txt
supporting_text: Binds 1 [2Fe-2S] cluster per subunit
- reference_id: file:worm/isp-1/isp-1-uniprot.txt
supporting_text: The Rieske protein is a high potential 2Fe-2S protein
- term:
id: GO:1902600
label: proton transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: involved_in
review:
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.
action: KEEP_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.
- term:
id: GO:0006122
label: mitochondrial electron transport, ubiquinol to cytochrome c
evidence_type: IMP
original_reference_id: PMID:16920626
qualifier: involved_in
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:16920626
supporting_text_fulltext: in isp-1 (complex III mutant)
full_text_unavailable: true
- reference_id: PMID:16920626
supporting_text_fulltext: somewhat diminished in the complex III ( isp-1 ) mutant
full_text_unavailable: true
core_functions:
- description: >-
Electron-transfer subunit of mitochondrial complex III: within the cytochrome
bc1 complex, ISP-1's mobile Rieske head accepts an electron from ubiquinol at the
Qo site and delivers it to cytochrome c1, the electron-transfer step of the
ubiquinol-cytochrome c reductase (EC 7.1.1.8) reaction in the protonmotive
Q-cycle.
supported_by:
- reference_id: PMID:26504246
supporting_text: >-
encodes the Rieske iron-sulfur protein subunit of cytochrome c
oxidoreductase (complex III of the electron transport chain)
- reference_id: PMID:21151885
supporting_text: subunits of complex I and III of the mitochondrial respiratory
chain
molecular_function:
id: GO:0009055
label: electron transfer activity
contributes_to_molecular_function:
id: GO:0008121
label: quinol-cytochrome-c reductase activity
directly_involved_in:
- id: GO:0006122
label: mitochondrial electron transport, ubiquinol to cytochrome c
locations:
- id: GO:0005743
label: mitochondrial inner membrane
in_complex:
id: GO:0045275
label: respiratory chain complex III
- description: >-
Coordinates the Rieske high-potential [2Fe-2S] cluster (one per subunit), the
redox cofactor that carries out the electron-transfer step of complex III.
supported_by:
- reference_id: file:worm/isp-1/isp-1-uniprot.txt
supporting_text: Binds 1 [2Fe-2S] cluster per subunit
molecular_function:
id: GO:0051537
label: 2 iron, 2 sulfur cluster binding
in_complex:
id: GO:0045275
label: respiratory chain complex III
knowledge_gaps:
- gap_statement: >-
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.
boundary: >-
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.
gap_kind:
- BIOLOGY
dark_aspect: RESIDUAL_SUBGAP
status: OPEN
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.
resolution: >-
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:
- reference_id: PMID:21151885
supporting_text: this elevation is necessary and sufficient to increase longevity
- reference_id: PMID:26504246
supporting_text: points to a common underlying molecular mechanism, for which
we propose a