isp-1 (C. elegans) — Gene Review Notes

UniProt: O44512 (O44512_CAEEL) · WormBase: WBGene00002162 / F42G8.12 · NCBI Gene: 177609
Locus: Chromosome IV · Protein: 276 aa · EC 7.1.1.8

Summary / identity

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.

• UniProt names it "Cytochrome b-c1 complex subunit Rieske, mitochondrial"; EC 7.1.1.8;
  belongs to the Rieske iron-sulfur protein family; binds 1 [2Fe-2S] cluster per subunit;
  localized to the mitochondrion inner membrane (isp-1-uniprot.txt, RuleBase RU004494/RU004495).
• PANTHER family PTHR10134 "CYTOCHROME B-C1 COMPLEX SUBUNIT RIESKE, MITOCHONDRIAL"
  (interpro/panther/PTHR10134/).
• Independent literature confirmation of identity: "The Caenorhabditis elegans isp-1 gene
  encodes the Rieske iron-sulfur protein subunit of cytochrome c oxidoreductase (complex III of
  the electron transport chain)." PMID:26504246
• "The nuo-6 and isp-1 genes of C. elegans encode, respectively, subunits of complex I and III
  of the mitochondrial respiratory chain." PMID:21151885

KNOWN (well established)

Core molecular function / localization

• Rieske [2Fe-2S] iron-sulfur subunit of complex III; electron transfer from ubiquinol to
  cytochrome c1; part of the ubiquinol–cytochrome c reductase reaction (EC 7.1.1.8).
  Cofactor: one [2Fe-2S] cluster (Rieske high-potential type). Source: UniProt
  (isp-1-uniprot.txt: CATALYTIC ACTIVITY, COFACTOR, MISCELLANEOUS "The Rieske protein is a
  high potential 2Fe-2S protein"), Rieske-family conservation (PANTHER PTHR10134, InterPro
  IPR017941 Rieske_2Fe-2S). Reactome R-CEL-611105 (Respiratory electron transport),
  R-CEL-9865881 (Complex III assembly).
• Mitochondrial inner membrane localization (UniProt SUBCELLULAR LOCATION; single-pass membrane
  anchor + Rieske catalytic head).

Biological process (respiration) — experimentally supported in worm

• The complex III mutant isp-1(qm150) reduces mitochondrial respiration: it shows impaired
  complex I-dependent (malate) and diminished complex II-dependent (succinate) oxidative
  phosphorylation capacity — expected because complex III is the common downstream acceptor.
  PMID:16920626 and
  PMID:16920626. This is the basis of
  the WormBase IMP annotation to GO:0006122.

The isp-1(qm150) longevity mutant (downstream phenotype, NOT the core MF)

• isp-1(qm150) is a partial (hypomorphic) loss-of-function missense allele. Phenotypes:
  "low oxygen consumption, decreased sensitivity to ROS, and increased life span."
  PMID:11709184
• It is one of the classic Mit longevity mutants: "longevity is increased by a partial
  loss-of-function mutation in the mitochondrial complex III subunit gene isp-1."
  PMID:20346072
• Additional pleiotropic phenotypes of qm150 (developmental rate, pharyngeal pumping, brood
  size, movement, constitutive UPR-mt reporter, CO2 production, OXPHOS, lifespan). PMID:26504246
• Mechanism of longevity is a mitohormetic superoxide signal, not reduced oxidative damage:
  "the generation of superoxide is elevated in the nuo-6 and isp-1 mitochondrial mutants ...
  this elevation is necessary and sufficient to increase longevity." PMID:21151885 and PMID:21151885
• qm150 mutation and isp-1(RNAi) act via distinct, separable mechanisms (additive lifespan
  effects). PMID:20346072

NOT KNOWN / knowledge gaps

• Mechanism linking the Rieske perturbation to the retrograde longevity signal. How the
  specific qm150 substitution in ISP-1 is converted into the elevated-superoxide signal that
  drives the pro-longevity transcriptional program is not molecularly defined. Kaeberlein and
  colleagues localized intragenic suppressors to a conserved six-residue "tether" region and
  proposed a "spring-loaded" gating model, but this is a hypothesis: "The focus on a single
  subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes
  points to a common underlying molecular mechanism, for which we propose a 'spring-loaded'
  model." PMID:26504246. The causal chain from tether-region dynamics
  → altered Qo-site electron transfer/superoxide → downstream gene expression remains open
  (BIOLOGY gap, RESIDUAL_SUBGAP; the textbook complex III function itself is solid).
• Whether ISP-1 has any function beyond complex III electron transfer (moonlighting) is not
  established; no evidence supports one, and none is claimed here.

GOA annotation review plan (9 annotations)

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.

References verified against PubMed (identity confirmed)

• PMID:11709184 — Feng, Bussière, Hekimi 2001 Dev Cell 1:633-44 (isp-1(qm150) discovery). VERIFIED.
  NOTE: my first guessed PMID "11740940" for this paper was WRONG (that PMID is a Drosophila
  neuralized paper); corrected to 11709184 via PubMed search + metadata.
• PMID:21151885 — Yang & Hekimi 2010 PLoS Biol 8:e1000556 (superoxide longevity signal). VERIFIED, full text.
• PMID:20346072 — Yang & Hekimi 2010 Aging Cell 9:433-47 (two modes; qm150 vs RNAi). VERIFIED.
• PMID:26504246 — Jafari...Kaeberlein 2015 PNAS 112:E6148-57 (tether suppressors; spring-loaded model). VERIFIED.
• PMID:16920626 — Falk et al 2006 Curr Biol 16:1641-5 (complex III mutant respiration; IMP source). VERIFIED, full text.