Reference - Detail
| RRC ID | 80830 |
|---|---|
| Author | Meisel JD, Miranda M, Skinner OS, Wiesenthal PP, Wellner SM, Jourdain AA, Ruvkun G, Mootha VK. |
| Title | Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism. |
| Journal | Cell |
| Abstract |
The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia. |
| Volume | 187(3) |
| Pages | 659-675.e18 |
| Published | 2024-2-1 |
| DOI | 10.1016/j.cell.2023.12.010 |
| PII | S0092-8674(23)01342-9 |
| PMID | 38215760 |
| PMC | PMC10919891 |
| MeSH | Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Electron Transport Complex I* / metabolism Hypoxia* / genetics Hypoxia* / metabolism Mice Mitochondria / genetics Mitochondria / metabolism Oxygen / metabolism |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | X(Twitter) |
| Total number of mentions | 66 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm5258 tm2751 tm1436 |