Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.

C. elegans NADH:ubiquinone oxidoreductase NDUFA6 NDUFS4 complex I electron transport chain hyperoxia hypoxia mitochondria oxygen

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
05 Jan 2024
Historique:
received: 20 02 2023
revised: 09 09 2023
accepted: 05 12 2023
medline: 13 1 2024
pubmed: 13 1 2024
entrez: 12 1 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2023.12.010 PMID: 38215760
pubmed: 38215760
pii: S0092-8674(23)01342-9
doi: 10.1016/j.cell.2023.12.010
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests V.K.M. is listed as an inventor on patents filed by MGH on therapeutic uses of hypoxia. V.K.M. is a paid advisor to 5am Ventures. O.S.S. was a paid consultant for Proteinaceous, Inc. V.K.M. is on the Advisory Board at Cell.

Auteurs

Joshua D Meisel (JD)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

Maria Miranda (M)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

Owen S Skinner (OS)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

Presli P Wiesenthal (PP)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.

Sandra M Wellner (SM)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

Alexis A Jourdain (AA)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

Gary Ruvkun (G)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: ruvkun@molbio.mgh.harvard.edu.

Vamsi K Mootha (VK)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: vamsi_mootha@hms.harvard.edu.

Classifications MeSH