Manganese-driven CoQ deficiency.

Autor: Diessl J; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden., Berndtsson J; Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden., Broeskamp F; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden., Habernig L; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden., Kohler V; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden., Vazquez-Calvo C; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden.; Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden., Nandy A; Institute of Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, 79104, Freiburg, Germany.; Faculty of Biology, University of Freiburg, 79104, Freiburg, Germany.; Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104, Freiburg, Germany., Peselj C; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden., Drobysheva S; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden., Pelosi L; Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France., Vögtle FN; Institute of Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, 79104, Freiburg, Germany.; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104, Freiburg, Germany.; Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, 69120, Heidelberg, Germany.; Network Aging Research, Heidelberg University, 69120, Heidelberg, Germany., Pierrel F; Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France., Ott M; Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden.; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 40530, Gothenburg, Sweden., Büttner S; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden. sabrina.buettner@su.se.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 13; Vol. 13 (1), pp. 6061. Date of Electronic Publication: 2022 Oct 13.
DOI: 10.1038/s41467-022-33641-x
Abstrakt: Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: