Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells.

Autor: Joshi PR; Broad Institute, Cambridge, Massachusetts, USA; Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA., Sadre S; Broad Institute, Cambridge, Massachusetts, USA; Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA., Guo XA; Broad Institute, Cambridge, Massachusetts, USA; Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA., McCoy JG; Broad Institute, Cambridge, Massachusetts, USA; Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA., Mootha VK; Broad Institute, Cambridge, Massachusetts, USA; Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: vamsi@hms.harvard.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2023 Sep; Vol. 299 (9), pp. 105075. Date of Electronic Publication: 2023 Jul 20.
DOI: 10.1016/j.jbc.2023.105075
Abstrakt: Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins are the ferredoxin (FDX) family of electron carriers. Humans have two FDXs- FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but FDXs were not included in that study. Here, we report that FDX1, but not FDX2, is dispensable under 1% O 2 in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC-containing enzyme lipoyl synthase. While hypoxia can rescue the growth phenotype of either FDX1 or lipoyl synthase KO cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.
Competing Interests: Conflict of interest V. K. M. is on the scientific advisory board of Janssen Pharmaceuticals and 5AM Ventures. V. K. M. is listed as an inventor on a patent application filed by Massachusetts General Hospital on the use of hypoxia as a therapy for mitochondrial and degenerative diseases.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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