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

ABSTRACT: Iron sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environment sensing, and catalysis. Amongst the most ancient ISC containing proteins are the ferredoxin family of electron carriers. Humans have two ferredoxins, FDX1 and FDX2, localized to the mitochondria and important for ISC synthesis itself. We previously showed that hypoxia can bypass the requirement for some, but not all, components of the ISC biosynthetic pathway, but ferredoxins were not tested at that time. Here we report that FDX1 and its reductase FDXR, but not FDX2, are dispensable under ambient 1% O2 in cultured cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC containing enzyme lipoyl synthase (LIAS). While hypoxia can rescue the growth phenotype of either FDX1 or LIAS knockout cells, lipoylation is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work identifies a role for FDX1/LIAS in lipoate synthesis and surprisingly reveals dispensability of lipoic acid altogether under low oxygen tensions in cell culture.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver, Epithelial Cell

DISEASE(S): Hepatocellular Carcinoma

SUBMITTER: Xiaoyan Guo

LAB HEAD: Vamsi K.

PROVIDER: PXD042589 | Pride | 2023-07-28

REPOSITORIES: Pride

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