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Cell Rep DOI:10.1016/j.celrep.2014.02.046

Inhibition of ATPIF1 ameliorates severe mitochondrial respiratory chain dysfunction in mammalian cells.

Publication TypeJournal Article
Year of Publication2014
AuthorsChen, WW, Birsoy, K, Mihaylova, MM, Snitkin, H, Stasinski, I, Yucel, B, Bayraktar, EC, Carette, JE, Clish, CB, Brummelkamp, TR, Sabatini, DD, Sabatini, DM
JournalCell Rep
Date Published2014 Apr 10
KeywordsAntimycin A, DNA, Mitochondrial, Electron Transport, Hepatocytes, Humans, Mitochondria, Oxidation-Reduction, Oxidative Phosphorylation, Oxidative Stress, Proteins

Mitochondrial respiratory chain disorders are characterized by loss of electron transport chain (ETC) activity. Although the causes of many such diseases are known, there is a lack of effective therapies. To identify genes that confer resistance to severe ETC dysfunction when inactivated, we performed a genome-wide genetic screen in haploid human cells with the mitochondrial complex III inhibitor antimycin. This screen revealed that loss of ATPIF1 strongly protects against antimycin-induced ETC dysfunction and cell death by allowing for the maintenance of mitochondrial membrane potential. ATPIF1 loss protects against other forms of ETC dysfunction and is even essential for the viability of human ρ° cells lacking mitochondrial DNA, a system commonly used for studying ETC dysfunction. Importantly, inhibition of ATPIF1 ameliorates complex III blockade in primary hepatocytes, a cell type afflicted in severe mitochondrial disease. Altogether, these results suggest that inhibition of ATPIF1 can ameliorate severe ETC dysfunction in mitochondrial pathology.


Alternate JournalCell Rep
PubMed ID24685140
PubMed Central IDPMC4040975
Grant ListR01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
F30 AG046047 / AG / NIA NIH HHS / United States
AI07389 / AI / NIAID NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
CA129105 / CA / NCI NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
T32 AI007389 / AI / NIAID NIH HHS / United States