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Cell Rep. 2014 Apr 10;7(1):27-34. doi: 10.1016/j.celrep.2014.02.046. Epub 2014 Mar 27.

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

Author information

1
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
2
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
3
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA.
5
Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121 1066 CX, Amsterdam, the Netherlands.
6
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Electronic address: sabatini@wi.mit.edu.

Abstract

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.

PMID:
24685140
PMCID:
PMC4040975
DOI:
10.1016/j.celrep.2014.02.046
[Indexed for MEDLINE]
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