title: Inhibition of ATPIF1 ameliorates severe mitochondrial respiratory chain dysfunction in mammalian cells.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine 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.
authors.forename: Walter W
authors.initials: WW
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research, Nine 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.
authors.forename: Kivanc
authors.initials: K
authors.lastname: Birsoy
authors.affiliation: Whitehead Institute for Biomedical Research, Nine 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.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mihaylova
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, 10016, USA.
authors.forename: Harriet
authors.initials: H
authors.lastname: Snitkin
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, 10016, USA.
authors.forename: Iwona
authors.initials: I
authors.lastname: Stasinski
authors.affiliation: Whitehead Institute for Biomedical Research, Nine 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.
authors.forename: Burcu
authors.initials: B
authors.lastname: Yucel
authors.affiliation: Whitehead Institute for Biomedical Research, Nine 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.
authors.forename: Erol C
authors.initials: EC
authors.lastname: Bayraktar
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Carette
authors.affiliation: Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121 1066 CX, Amsterdam, The Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, 10016, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Sabatini
authors.affiliation: Whitehead Institute for Biomedical Research, Nine 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000378:metabolism; D004579:Electron Transport; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
chemical_list: D000968:Antimycin A; D004272:DNA, Mitochondrial; D011506:Proteins; D000097795:ATPase Inhibitory Protein; C032456:antimycin