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A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering.
To, Tsz-Leung; Cuadros, Alejandro M; Shah, Hardik; Hung, Wendy H W; Li, Yang; Kim, Sharon H; Rubin, Daniel H F; Boe, Ryan H; Rath, Sneha; Eaton, John K; Piccioni, Federica; Goodale, Amy; Kalani, Zohra; Doench, John G; Root, David E; Schreiber, Stuart L; Vafai, Scott B; Mootha, Vamsi K.
Afiliação
  • To TL; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Cuadros AM; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Shah H; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Hung WHW; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Li Y; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Kim SH; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Rubin DHF; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Boe RH; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Rath S; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Eaton JK; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Piccioni F; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Goodale A; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Kalani Z; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Doench JG; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Root DE; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Schreiber SL; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • Vafai SB; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Mootha VK; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electro
Cell ; 179(5): 1222-1238.e17, 2019 11 14.
Article em En | MEDLINE | ID: mdl-31730859
ABSTRACT
Mitochondrial dysfunction is associated with a spectrum of human conditions, ranging from rare, inborn errors of metabolism to the aging process. To identify pathways that modify mitochondrial dysfunction, we performed genome-wide CRISPR screens in the presence of small-molecule mitochondrial inhibitors. We report a compendium of chemical-genetic interactions involving 191 distinct genetic modifiers, including 38 that are synthetic sick/lethal and 63 that are suppressors. Genes involved in glycolysis (PFKP), pentose phosphate pathway (G6PD), and defense against lipid peroxidation (GPX4) scored high as synthetic sick/lethal. A surprisingly large fraction of suppressors are pathway intrinsic and encode mitochondrial proteins. A striking example of such "intra-organelle" buffering is the alleviation of a chemical defect in complex V by simultaneous inhibition of complex I, which benefits cells by rebalancing redox cofactors, increasing reductive carboxylation, and promoting glycolysis. Perhaps paradoxically, certain forms of mitochondrial dysfunction may best be buffered with "second site" inhibitors to the organelle.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genes Modificadores / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genes Modificadores / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos