A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering.
Autoantigens
/ metabolism
Cell Death
/ drug effects
Cytosol
/ drug effects
Electron Transport Complex I
/ metabolism
Epistasis, Genetic
/ drug effects
Ferroptosis
/ drug effects
Genes, Modifier
Genome
Glutathione Peroxidase
/ metabolism
Glycolysis
/ drug effects
Humans
K562 Cells
Mitochondria
/ drug effects
Oligomycins
/ toxicity
Oxidation-Reduction
Oxidative Phosphorylation
/ drug effects
Pentose Phosphate Pathway
/ drug effects
Reactive Oxygen Species
/ metabolism
Ribonucleoproteins
/ metabolism
SS-B Antigen
CRISPR screening
G6PD
GPX4
LARP1
complex I
genetic modifier
metformin
mitochondria
redox cofactors
reductive carboxylation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
14 11 2019
14 11 2019
Historique:
received:
21
01
2019
revised:
12
09
2019
accepted:
23
10
2019
entrez:
16
11
2019
pubmed:
16
11
2019
medline:
27
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31730859
pii: S0092-8674(19)31182-1
doi: 10.1016/j.cell.2019.10.032
pmc: PMC7053407
mid: NIHMS1542953
pii:
doi:
Substances chimiques
Autoantigens
0
Oligomycins
0
Reactive Oxygen Species
0
Ribonucleoproteins
0
Glutathione Peroxidase
EC 1.11.1.9
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1222-1238.e17Subventions
Organisme : NCI NIH HHS
ID : K00 CA212468
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122455
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published by Elsevier Inc.
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