Suppressors of Superoxide-H2O2Production at Site IQof Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury.
Using high-throughput screening we identified small molecules that suppress superoxide and/or H2O2production during reverse electron transport through mitochondrial respiratory complex I (site IQ) without affecting oxidative phosphorylation (suppressors of site IQelectron leak, "S1QELs"). S1QELs diminished endogenous oxidative damage in primary astrocytes cultured at ambient or low oxygen tension, showing that site IQis a normal contributor to mitochondrial superoxide-H2O2production in cells. They diminished stem cell hyperplasia in Drosophila intestine in vivo and caspase activation in a cardiomyocyte cell model driven by endoplasmic reticulum stress, showing that superoxide-H2O2production by site IQis involved in cellular stress signaling. They protected against ischemia-reperfusion injury in perfused mouse heart, showing directly that superoxide-H2O2production by site IQis a major contributor to this pathology. S1QELs are tools for assessing the contribution of site IQto cell physiology and pathology and have great potential as therapeutic leads.
Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: mbrand@buckinstitute.org.
Martin D
MD
Brand
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Renata L S
RL
Goncalves
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Adam L
AL
Orr
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Leonardo
L
Vargas
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Akos A
AA
Gerencser
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Martin
M
Borch Jensen
Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Yves T
YT
Wang
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Simon
S
Melov
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Carolina N
CN
Turk
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Jason T
JT
Matzen
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Victoria J
VJ
Dardov
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
H Michael
HM
Petrassi
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Shelly L
SL
Meeusen
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Irina V
IV
Perevoshchikova
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Heinrich
H
Jasper
Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Paul S
PS
Brookes
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Edward K
EK
Ainscow
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004330:Drosophila / Q000187:drug effects / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006965:Hyperplasia; D007422:Intestines / Q000166:cytology; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D013481:Superoxides / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology
D013481:Superoxides; D014415:Tunicamycin; D006861:Hydrogen Peroxide; D053148:Caspase 3; D053179:Caspase 7; D042967:Electron Transport Complex I
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