Suppressors of Superoxide-H2O2 Production at Site IQ of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury

被引：173

作者：

Brand, Martin D. ^{[1
]}

Goncalves, Renata L. S. ^{[1
,4
]}

Orr, Adam L. ^{[1
,5
]}

Vargas, Leonardo ^{[2
]}

Gerencser, Akos A. ^{[1
]}

Jensen, Martin Borch ^{[1
]}

Wang, Yves T. ^{[3
]}

Melov, Simon ^{[1
]}

Turk, Carolina N. ^{[2
]}

Matzen, Jason T. ^{[2
]}

Dardov, Victoria J. ^{[2
]}

Petrassi, H. Michael ^{[2
]}

Meeusen, Shelly L. ^{[2
]}

Perevoshchikova, Irina V. ^{[1
,6
]}

Jasper, Heinrich ^{[1
]}

Brookes, Paul S. ^{[3
]}

Ainscow, Edward K. ^{[2
]}

机构：

[1] Buck Inst Res Aging, Novato, CA 94945 USA

[2] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[3] Univ Rochester, Med Ctr, Dept Anesthesiol, Rochester, NY 14642 USA

[4] TH Chan Harvard Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[5] Gladstone Inst, San Francisco, CA 94158 USA

[6] BioMarin Pharmaceut Inc, San Rafael, CA 94901 USA

来源：

CELL METABOLISM | 2016年 / 24卷 / 04期

关键词：

HYDROGEN-PEROXIDE PRODUCTION; OXYGEN SPECIES GENERATION; SUPEROXIDE/HYDROGEN PEROXIDE; BINDING SITE; LIFE-SPAN; DROSOPHILA; ROS; DEHYDROGENASE; RATES; HOMEOSTASIS;

D O I：

10.1016/j.cmet.2016.08.012

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Using high-throughput screening we identified small molecules that suppress superoxide and/or H2O2 production during reverse electron transport through mitochondrial respiratory complex I (site I-Q) without affecting oxidative phosphorylation (suppressors of site I-Q electron leak, "S1QELs"). S1QELs diminished endogenous oxidative damage in primary astrocytes cultured at ambient or low oxygen tension, showing that site I-Q is a normal contributor to mitochondrial superoxide-H2O2 production 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-H2O2 production by site I-Q is involved in cellular stress signaling. They protected against ischemia-reperfusion injury in perfused mouse heart, showing directly that superoxide-H2O2 production by site I-Q is a major contributor to this pathology. S1QELs are tools for assessing the contribution of site I-Q to cell physiology and pathology and have great potential as therapeutic leads.

引用

页码：582 / 592

页数：11

共 34 条

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