title: A Small Molecule That Protects the Integrity of the Electron Transfer Chain Blocks the Mitochondrial Apoptotic Pathway.
abstract: In response to apoptotic stimuli, mitochondria in mammalian cells release cytochrome c and other apoptogenic proteins, leading to the subsequent activation of caspases and apoptotic cell death. This process is promoted by the pro-apoptotic members of the Bcl-2 family of proteins, such as Bim and Bax, which, respectively, initiate and execute cytochrome c release from the mitochondria. Here we report the discovery of a small molecule that efficiently blocks Bim-induced apoptosis after Bax is activated on the mitochondria. The cellular target of this small molecule was identified to be the succinate dehydrogenase subunit B (SDHB) protein of complex II of the mitochondrial electron transfer chain (ETC). The molecule protects the integrity of the ETC and allows treated cells to continue to proliferate after apoptosis induction. Moreover, this molecule blocked dopaminergic neuron death and reversed Parkinson-like behavior in a rat model of Parkinson's disease.
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Ying
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Chenjie
authors.initials: C
authors.lastname: Pan
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Shaoqiang
authors.initials: S
authors.lastname: Huang
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Dai
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China. Electronic address: wangxiaodong@nibs.ac.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D011485:Protein Binding; D011728:Pyridones / Q000378:metabolism* / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000378:metabolism* / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C000622061:1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one; D000978:Antiparkinson Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D018696:Neuroprotective Agents; D011728:Pyridones; D013450:Sulfones; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D016627:Oxidopamine; D045304:Cytochromes c; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase