A Small Molecule That Protects the Integrity of the Electron Transfer Chain Blocks the Mitochondrial Apoptotic Pathway

Xian Jiang; Li Li; Zhengxin Ying; Chenjie Pan; Shaoqiang Huang; Lin Li; Miaomiao Dai; Bo Yan; Ming Li; Hui Jiang; She Chen; Zhiyuan Zhang; Xiaodong Wang

doi:10.1016/j.molcel.2016.06.016

A Small Molecule That Protects the Integrity of the Electron Transfer Chain Blocks the Mitochondrial Apoptotic Pathway

Mol Cell. 2016 Jul 21;63(2):229-239. doi: 10.1016/j.molcel.2016.06.016.

Authors

Xian Jiang¹, Li Li², Zhengxin Ying¹, Chenjie Pan¹, Shaoqiang Huang¹, Lin Li¹, Miaomiao Dai¹, Bo Yan¹, Ming Li¹, Hui Jiang¹, She Chen¹, Zhiyuan Zhang¹, Xiaodong Wang³

Affiliations

¹ National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
² School of Life Sciences, Peking University, Beijing 100871, China.
³ National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China. Electronic address: [email protected].

PMID: 27447985
DOI: 10.1016/j.molcel.2016.06.016

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.

Publication types

Video-Audio Media
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiparkinson Agents / metabolism
Antiparkinson Agents / pharmacology*
Apoptosis / drug effects*
Bcl-2-Like Protein 11 / metabolism
Behavior, Animal / drug effects
Cell Proliferation / drug effects
Cytochromes c / metabolism
Disease Models, Animal
Dopaminergic Neurons / drug effects*
Dopaminergic Neurons / metabolism
Dopaminergic Neurons / pathology
Dose-Response Relationship, Drug
Electron Transport
HeLa Cells
Humans
Mitochondria / drug effects*
Mitochondria / metabolism
Mitochondria / pathology
Motor Activity / drug effects
Neuroprotective Agents / metabolism
Neuroprotective Agents / pharmacology*
Oxidopamine
Parkinsonian Disorders / metabolism
Parkinsonian Disorders / pathology
Parkinsonian Disorders / prevention & control*
Parkinsonian Disorders / psychology
Protein Binding
Pyridones / metabolism*
Pyridones / pharmacology*
RNA Interference
Rats
Signal Transduction / drug effects
Succinate Dehydrogenase / genetics
Succinate Dehydrogenase / metabolism*
Sulfones / metabolism*
Sulfones / pharmacology*
Time Factors
Transfection
bcl-2 Homologous Antagonist-Killer Protein / metabolism
bcl-2-Associated X Protein / metabolism

Substances

1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one
Antiparkinson Agents
BAK1 protein, human
BAX protein, human
BCL2L11 protein, human
Bcl-2-Like Protein 11
Neuroprotective Agents
Pyridones
Sulfones
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Oxidopamine
Cytochromes c
SDHB protein, human
Succinate Dehydrogenase