Research News
In July 21st issue of Molecular Cell,Xiaodong Wang and Zhiyuan Zhang’s lab collaborated in publishing the feature article entitled” A Small Molecule That Protects the Integrity of the Electron Transfer Chain Blocks the Mitochondrial Apoptotic Pathway"
In July 21st issue of Molecular Cell, NIBS Xiaodong Wang and Zhiyuan Zhang’s lab collaborated in publishing the feature article entitled” A Small Molecule That Protects the Integrity of the Electron Transfer Chain Blocks the Mitochondrial Apoptotic Pathway”. In this article, their labs described for the first time, a small molecule compound targeting the electron transfer chain of mitochondria, is able to block apoptosis.
20 years ago, Xiaodong Wang’s laboratory reported that a component of electron transfer chain, cytochrome c, is also an apoptotic proteases, caspases, activator when released from mitochondria to the cytosol. Subsequently, they delineated a biochemical pathway through which the released cytochrome c activates apoptotic caspases. However, how cytochrome c is released from mitochondria in response to apoptotic stimuli remains to be the unresolved question in apoptosis research.
Previous works from several labs, notably the late Stanley Korsmeyer lab at Harvard medical School have demonstrated that Bax and Bak proteins might be the “gateway” for cytochrome c to come out mitochondria once Bax and Bak are activated by the so-called BH3-only protein like Bim or tBid. The activated Bax and Bak manifest as higher order of protein complexes (oligomer), which was perceived as a protein channel or pore that allows cytochrome c to pass through.
Several years ago, we established a cell-based apoptosis system in which Bim or tBid can be inducibly expressed that induces apoptosis in a robust and synchronized fashion. Using this system, we have demonstrated that mitochondrial protease OMA1, through cleavage of OPA1, causes mitochondrial inner membrane cristae remodeling and such events inside mitochondria are required for cytochrome c release (Jiang et al., PNAS, 2014).
The same apoptosis system was also used for chemical library screen. The compounds from more than 200,000 compound library that are able to block apoptosis were further characterized and improved by medicinal chemistry to yield a highly potent compound that can block apoptosis by preventing cytochrome c release and OMA1 activation but not Bax and Bak activation, indicating that the compound woks inside mitochondria.
As reported as a cover story of this issue of Molecular Cell, Jiang et al demonstrated that the target identified through an affinity probe is a component of complex II of the electron transfer chain, succinate dehydrogenase subunit B. By forming a covalent interaction with SDHB, the compound prevents electron transfer chain super-complex disassembly during apoptosis and keeps the electron transfer chain functioning after Bax and Bak activation.
The compound is the first of its kind that can keep the cells alive for long term under apoptotic insults. The compound has demonstrated efficacy in a rat Parkinson disease model.
Xian Jiang from Xiaodong Wang’s lab performed high throughput compound screening and initial compound characterization with the help of the Chemical Screening Core facility of the Department of Biochemistry, UT-Southwestern and Dr. Hui Jiang. Li Li and Shaoqiang Huang in Zhiyuan Zhang’s lab did the medicinal chemistry that yield the compound and the affinity probe used in this paper. Lin Li and She Chen did the mass spec analysis that identified the binding site of the compound. Zhengxin Ying and Chenjie Pan performed Parkinson disease experiment; Bo ZhangYan, Ming Li and Miaomiao Dai also contributed to the paper.
