A small molecule protects mitochondrial integrity by inhibiting mTOR activity.

Abstract

Apoptosis activation by cytochrome c release from mitochondria to cytosol is a normal cellular response to mitochondrial damage. Using cellular apoptosis assay, we have found small-molecule apoptosis inhibitors that protect cells from mitochondrial damage. Previously, we reported the discovery of a small molecule, Compound A, which blocks dopaminergic neuron death in a rat model of Parkinson's disease through targeting succinate dehydrogenase subunit B (SDHB) of complex II to protect the integrity of the mitochondrial respiratory chain. Here, we report a small molecule, Compound R6, which saves cells from apoptosis via mammalian target of rapamycin (mTOR)-mediated induction of autophagy. Additionally, we show that Compound R6 protects mitochondrial integrity and respiration after induction of the intrinsic apoptosis pathway. Encouragingly, and supporting the potential further application of Compound R6 as a tool for basic and medicinal research, a pharmacokinetics (PK) profiling study showed that Compound R6 is metabolically stable and can pass the blood-brain barrier. Moreover, Compound R6 accumulates in the brain of test animals via intravenous and intraperitoneal administration. Finally, we found that Compound R6 confers significant neuroprotective effects on a rat cerebral ischemia/reperfusion model, demonstrating its potential as a promising drug candidate for neurodegenerative diseases.

• Authors: Ran Cao, Li Li, Zhengxin Ying, Zichen Cao, Yongfen Ma, Xiaoxu Mao, Jiaojiao Li, Xiangbing Qi, Zhiyuan Zhang, Xiaodong Wang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 46 Pg. 23332-23338 (11 12 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31653761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bcl-2-Like Protein 11
• Bcl2l11 protein, rat
• Neuroprotective Agents
• mTOR protein, rat
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Bcl-2-Like Protein 11 (metabolism)
• Drug Evaluation, Preclinical
• Male
• Mitochondria (drug effects)
• Neurodegenerative Diseases (drug therapy)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• TOR Serine-Threonine Kinases (antagonists & inhibitors)