Molecular mechanism of the ischemia-induced regulatory switch in mammalian complex I

• 成果类型: Article
• 署名作者: Grba, Daniel N.; Wright, John J.; Yin, Zhan; Fisher, William; Hirst, Judy
• 署名单位: University of Cambridge; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); University of Cambridge
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9975
• DOI: 10.1126/science.ado2075
• 发表日期: 2024-06-14
• 页码: 1247-1253
• 关键词: nadh-ubiquinone oxidoreductase; active-inactive transition; beam-induced motion; cryo-em; coupling mechanism; subunit; binding; mitochondria; orientation; reduction

摘要

Respiratory complex I is an efficient driver for oxidative phosphorylation in mammalian mitochondria, but its uncontrolled catalysis under challenging conditions leads to oxidative stress and cellular damage. Ischemic conditions switch complex I from rapid, reversible catalysis into a dormant state that protects upon reoxygenation, but the molecular basis for the switch is unknown. We combined precise biochemical definition of complex I catalysis with high-resolution cryo-electron microscopy structures in the phospholipid bilayer of coupled vesicles to reveal the mechanism of the transition into the dormant state, modulated by membrane interactions. By implementing a versatile membrane system to unite structure and function, attributing catalytic and regulatory properties to specific structural states, we define how a conformational switch in complex I controls its physiological roles.