Bose Himangshu S, Marshall Brendan, Debnath Dilip K, Perry Elizabeth W, Whittal Randy M
Biomedical Sciences, Mercer U School of Medicine, Memorial University Medical Center, 1250 East 66th Street, Savannah, GA 31404, USA; Anderson Cancer Institute, Savannah, GA, USA.
Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA.
iScience. 2020 Jul 24;23(7):101295. doi: 10.1016/j.isci.2020.101295. Epub 2020 Jun 20.
The first steroidogenic enzyme, cytochrome P450-side-chain-cleavage (SCC), requires electron transport chain (ETC) complexes III and IV to initiate steroid metabolic processes for mammalian survival. ETC complex II, containing succinate dehydrogenase (quinone), acts with the TCA cycle and has no proton pumping capacity. We show that complex II is required for SCC activation through the proton pump, generating an intermediate state for addition of phosphate by succinate. Phosphate anions in the presence of succinate form a stable mitochondrial complex with higher enthalpy (-ΔH) and enhanced activity. Inhibition of succinate action prevents SCC processing at the intermediate state and ablates activity and mitochondrial protein network. This is the first report directly showing that a protein intermediate state is activated by succinate, facilitating the ETC complex II to interact with complexes III and IV for continued mitochondrial metabolic process, suggesting complex II is essential for steroid metabolism regulation.
第一种类固醇生成酶，细胞色素P450侧链裂解酶（SCC），需要电子传递链（ETC）复合物III和IV来启动类固醇代谢过程，以维持哺乳动物的生存。ETC复合物II含有琥珀酸脱氢酶（醌），与三羧酸循环协同作用，且没有质子泵功能。我们发现复合物II通过质子泵激活SCC是必需的，它会生成一种中间状态，以便琥珀酸添加磷酸。在琥珀酸存在的情况下，磷酸阴离子会形成一种具有更高焓值（-ΔH）和增强活性的稳定线粒体复合物。抑制琥珀酸的作用会阻止SCC在中间状态的加工，并消除活性和线粒体蛋白网络。这是第一份直接表明蛋白质中间状态被琥珀酸激活的报告，它促进了ETC复合物II与复合物III和IV相互作用，以持续进行线粒体代谢过程，这表明复合物II对于类固醇代谢调节至关重要。
