产热素
2,4-二硝基苯酚
化学
线粒体
生物能学
生物物理学
生物化学
作用机理
线粒体内膜
辅酶Q-细胞色素c还原酶
产热
生物
脂肪组织
细胞色素c
体外
作者
Ambre M. Bertholet,Andrew M. Natale,Paola Bisignano,Junji Suzuki,Andriy Fedorenko,James Hamilton,Tatiana Brustovetsky,Lawrence Kazak,Ryan Garrity,Edward T. Chouchani,Nickolay Brustovetsky,Michael Grabe,Yuriy Kirichok
出处
期刊:Nature
[Springer Nature]
日期:2022-05-25
卷期号:606 (7912): 180-187
被引量:52
标识
DOI:10.1038/s41586-022-04747-5
摘要
Mitochondria generate heat due to H+ leak (IH) across their inner membrane1. IH results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat2-6 and ADP/ATP carrier (AAC) in other tissues1,7-9, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of IH through UCP1 and AAC is lacking, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)10,11. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models12-14, their clinical potential for treating human disease is limited due to indiscriminately increasing H+ conductance across all biological membranes10,11 and adverse side effects15. Here we report the direct measurement of IH induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH through AAC. Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.
科研通智能强力驱动
Strongly Powered by AbleSci AI