| First Author | Bertholet AM | Year | 2022 |
| Journal | Nature | Volume | 606 |
| Issue | 7912 | Pages | 180-187 |
| PubMed ID | 35614225 | Mgi Jnum | J:330913 |
| Mgi Id | MGI:7367089 | Doi | 10.1038/s41586-022-04747-5 |
| Citation | Bertholet AM, et al. (2022) Mitochondrial uncouplers induce proton leak by activating AAC and UCP1. Nature 606(7912):180-187 |
| abstractText | Mitochondria generate heat due to H(+) leak (IH) across their inner membrane(1). IH results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat(2-6) and ADP/ATP carrier (AAC) in other tissues(1,7-9), 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 models(12-14), their clinical potential for treating human disease is limited due to indiscriminately increasing H(+) conductance across all biological membranes(10,11) and adverse side effects(15). 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. |
