TY - JOUR
T1 - H+ transport is an integral function of the mitochondrial ADP/ATP carrier
AU - Bertholet, Ambre M.
AU - Chouchani, Edward T.
AU - Kazak, Lawrence
AU - Angelin, Alessia
AU - Fedorenko, Andriy
AU - Long, Jonathan Z.
AU - Vidoni, Sara
AU - Garrity, Ryan
AU - Cho, Joonseok
AU - Terada, Naohiro
AU - Wallace, Douglas C.
AU - Spiegelman, Bruce M.
AU - Kirichok, Yuriy
N1 - Funding Information:
Acknowledgements We thank S. Bal Craquin and the members of the Y.K. laboratory for helpful discussions. This work was supported by NIH grants R01GM107710 and R01GM118939 to Y.K. and grants NS021328, MH108592, OD010944 (NIH), and W81XWH-16-1-0401 (DOD) to D.C.W. as well as a Canadian Institutes of Health Research postdoctoral fellowship to L.K. B.M.S. received funding from the JPB Foundation.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/7/25
Y1 - 2019/7/25
N2 - The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H+ transport. The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H+ leak, but does not completely inhibit it. This suggests that the H+ leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.
AB - The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H+ transport. The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H+ leak, but does not completely inhibit it. This suggests that the H+ leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.
UR - http://www.scopus.com/inward/record.url?scp=85069716355&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1400-3
DO - 10.1038/s41586-019-1400-3
M3 - Article
C2 - 31341297
AN - SCOPUS:85069716355
SN - 0028-0836
VL - 571
SP - 515
EP - 520
JO - Nature
JF - Nature
IS - 7766
ER -