H+ transport is an integral function of the mitochondrial ADP/ATP carrier

Ambre M. Bertholet, Edward T. Chouchani, Lawrence Kazak, Alessia Angelin, Andriy Fedorenko, Jonathan Z. Long, Sara Vidoni, Ryan Garrity, Joonseok Cho, Naohiro Terada, Douglas C. Wallace, Bruce M. Spiegelman and Yuriy Kirichok ()
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Ambre M. Bertholet: University of California San Francisco
Edward T. Chouchani: Harvard Medical School
Lawrence Kazak: Harvard Medical School
Alessia Angelin: University of Pennsylvania
Andriy Fedorenko: University of California San Francisco
Jonathan Z. Long: Harvard Medical School
Sara Vidoni: Harvard Medical School
Ryan Garrity: Harvard Medical School
Joonseok Cho: University of Florida College of Medicine
Naohiro Terada: University of Florida College of Medicine
Douglas C. Wallace: University of Pennsylvania
Bruce M. Spiegelman: Harvard Medical School
Yuriy Kirichok: University of California San Francisco

Nature, 2019, vol. 571, issue 7766, 515-520

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1400-3

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