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Nature. 2019 Jul;571(7766):515-520. doi: 10.1038/s41586-019-1400-3. Epub 2019 Jul 24.

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

Author information

1
Department of Physiology, University of California San Francisco, San Francisco, CA, USA.
2
Dana-Farber Cancer Institute & Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
3
Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
5
Department of Physiology, University of California San Francisco, San Francisco, CA, USA. yuriy.kirichok@ucsf.edu.

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.

PMID:
31341297
PMCID:
PMC6662629
[Available on 2020-01-24]
DOI:
10.1038/s41586-019-1400-3
[Indexed for MEDLINE]

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