SUMMARY 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 ATP production. In addition, AAC may mediate mitochondrial uncoupling, but this AAC function and its mechanisms remain elusive. Here we record AAC currents directly from inner mitochondrial membrane of various 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 of brown fat. The ADP/ATP exchange via AAC negatively regulates the H + leak, but without complete inhibition. 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 intimately connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.

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