Voltage-energized Calcium-sensitive ATP Production by Mitochondria.

Regulation of ATP production by mitochondria, critical to multicellular life, is poorly understood. Here we investigate the molecular controls of this process in heart and provide a framework for its Ca-dependent regulation. We find that the entry of Ca into the matrix through the mitochondrial calcium uniporter (MCU) in heart has neither an apparent cytosolic Ca threshold nor gating function and guides ATP production by its influence on the inner mitochondrial membrane (IMM) potential, ΔΨ. This regulation occurs by matrix Ca-dependent modulation of pyruvate and glutamate dehydrogenase activity and not through any effect of Ca on ATP Synthase or on Electron Transport Chain Complexes II, III or IV. Examining the ΔΨ dependence of ATP production over the range of -60 mV to -170 mV in detail reveals that cardiac ATP synthase has a voltage dependence that distinguishes it fundamentally from the previous standard, the bacterial ATP synthase. Cardiac ATP synthase operates with a different ΔΨ threshold for ATP production than bacterial ATP synthase and reveals a concave-upwards shape without saturation. Skeletal muscle MCU Ca flux, while also having no apparent cytosolic Ca threshold, is substantially different from the cardiac MCU, yet the ATP synthase voltage dependence in skeletal muscle is identical to that in the heart. These results suggest that while the conduction of cytosolic Ca signals through the MCU appears to be tissue-dependent, as shown by earlier work, the control of ATP synthase by ΔΨ appears to be broadly consistent among tissues but is clearly different from bacteria.