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 Ca²⁺-dependent regulation. We find that the entry of Ca²⁺ into the matrix through the mitochondrial calcium uniporter (MCU) in heart has neither an apparent cytosolic Ca²⁺ threshold nor gating function and guides ATP production by its influence on the inner mitochondrial membrane (IMM) potential, ΔΨ_m. This regulation occurs by matrix Ca²⁺-dependent modulation of pyruvate and glutamate dehydrogenase activity and not through any effect of Ca²⁺ on ATP Synthase or on Electron Transport Chain Complexes II, III or IV. Examining the ΔΨ_m 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_m threshold for ATP production than bacterial ATP synthase and reveals a concave-upwards shape without saturation. Skeletal muscle MCU Ca²⁺ flux, while also having no apparent cytosolic Ca²⁺ 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 Ca²⁺ signals through the MCU appears to be tissue-dependent, as shown by earlier work¹, the control of ATP synthase by ΔΨ_m appears to be broadly consistent among tissues but is clearly different from bacteria.