Voltage-energized calcium-sensitive ATP production by mitochondria

The regulation of ATP production by mitochondria, crucial for multicellular life, is poorly understood. Here, we investigate the molecular controls of this process in the 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 the heart has neither an apparent cytosolic Ca2+ threshold nor a gating function, and guides ATP production by its influence on the inner mitochondrial membrane (IMM) potential, Delta Psi(m). This regulation occurs through 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 Delta Psi(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 Delta Psi(m) threshold for ATP production than bacterial ATP synthase and reveals a concave-upward 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 work(1), the control of ATP synthase by Delta Psi(m) appears to be broadly consistent among tissues but is clearly different from that in bacteria.