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, ΔΨm. 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 ΔΨm 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 ΔΨm 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 ΔΨm appears to be broadly consistent among tissues but is clearly different from bacteria.

中文翻译：

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线粒体产生电压激发的钙敏感 ATP。

人们对线粒体对 ATP 产生的调节（对多细胞生命至关重要）知之甚少。在这里，我们研究了心脏中这一过程的分子控制，并为其 Ca2+ 依赖性调节提供了一个框架。我们发现，Ca2+ 通过心脏线粒体钙单向转运体 (MCU) 进入基质既没有明显的细胞溶质 Ca2+ 阈值，也没有门控功能，而是通过影响线粒体内膜 (IMM) 电位 ΔΨm 来指导 ATP 的产生。这种调节通过丙酮酸和谷氨酸脱氢酶活性的基质 Ca2+ 依赖性调节发生，而不是通过 Ca2+ 对 ATP 合酶或电子传输链复合物 II、III 或 IV 的任何影响。详细检查 ATP 产生在 -60 mV 至 -170 mV 范围内的 ΔΨm 依赖性表明心脏 ATP 合酶具有电压依赖性，这从根本上将其与以前的标准细菌 ATP 合酶区分开来。心脏 ATP 合酶与细菌 ATP 合酶相比，以不同的 ΔΨm 阈值运行 ATP 生产，并显示出不饱和的凹向上形状。骨骼肌 MCU Ca2+ 通量虽然也没有明显的细胞溶质 Ca2+ 阈值，但与心脏 MCU 有很大不同，但骨骼肌中的 ATP 合酶电压依赖性与心脏中的相同。这些结果表明，虽然细胞溶质 Ca2+ 信号通过 MCU 的传导似乎是组织依赖性的，如早期工作 1 所示，