Mitochondrial Calcium Signaling Tunes Voltage‐Energized ATP Production

Abstract

How mitochondrial ATP production dynamically responds to cellular metabolic needs is poorly understood. Here we report on quantitative investigations in heart muscle that identify the key molecular and cellular controls of ATP production. We show that Ca2+ influx into the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) is small with no cytosolic Ca2+ threshold and tissue‐specific Ca2+ sensitive gating. MCU controls ATP production by its influence on matrix Ca2+ concentration ([Ca2+]m) which regulates pyruvate and oxoglutarate dehydrogenases and hence Krebs cycle production of NADH. The NADH level affects the voltage‐gradient across the inner mitochondrial membrane (Δψm) which in turn regulates ATP synthase. Our first report of the voltage‐dependence of ATP synthase in mammalian system is determined by measuring its ATP production. By this means, we show that the Δψm dependence of ATP synthase is different from the previous “gold standard”, the voltage‐dependence of bacterial ATP synthase. Additionally, we show how ATP production in cardiac mitochondria depends on both [Ca2+]m and on cytosolic [ADP]. Higher heart rates and contraction under load increase both Ca2+ sensitive and Ca2+ insensitive ATP production. These findings provide a new and different understanding of how mitochondria generate ATP in response to metabolic need, how ATP production is powered by Δψm, and how Δψm is regulated by mitochondrial Ca2+ signaling.Support or Funding InformationThis research was supported by American Heart Association grants SDG 15SDG22100002 (to L.B.) and 16PRE31030023 (to A.P.W.); by NIH R01 HL106056, R01 HL105239, U01 HL116321, 1R01HL142290, 1 R01 HL140934 and 1R01 AR071618 (to W.J.L.); by the Medical Scientist Training Program and Training Program in Integrative Membrane Biology, NIH 2T32GM092237‐06 and 5T32GM008181‐28 (to A.P.W.).