Goldilocks calcium and the mitochondrial respiratory chain: too much, too little, just right

Abstract

Calcium (Ca ²⁺ ) is a key regulator in diverse intracellular signaling pathways, and has long been implicated in metabolic control and mitochondrial function. Mitochondria can actively take up large amounts of Ca ²⁺ , thereby acting as important intracellular Ca ²⁺ buffers and affecting cytosolic Ca ²⁺ transients. Excessive mitochondrial matrix Ca ²⁺ is known to be deleterious due to opening of the mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, leading to mitochondrial swelling, rupture and cell death. But moderate Ca ²⁺ within the organelle can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. However, in vitro studies involving the regulation of mitochondrial enzymes by Ca ²⁺ may not uncover its full effects on oxidative phosphorylation. Here, we aimed to determine if extra or intramitochondrial Ca ²⁺ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocytes. We found that isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low and medium Ca ²⁺ concentrations in the presence of complex I-linked substrates pyruvate plus malate and α-ketoglutarate, respectively, but not complex II-linked succinate. In intact hepatocytes, both low and high cytosolic Ca ²⁺ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca ²⁺ decreased mitochondrial respiration in cells in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca ²⁺ on liver mitochondria, with specific “just right” concentrations that activate oxidative phosphorylation.