Goldilocks calcium and the mitochondrial respiratory chain: too much, too little, just right
Listed in
- @ZonaPellucida_'s saved articles (unknown_user_13)
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. Moderate Ca 2+ within the organelle, on the other hand, can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. Here, we aimed to determine in a quantitative manner if extra or intramitochondrial Ca 2+ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supra-physiological increases in cytosolic and mitochondrial Ca 2+ on oxygen consumption rates. Isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low (2.4 ± 0.6 μM) and medium (22.0 ± 2.4 μM) 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 cells, 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 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.