Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: Too much, too little, or just right

• Published in: The Journal of biological chemistry Vol. 299; no. 3; p. 102904
• Main Authors: Vilas-Boas, Eloisa A., Cabral-Costa, João Victor, Ramos, Vitor M., Caldeira da Silva, Camille C., Kowaltowski, Alicia J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2023; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Calcium - metabolism; calcium transport; electron transfer chain; metabolic flux; Mice; mitochondria; Mitochondria - metabolism; Oxidative Phosphorylation; RCR; NCLX; mitochondria; electron transfer chain; SERCA; ER; oxidative phosphorylation; ADR; CsA; BSA; DMEM; TG; metabolic flux; PDH; α-KG; calcium transport; MCU; OCR
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2023.102904

Calcium (Ca2+) 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 Ca2+, thereby acting as important intracellular Ca2+ buffers and affecting cytosolic Ca2+ transients. Excessive mitochondrial matrix Ca2+ 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 Ca2+ 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 Ca2+ modulates oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supraphysiological increases in cytosolic and mitochondrial Ca2+ 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) Ca2+ 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 Ca2+ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca2+ decreased mitochondrial respiration in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific “just right” concentrations that activate oxidative phosphorylation.