Vilas-Boas 2023 J Biol Chem

Vilas-Boas EA, Cabral-Costa JV, Ramos VM, Caldeira da Silva CC, Kowaltowski AJ (2023) Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right. https://doi.org/10.1016/j.jbc.2023.102904

» J Biol Chem [Epub ahead of print]. PMID: 36642177 Open Access

Vilas-Boas Eloisa A,  Cabral-Costa Joao Victor,  Ramos Vitor M,  Caldeira da Silva Camille C,  Kowaltowski Alicia J (2023) J Biol Chem

Abstract: 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⁺ 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 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. • Keywords: Calcium transport, Electron transfer chain, Metabolic flux, Mitochondria, Oxidative phosphorylation • Bioblast editor: Plangger M • O2k-Network Lab: BR Sao Paulo Kowaltowski AJ

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Regulation: Calcium  Coupling state: LEAK, OXPHOS, ET  Pathway: N, S  HRR: Oxygraph-2k 

2023-01