Cardiac-specific deficiency of the mitochondrial calcium uniporter augments fatty acid oxidation and functional reserve

• Published in: Journal of molecular and cellular cardiology 2019-02, Vol.127, p.223-231
• Main Authors: Altamimi, Tariq R., Karwi, Qutuba G., Uddin, Golam Mezbah, Fukushima, Arata, Kwong, Jennifer Q., Molkentin, Jeffery D., Lopaschuk, Gary D.
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Calcium Channels - deficiency; Calcium Channels - metabolism; Energy Metabolism - drug effects; Fatty acid oxidation; Fatty Acids - metabolism; Glucose oxidation; Heart Function Tests; Heart Rate - drug effects; High workload; Isoproterenol - pharmacology; Lysine acetylation; Malonyl CoA; Mice; Mitochondrial calcium uniporter; Myocardium - metabolism; Organ Specificity; Oxidation-Reduction; Phosphorylation - drug effects
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2018.12.019

The mitochondrial calcium uniporter (MCU) relays cytosolic Ca2+ transients to the mitochondria. We examined whether energy metabolism was compromised in hearts from mice with a cardiac-specific deficiency of MCU subjected to an isoproterenol (ISO) challenge. Surprisingly, isolated working hearts from cardiac MCU-deficient mice showed higher cardiac work, both in the presence or absence of ISO. These hearts were not energy-starved, with ISO inducing a similar increase in glucose oxidation rates compared to control hearts, but a greater increase in fatty acid oxidation rates. This correlated with lower levels of the fatty acid oxidation inhibitor malonyl CoA, and to an increased stimulatory acetylation of its degrading enzyme malonyl CoA decarboxylase and of the fatty acid β-oxidation enzyme β-hydroxyacyl CoA dehydrogenase. We conclude that impaired mitochondrial Ca2+ uptake does not compromise cardiac energetics due to a compensatory stimulation of fatty acid oxidation that provides a higher energy reserve during acute adrenergic stress. •The MCU is dispensable for baseline and isoproterenol-stimulated cardiac function.•MCU deletion does not compromise cardiac energetics.•Impaired MCU function increases the acetylation of key metabolic enzymes.•Deletion of MCU enhances fatty acid oxidation under increased cardiac workload.