4.8 Article

MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle

Journal

CELL REPORTS
Volume 42, Issue 11, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2023.113465

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MCUb is an inducible control point that regulates skeletal muscle mitochondrial Ca2+ levels and substrate utilization, impacting overall metabolic balance.
Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca2+ uniporter (MCU) and Ca2+ levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca2+ influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca2+ influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight. In contrast, mice lacking Mcub in skeletal muscle showed increased py-ruvate dehydrogenase activity, increased muscle malonyl coenzyme A (CoA), reduced fatty acid utilization, glucose intolerance, and increased adiposity. Mechanistically, pyruvate dehydrogenase kinase 4 (PDK4) over -expression in muscle of Mcubdeleted mice abolished altered substrate preference. Thus, MCUb is an inducible control point in regulating skeletal muscle mitochondrial Ca2+ levels and substrate utilization that impacts total metabolic balance.

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