MCU genetically altered mice suggest how mitochondrial Ca regulates metabolism.

Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca regulates metabolism.