Crosstalk between Mitochondrial Ca(2+) Uptake and Autophagy in Skeletal Muscle

Autophagy is responsible for the maintenance of skeletal muscle homeostasis, thanks to the removal of aberrant and dysfunctional macromolecules and organelles. During fasting, increased autophagy ensures the maintenance of the amino acid pool required for energy production. The activity of the mitochondrial Ca(2+) uniporter (MCU), the highly selective channel responsible for mitochondrial Ca(2+) uptake, controls skeletal muscle size, force, and nutrient utilization. Thus, both autophagy and mitochondrial Ca(2+) accumulation play a pivotal role to maintain muscle homeostasis and to sustain muscle function. Here, we address whether, in skeletal muscle, mitochondrial Ca(2+) uptake and autophagy are mutually related. Muscle-restricted MCU silencing partially inhibits the autophagy flux. Moreover, skeletal muscle-specific deletion of the essential autophagy gene Atg7, known to cause the accumulation of dysfunctional mitochondria, drastically reduces mitochondrial Ca(2+) accumulation. Thus, a vicious cycle takes place, in which reduced MCU activity hampers the autophagic flux, and loss of autophagy further impairs mitochondrial Ca(2+) signaling.