Crosstalk between Mitochondrial Ca2+ Uptake and Autophagy in Skeletal Muscle

Abstract

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 Ca²⁺ uniporter (MCU), the highly selective channel responsible for mitochondrial Ca²⁺ uptake, controls skeletal muscle size, force, and nutrient utilization. Thus, both autophagy and mitochondrial Ca²⁺ accumulation play a pivotal role to maintain muscle homeostasis and to sustain muscle function. Here, we address whether, in skeletal muscle, mitochondrial Ca²⁺ 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 Ca²⁺ accumulation. Thus, a vicious cycle takes place, in which reduced MCU activity hampers the autophagic flux, and loss of autophagy further impairs mitochondrial Ca²⁺ signaling.