Proposed relationship between PGC-1α expression, mitochondrial function, and mitophagy during cellular stress. (A-B) Upon cellular metabolic stress such as denervation or nutrient deprivation lack of PGC-1α results in diminished mitochondrial function, biogenesis, and impaired autophagy and mitophagy, whereas its overexpression results in superior mitochondrial function and biogenesis as well as enhanced autophagy, but reduced mitophagy. (A) Hypothetical graphical representation of the relationship between levels of PGC-1α, mitochondrial function, and mitophagy. (B) Schematic outlining mitochondrial turnover during denervation-induced metabolic stress in muscle in light of variations in PGC-1α expression. Steady state mitochondrial content is represented in the center of each panel. In the presence of endogenous PGC-1α levels (middle panel), biogenesis is active at a low level during denervation, but both mitophagy and autophagy flux are enhanced leading to a reduced steady state mitochondrial content. When the expression of PGC-1α is abolished (upper panel), biogenesis is further reduced during denervation, as are autophagy and mitophagy flux, leading to a smaller, dysfunctional pool of mitochondria. When PGC-1α levels are elevated (lower panel), biogenesis is higher while mitophagy is lower than normal during denervation, leading to a maintained organelle content. Arrow thickness provides an indication of the magnitude of the pathway. AAs, amino acids; PGC-1α, peroxisome proliferator co-activator 1 alpha; ROS, reactive oxygen species.