FIGURE 1.

Skeletal muscle mitochondrial quality control in health and disease. (A) Exercise is a potent promotor of mitochondrial health by eliciting increases in mitochondrial quality control machinery. Upstream signaling kinases respond to muscle contractile activity leading to activation of PGC-1α and augmented transcription of nuclear genes encoding mitochondrial proteins (NuGEMPs). Newly translated mitochondrial-targeted proteins are then transported into the mitochondrion via the protein import machinery (PIM) and are subsequently met by resident chaperones and proteases to facilitate their incorporation within the organelle. The UPRmt is responsible for regulating the expression of mitochondrial chaperones and proteases in the presence of a stress stimulus such as exercise. As mitochondrial volume within the myofiber expands, fusion machinery adjoins neighboring organelles’ inner and outer membranes to facilitate transfer of metabolites, mtDNA, etc. Dysfunctional mitochondrial segments that lose their membrane potential and emit excessive ROS are cleaved from the reticulum by the fission proteins, thereby allowing mitophagy machinery to selectively encapsulate and degrade these non-functioning organelles for delivery to the lysosome. Exercise activates both the biogenesis and mitophagy pathways of MQC to promote the health and viability of the mitochondrial pool within muscle. (B) Mitochondrial dysfunction is a hallmark feature of disease, including cancer, aging and associated mitochondrial disorders. In general, activation of signaling kinases is impaired and reduces the drive for mitochondrial biogenesis from the nucleus, while mtDNA copy number can be reduced or have a high proportion of mutated mtDNA, which can serve to blunt mitochondrial expansion. Reductions in fission and fusion machinery impair mitochondrial morphology and shift the fission:fusion ratio in favor of network fragmentation and organelle ROS production. Further exacerbating the mitochondrial derangements is the impaired mitochondrial removal via reduced mitophagic clearance by the lysosome, thus contributing to the poor morphology and function of the mitochondrial network. As described in the text, exercise can reverse many of the pathways that lead to mitochondrial dysfunction, thereby restoring muscle health.