Mitochondrial protein import and UPR^mt in skeletal muscle remodeling and adaptation

The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPR^mt). Protein import and UPR^mt activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPR^mt systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.