Mitochondrial protein import and UPRmt 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 (UPRmt). Protein import and UPRmt 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 UPRmt 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.

Measurement of Protein Import Capacity of Skeletal Muscle Mitochondria.

Mitochondria are key metabolic and regulatory organelles that determine the energy supply as well as the overall health of the cell. In skeletal muscle, mitochondria exist in a series of complex morphologies, ranging from small oval organelles to a broad, reticulum-like network. Understanding how the mitochondrial reticulum expands and develops in response to diverse stimuli such as alterations in energy demand has long been a topic of research. A key aspect of this growth, or biogenesis, is the import of precursor proteins, originally encoded by the nuclear genome, synthesized in the cytosol, and translocated into various mitochondrial sub-compartments. Mitochondria have developed a sophisticated mechanism for this import process, involving many selective inner and outer membrane channels, known as the protein import machinery (PIM). Import into the mitochondrion is dependent on viable membrane potential and the availability of organelle-derived ATP through oxidative phosphorylation. Therefore its measurement can serve as a measure of organelle health. The PIM also exhibits a high level of adaptive plasticity in skeletal muscle that is tightly coupled to the energy status of the cell. For example, exercise training has been shown to increase import capacity, while muscle disuse reduces it, coincident with changes in markers of mitochondrial content. Although protein import is a critical step in the biogenesis and expansion of mitochondria, the process is not widely studied in skeletal muscle. Thus, this paper outlines how to use isolated and fully functional mitochondria from skeletal muscle to measure protein import capacity in order to promote a greater understanding of the methods involved and an appreciation of the importance of the pathway for organelle turnover in exercise, health, and disease.

Exercise Is Muscle Mitochondrial Medicine.

Exercise stimulates the biogenesis of mitochondria in muscle. Some literature supports the use of pharmaceuticals to enhance mitochondria as a substitute for exercise. We provide evidence that exercise rejuvenates mitochondrial function, thereby augmenting muscle health with age, in disease, and in the absence of cellular regulators. This illustrates the power of exercise to act as mitochondrial medicine in muscle.