Mitochondria are multifunctional organelles, primarily involved in the fundamental biological process of respiration. The efficient functioning of mitochondria depends on the proper transport, sorting, and assembly of mitochondrial proteins that originate either from nuclear or mitochondrial genomes. Both nuclear and mitochondrial gene defects that result in pathological variants of proteins have been implicated in a variety of mitochondrial diseases. The nuclear‑encoded proteins make up the large majority of proteins involved in the formation of mitochondria, including the respiratory chain complexes. The ubiquitin proteasome system (UPS) in the cytosol is involved in degradation of cellular proteins and maintaining protein homeostasis. By multiple lines of evidence, we have demonstrated the contribution of the UPS to mitochondrial protein quality control. The UPS degrades a portion of mitochondrial proteins, including mislocalized proteins, in both yeast and mammalian systems. Furthermore, mislocalization of mitochondrial proteins increases the ability of the proteasome to degrade cellular proteins. Thus, the UPS constitutes an important factor that affects the mitochondrial protein import, influences the mitochondrial proteome, and links the mitochondrial status with regulation of cellular protein homeostasis. Interestingly, pathologic variants of mitochondrial proteins can be mistargeted and fully degraded by the proteasome before they reach their final destination inside mitochondria. Inhibition of proteasomal degradation by commonly used proteasome inhibitors results in rescue of proteins and their import into the mitochondria. Thus, UPS inhibition can provide a benefit to malfunctioning mitochondria and cells. We propose that targeting the UPS should be considered as a therapeutic strategy for mitochondrial diseases.
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