Abstract

Mitochondria are multifunctional organelle, primarily involved in fundamental biological process, 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 genome defects resulting in mutated proteins have been implicated in variety of mitochondrial diseases. The nuclear encoded proteins make up for the large majority of the proteins involved in formation of mitochondria including the respiratory chain complexes. The ubiquitin – proteasome system (UPS) in cytosol is largely involved in degradation of cellular proteins and maintaining protein homeostasis. By multiple lines of evidence we have demonstrated the contribution of UPS to mitochondrial IMS protein quality control. The UPS degrades a portion of mitochondrial proteins including mislocalised 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 influences mitochondrial proteome in physiology and links mitochondrial status with regulation of cellular protein homeostasis. Malfunctioning of mitochondria is a cause of devastating mitochondrial disease. 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 leads to rescue of proteins and their import into mitochondria. Thus, UPS inhibition can provide a benefit to malfunctioning mitochondria. We propose that targeting the UPS should be considered as a therapeutic strategy for mitochondrial diseases.