Immunoproteasome-specific Subunit Alterations as a Potential Therapeutic Target for Mitochondriopathies.

Mitochondria are double-membrane organelles crucial for eukaryotic cells due to their role in ATP production by oxidative phosphorylation (OXPHOS). Most of the ∼1500 proteins of the mitochondrial proteome are encoded in the nuclear genome, synthesized in the cytosol, and actively transported into mitochondria. The proteasome, a major cellular proteolytic machinery, plays an important role in the quality control of their transport by degradation of inefficiently imported mitochondrial proteins in the cytosol. Proteasome inhibition by bortezomib was described as a strategy to alleviate deficiencies stemming from an inefficient import of proteins into the mitochondria. Notably, an impairment of the respiratory complexes was shown to induce a rearrangement of the proteasome composition to incorporate some of the immunoproteasome catalytic subunits, such as PSMB9. In this study, we demonstrated that targeting immunoproteasome inhibited degradation, and thus restored the abundance of inefficiently imported respiratory complex IV proteins in the patient derived fibroblasts. Furthermore, we demonstrated that the immunoproteasome-specific inhibitors displayed a decreased toxicity compared to bortezomib. Our results indicate that immunoproteasome subunits present a novel molecular target for future therapies of mitochondriopathies.