The proteasome: friend and foe of mitochondrial biogenesis

Most mitochondrial proteins are synthesized in the cytosol and subsequently translocated as unfolded polypeptides into mitochondria. Cytosolic chaperones maintain precursor proteins in an import-competent state. This post-translational import reaction is under surveillance of the cytosolic ubiquitin-proteasome system, which carries out several distinguishable activities. On the one hand, the proteasome degrades nonproductive protein precursors from the cytosol and nucleus, import intermediates that are stuck in mitochondrial translocases, and misfolded or damaged proteins from the outer membrane and the intermembrane space. These surveillance activities of the proteasome are essential for mitochondrial functionality, as well as cellular fitness and survival. On the other hand, the proteasome competes with mitochondria for nonimported cytosolic precursor proteins, which can compromise mitochondrial biogenesis. In order to balance the positive and negative effects of the cytosolic protein quality control system on mitochondria, mitochondrial import efficiency directly regulates the capacity of the proteasome via transcription factor Rpn4 in yeast and nuclear respiratory factor (Nrf) 1 and 2 in animal cells. In this review, we provide a thorough overview of how the proteasome regulates mitochondrial biogenesis.