The role of the proteasome in mitochondrial protein quality control

Abstract

The abundance of each cellular protein is dynamically adjusted to the prevailing metabolic and stress conditions by modulation of their synthesis and degradation rates. The proteasome represents the major machinery for the degradation of proteins in eukaryotic cells. How the ubiquitin‐proteasome system (UPS) controls protein levels and removes superfluous and damaged proteins from the cytosol and the nucleus is well characterized. However, recent studies showed that the proteasome also plays a crucial role in mitochondrial protein quality control. This mitochondria‐associated degradation (MAD) thereby acts on two layers: first, the proteasome removes mature, functionally compromised or mis‐localized proteins from the mitochondrial surface; and second, the proteasome cleanses the mitochondrial import pore of import intermediates of nascent proteins that are stalled during translocation. In this review, we provide an overview about the components and their specific functions that facilitate proteasomal degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. Thereby we explain how the proteasome, in conjunction with a set of intramitochondrial proteases, maintains mitochondrial protein homeostasis and dynamically adapts the levels of mitochondrial proteins to specific conditions.

Proteasome localization and activity in pig brain and in vivo small molecule screening for activators

“…VDAC and cyclophilin D are well-known mitochondrial proteins ( Martin et al, 2009 , 2011 ). Though cytoplasmic proteasomes have recently been associated with mitochondrial protein quality control in a process in yeast called mitochondria-associated degradation ( Rödl and Herrmann, 2023 ), a mitochondrial localization of proteasome has not been shown before. The proteasome could be tethered to the outer mitochondrial membrane, like DNA methyltransferase-1 ( Wong et al, 2013 ), potentially associated with the translocator of the outer mitochondrial membrane ( Bertolin et al, 2013 ), or within the intermembrane space, inner membrane, or mitochondrial matrix.…”