The Emerging Role of Proteolysis in Mitochondrial Quality Control and the Etiology of Parkinson’s Disease
Figure 1
A model of UPS-mediated mitochondrial protein degradation. (a) Damaged and/or misfolded nuclear-encoded proteins that are destined for import into the mitochondria are intercepted by E3 ubiquitin ligases and labeled with K48-linked polyubiquitin chains. Subsequently, these proteins undergo degradation by the cytoplasmic 26S proteasome. Only the substrate alone is degraded, while ubiquitin is recycled by one or more of the proteasomal-specific deubiquitinating enzymes (DUBs, shown in red). (b) The turnover of proteins that are already at the mitochondria occurs via a process called mitochondria-associated degradation (MAD). Defective proteins at the OMM are polyubiquitinated by E3 ligases. These proteins are then extracted from the membrane by the AAA-ATPase p97 and delivered to the proteasome for proteolysis. Alternatively, mitochondrial-associated DUBs may rescue proteins from degradation by editing or removing the degradative ubiquitin signal. Hence, DUBs may enhance the stability of mitochondrial proteins. In addition, many lines of evidence suggest that the UPS also facilitates the degradation of non-OMM proteins. However, the mechanistic details of how proteasomal substrates within inner compartments retrotranslocate to the OMM have not yet been established.
