Parkin, an E3 ubiquitin ligase linked to Parkinson's disease, promotes the degradation of dysfunctional mitochondria through mitophagy. This study shows that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for the degradation of outer membrane proteins. This is evidenced by increased K48-linked polyubiquitination, recruitment of the 26S proteasome, and rapid degradation of multiple outer membrane proteins. The degradation occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in various cell types. While mitofusins Mfn1 and Mfn2 are rapidly degraded, other targets are essential for mitophagy. These findings indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates. Parkin-mediated degradation of outer membrane proteins occurs via the UPS and is independent of the autophagy pathway. The UPS is essential for Parkin-mediated mitophagy, as inhibition of the proteasome blocks mitophagy. The study also shows that degradation of outer membrane proteins precedes mitophagy and is distinct from it. The UPS is critical for Parkin-mediated mitophagy, and its inhibition blocks the process. The results highlight the role of the UPS in mitochondrial quality control and suggest that additional remodeling of the mitochondrial outer membrane proteome is necessary for mitophagy. The study provides evidence that the UPS and autophagy are functionally linked, and further research is needed to understand how the UPS facilitates mitophagy. The findings have implications for the pathogenesis of Parkinson's disease and other neurodegenerative disorders.Parkin, an E3 ubiquitin ligase linked to Parkinson's disease, promotes the degradation of dysfunctional mitochondria through mitophagy. This study shows that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for the degradation of outer membrane proteins. This is evidenced by increased K48-linked polyubiquitination, recruitment of the 26S proteasome, and rapid degradation of multiple outer membrane proteins. The degradation occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in various cell types. While mitofusins Mfn1 and Mfn2 are rapidly degraded, other targets are essential for mitophagy. These findings indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates. Parkin-mediated degradation of outer membrane proteins occurs via the UPS and is independent of the autophagy pathway. The UPS is essential for Parkin-mediated mitophagy, as inhibition of the proteasome blocks mitophagy. The study also shows that degradation of outer membrane proteins precedes mitophagy and is distinct from it. The UPS is critical for Parkin-mediated mitophagy, and its inhibition blocks the process. The results highlight the role of the UPS in mitochondrial quality control and suggest that additional remodeling of the mitochondrial outer membrane proteome is necessary for mitophagy. The study provides evidence that the UPS and autophagy are functionally linked, and further research is needed to understand how the UPS facilitates mitophagy. The findings have implications for the pathogenesis of Parkinson's disease and other neurodegenerative disorders.