Parkin and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. Parkin, an E3 ubiquitin ligase mutated in Parkinson's disease, induces selective autophagy of damaged mitochondria. This study shows that Parkin ubiquitinates mitofusins Mfn1 and Mfn2, leading to their proteasome- and p97-dependent degradation. Upon mitochondrial depolarization, Parkin prevents or delays mitochondrial refusion by eliminating mitofusins. p97, a AAA+ ATPase, accumulates on mitochondria and is required for Parkin-mediated mitophagy. Inhibition of p97 or proteasome activity prevents Parkin-induced mitophagy. Parkin translocation to mitochondria is dependent on PINK1 activity. The study also shows that Parkin-mediated ubiquitination of Mfn1 and Mfn2 is essential for mitophagy. p97 is required for the degradation of ubiquitinated Mfn1 and for the accumulation of p97 on mitochondria after depolarization. The findings suggest that Parkin-mediated mitophagy involves the degradation of mitofusins to prevent mitochondrial fusion and facilitate their selective elimination by autophagy. The study also shows that mitochondrial fission is required for Parkin-mediated mitophagy, as inhibition of mitochondrial fission hinders Parkin-induced mitophagy. The results indicate that Parkin promotes mitochondrial fragmentation, which may facilitate subsequent mitophagy. The study highlights the role of Parkin and p97 in the degradation of mitofusins and the regulation of mitochondrial dynamics in mitophagy.Parkin and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. Parkin, an E3 ubiquitin ligase mutated in Parkinson's disease, induces selective autophagy of damaged mitochondria. This study shows that Parkin ubiquitinates mitofusins Mfn1 and Mfn2, leading to their proteasome- and p97-dependent degradation. Upon mitochondrial depolarization, Parkin prevents or delays mitochondrial refusion by eliminating mitofusins. p97, a AAA+ ATPase, accumulates on mitochondria and is required for Parkin-mediated mitophagy. Inhibition of p97 or proteasome activity prevents Parkin-induced mitophagy. Parkin translocation to mitochondria is dependent on PINK1 activity. The study also shows that Parkin-mediated ubiquitination of Mfn1 and Mfn2 is essential for mitophagy. p97 is required for the degradation of ubiquitinated Mfn1 and for the accumulation of p97 on mitochondria after depolarization. The findings suggest that Parkin-mediated mitophagy involves the degradation of mitofusins to prevent mitochondrial fusion and facilitate their selective elimination by autophagy. The study also shows that mitochondrial fission is required for Parkin-mediated mitophagy, as inhibition of mitochondrial fission hinders Parkin-induced mitophagy. The results indicate that Parkin promotes mitochondrial fragmentation, which may facilitate subsequent mitophagy. The study highlights the role of Parkin and p97 in the degradation of mitofusins and the regulation of mitochondrial dynamics in mitophagy.