Stress-induced phospho-ubiquitin formation causes parkin degradation

Lyudmila Kovalchuke; Eugene V. Mosharov; Oren A. Levy; Lloyd A. Greene

The lack of evidence for phospho-poly-Ub formation by exogenous parkin following L-DOPA treatment suggests that endogenous parkin similarly does not contribute to the formation of these chains in the L-DOPA model. To examine this possibility for mitochondrial phosphopoly-Ub, we assessed ubiquitination of the mitochondrial GTPase mitofusin-2 (Mfn2) following L-DOPA treatment. A recent study showed that Mfn2 is a preferred mitochondrial parkin substrate during mitophagy and provided evidence that Mfn2 poly-ubiquitination by parkin precedes and may be required for parkin to efficiently ubiquitinate other mitochondrial substrates [97] . This primacy of Mfn2 ubiquitination, coupled with the finding that poly-ubiquitin chains on mitochondrial proteins are phosphorylated to generate mitochondrial phospho-poly-Ub, makes Mfn2 ubiquitination a useful proxy for the contribution of endogenous parkin to mitochondrial phospho-poly-Ub formation.