Fig. 10

A model to describe the responses of the PINK1:Parkin pathway to mitochondrial stresses of differing magnitude and duration. a Model representing the changes in PINK1, Parkin, and phospho-ubiquitin chain levels at the mitochondria with changing ΔΨm. (1) In polarized, actively respiring mitochondria, PINK1 is rapidly imported, proteolytically cleaved, and degraded. (2) Phospho-ubiquitin chains are removed by mitochondria-associated USPs (and possibly phosphatases) in depolarized and repolarized mitochondria but the kinetics of this process are slow. (3) In partially depolarized mitochondria, small fluctuations in ΔΨm may generate short pulses of PINK1 activity. If these occur sufficiently frequently, ppUb chain density at the OMM may either be maintained or build due to their slow removal by USPs. b Diagrammatic representation of PINK1:Parkin pathway feedback loops. Parkin activation FFL – PINK1 activates Parkin directly through phosphorylation of the Parkin Ubl at Ser65 and indirectly by phosphorylating ubiquitin proteins at Ser65, which relieve autoinhibition of Parkin protein, constituting a coherent FFL. Phospho-polyubiquitin FFL - PINK1 activates Parkin directly through phosphorylation of the Parkin Ubl at Ser65, enabling Parkin to poly-ubiquitinate proteins on the OMM and these chains are phosphorylated by PINK1, forming a second coherent FFL. Parkin recruitment positive feedback loop – The ppUb chains produced by PINK1 and Parkin activity at the OMM serve as docking sites for the recruitment and activation of more Parkin. c Graphs to represent predicted changes in OMM-associated PINK1 (blue) and Parkin (green) levels in response to the indicated changes in ΔΨm (red)