Fig. 6. Proposed model for the role of BAG5 in regulating Parkin’s functions in mitophagy and cell death.

At baseline conditions, Parkin exists in an inactive state and when activated by PINK1 following mitochondrial depolarization, BAG5 inhibits its recruitment and action in mitophagy while enhancing degradation of Mcl-1, which in turn promotes apoptosis. An additional network of “stress sensor” chaperone proteins is likely required for full activation of Parkin’s cytotoxic action. For example BAG2¹⁸, BAG4¹⁹, and CHIP³³ are co-chaperones involved in context-dependent regulation of PINK1 and Parkin.