PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function

Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1; also known as DNM1L). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1; however, the precise regulation of PGAM5 activity is unknown. Here, we show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association and, instead of forming dodecamers, forms dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane-resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as crucial regulators of its function.