PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics

Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein 1 (DRP1). Mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is emerging as a regulator of these post-translational modifications; however, its precise role in the regulation of mitochondrial morphology is unknown. We show that PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner. PGAM5 regulates MFN2 phosphorylation and consequently protects it from ubiquitination and degradation. Further, phosphorylation and dephosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances fission and degradation, whereas dephosphorylation enhances fusion. PGAM5 dephosphorylates MFN2 to promote mitochondrial network formation. Further, using a Drosophila genetic model, we demonstrate that the MFN2 homolog Marf and dPGAM5 are in the same biological pathway. Our results identify MFN2 dephosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase. [Display omitted] •PGAM5 conformations regulate mitochondrial morphology differentially•PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner•PGAM5-driven mitochondrial elongation is dependent on MFN2•MFN2 phosphorylation state is a determinant of mitochondrial morphology Nag et al. show that PGAM5 controls mitochondrial morphology by regulating MFN2 function. PGAM5 interacts with MFN2 in a stress-sensitive manner. The PGAM5-MFN2 interaction protects MFN2 from phosphorylation and enhances its stability and fusogenic activity. PGAM5 depletion results in enhanced MFN2 phosphorylation, suggesting its role as a possible MFN2 phosphatase.