PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics
Sudeshna Nag,
Kaitlin Szederkenyi,
Olena Gorbenko,
Hannah Tyrrell,
Christopher M. Yip,
G. Angus McQuibban
Affiliations
Sudeshna Nag
Department of Biochemistry, University of Toronto, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G 1M1, Canada
Kaitlin Szederkenyi
Department of Biochemistry, University of Toronto, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G 1M1, Canada; Terrence Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada
Olena Gorbenko
Department of Biochemistry, University of Toronto, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G 1M1, Canada
Hannah Tyrrell
Department of Biochemistry, University of Toronto, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G 1M1, Canada
Christopher M. Yip
Department of Biochemistry, University of Toronto, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G 1M1, Canada; Terrence Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada
G. Angus McQuibban
Department of Biochemistry, University of Toronto, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G 1M1, Canada; Corresponding author
Summary: 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.
