Year: 2024
Type: dissertation
Abstract: Mitochondrial morphology is a key indicator of cellular health and function. It is primarily regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (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 dynamics is unknown. In this study, we show that PGAM5 functions as a profusion protein in steady-state conditions and PGAM5 localization and conformations play key roles in the regulation of mitochondrial morphology. Further, we aimed to identify the mechanism of PGAM5 in mitochondrial dynamics. We discovered MFN2 as a new interacting partner of PGAM5. 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 de-phosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances MFN2 degradation and mitochondrial fragmentation whereas de-phosphorylation enhances network formation. 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 de-phosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase.
Source: TSpace (University of Toronto)
Author: Nag, Sudeshna
Institution: University of Toronto
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7133057660