PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation

Area of Science:

• Mitochondrial biology
• Epigenetics
• DNA repair

Background:

• Protein arginine methyltransferase 5 (PRMT5) regulates nuclear processes including proliferation and DNA damage response.
• The role of PRMT5 in mitochondria and its impact on mitochondrial DNA (mtDNA) homeostasis remain largely unexplored.

Purpose of the Study:

• To investigate the mitochondrial localization and function of PRMT5.
• To elucidate the role of PRMT5 in maintaining mitochondrial DNA (mtDNA) integrity and cellular respiration.

Main Methods:

• Generation and analysis of PRMT5 knockout cells.
• Assessment of mtDNA copy number, nucleoid counts, and mitochondrial morphology.
• Identification of PRMT5 interacting partners using co-immunoprecipitation.
• Analysis of TFAM methylation status and stability.

Main Results:

• Nuclear-encoded PRMT5 localizes to mitochondria and is essential for mtDNA homeostasis.
• PRMT5 deficiency leads to reduced mtDNA copy numbers, disrupted mitochondrial dynamics, and impaired respiration.
• PRMT5 directly interacts with TFAM, catalyzing its symmetric dimethylation at R82, which is critical for mtDNA binding and stability.
• Loss of R82 methylation destabilizes TFAM, leading to its degradation by LonP1.

Conclusions:

• PRMT5 functions as a mitochondrial enzyme regulating mtDNA maintenance.
• PRMT5-mediated methylation of TFAM is a key mechanism for preserving mtDNA integrity and cellular function.
• Dysregulation of PRMT5 impacts mitochondrial health and cellular viability.