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<p>Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates cellular functions such as proliferation, RNA splicing, and nuclear DNA damage response. This study uncovers that a fraction of nuclear-encoded PRMT5 localizes to the mitochondria, which is critical for maintaining mitochondrial DNA (mtDNA) homeostasis. PRMT5 knockout (PRMT5<sup>-/-</sup>) cells had reduced nucleoid counts, diminished mtDNA copy numbers, disrupted the balance of the mitochondrial fission-fusion cycle, impaired mitochondrial plasticity, and nucleoid trafficking. PRMT5<sup>-/-</sup> cells are hypersensitive to mtDNA-damaging agents, exhibit reduced mitochondrial transcripts, oxidative phosphorylation, and respiratory capacity that triggers cell death. We identify TFAM as a previously unrecognized interacting partner of PRMT5, which catalyzes symmetric dimethylation of TFAM at R82 residue, which is crucial for mtDNA binding and protection. Defective R82-methylation destabilizes TFAM, which is then degraded by LonP1. Together, we establish that PRMT5 is a mitochondrial enzyme and a key regulator of TFAM in mtDNA maintenance.</p>

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PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月23日

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  • Sangheeta Bhattacharjee,
  • Sayan Das,
  • Banhi Chowdhury,
  • Benu Brata Das

摘要

Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates cellular functions such as proliferation, RNA splicing, and nuclear DNA damage response. This study uncovers that a fraction of nuclear-encoded PRMT5 localizes to the mitochondria, which is critical for maintaining mitochondrial DNA (mtDNA) homeostasis. PRMT5 knockout (PRMT5-/-) cells had reduced nucleoid counts, diminished mtDNA copy numbers, disrupted the balance of the mitochondrial fission-fusion cycle, impaired mitochondrial plasticity, and nucleoid trafficking. PRMT5-/- cells are hypersensitive to mtDNA-damaging agents, exhibit reduced mitochondrial transcripts, oxidative phosphorylation, and respiratory capacity that triggers cell death. We identify TFAM as a previously unrecognized interacting partner of PRMT5, which catalyzes symmetric dimethylation of TFAM at R82 residue, which is crucial for mtDNA binding and protection. Defective R82-methylation destabilizes TFAM, which is then degraded by LonP1. Together, we establish that PRMT5 is a mitochondrial enzyme and a key regulator of TFAM in mtDNA maintenance.