Abstract
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.
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Acknowledgements
The BBD team is supported by SERB core research grant (CRG/2022/001322), ANRF-SUPRA grant (SPR/2023/000321), and ICMR grant (2021-11299/ CMB/ADHOC-BMS), and IACS intramural funds. SB is the recipient of the IACS Research Associate fellowship, and SD is the recipient of the CSIR-NET Senior Research Fellowship. BC is the recipient of the UGC-NET Senior Research Fellowship.
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S.B. and B.B.D conceived and designed the study. S.B., S.D., and B.C. performed the experiments. B.B.D supervised the experiments. S.B. and B.B.D curated the data. S.B. wrote the draft manuscript, which was finalized by B.B.D. All funding was acquired by B.B.D.
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Bhattacharjee, S., Das, S., Chowdhury, B. et al. PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69676-7
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DOI: https://doi.org/10.1038/s41467-026-69676-7
