Abstract
Mitochondria are essential for cellular homeostasis, supplying key metabolites and energy. While post-translational modifications regulate mitochondrial enzymes, their roles remain less explored compared to those in the nucleus and cytoplasm. Here, we demonstrate that reversible arginine methylation governs the activity of several mitochondrial enzymes, with a particular focus on isocitrate dehydrogenase 2 (IDH2). We identify coactivator-associated arginine methyltransferase 1 (CARM1) as a mitochondrial enzyme that asymmetrically dimethylates IDH2 at R188, leading to enzymatic inhibition while enhancing protein stability. This modification is dynamically reversed by the lysine demethylases KDM3A and KDM4A, which restore IDH2 activity. Notably, despite its reduced stability, demethylated IDH2 promotes α-ketoglutarate production, enhancing mitochondrial membrane potential and oxygen consumption. These findings highlight the critical role of reversible arginine methylation in fine-tuning mitochondrial enzyme function and maintaining mitochondrial homeostasis.
Data availability
Supplementary information is available with this paper. All other data supporting the findings of this study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank M. Bedford for helpful discussions and SA Kim for help with metabolome analysis and helpful discussions. Graphics were created using the BioRender.com software. This study was supported by grants from the National Research Foundation of Korea (NRF) and the Korean government (MSIT) [Grant numbers: RS-2024-00412728 (YC), RS-2025-00563180 (YKK), RS-2024-00509503 (YKK), and RS-2022-NR070845 (YKK)], and the Korea Institute of Science and Technology (KIST) intramural grant.
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YC planned and conducted experiments and analyzed data. JW, DGS, KBK, DHN, and SNK performed and analyzed mass spectrometry experiments. YC, SNK, and YKK designed the research and wrote the manuscript with input and contributions from all authors.
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Cho, Y., Winarto, J., Song, DG. et al. Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08444-3
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DOI: https://doi.org/10.1038/s41419-026-08444-3
