Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.

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.