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

## TL;DR

The study reveals that reversible arginine methylation controls mitochondrial enzyme activity, specifically IDH2, through a balance between CARM1 and KDM3A/4A enzymes.

## Contribution

This work identifies reversible arginine methylation as a novel regulatory mechanism for mitochondrial enzyme function, specifically IDH2.

## Key findings

- CARM1 asymmetrically dimethylates IDH2 at R188, inhibiting its activity but increasing protein stability.
- KDM3A and KDM4A reverse this methylation, restoring IDH2 activity and promoting α-ketoglutarate production.
- Demethylated IDH2 enhances mitochondrial membrane potential and oxygen consumption despite reduced stability.

## 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.