Work

Dynamic S-acylation of IDH2 regulates mitochondrial redox homeostasis

Year: 2026

Type: article

Abstract: Mitochondrial redox homeostasis is fundamental for cellular function, and its dysregulation is associated with various diseases, including cancer. Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains this balance by generating NADPH. However, the mechanisms controlling IDH2 subcellular localization remain incompletely understood. Here, we identify reversible S-acylation as a critical regulator of IDH2 localization. Using chemical reporters, we demonstrate that IDH2 is S-acylated at a conserved cysteine residue, mediated by ZDHHC3 and APT1. Loss of IDH2 S-acylation disrupts its mitochondrial localization by reducing its interaction with the mitochondrial import receptor TOMM20, leading to NADPH deficiency, redox imbalance, and impaired oxidative phosphorylation. Consistently, ZDHHC3 knockout phenocopies IDH2 S-acylation deficiency, impairing its mitochondrial localization and function. Genetic ablation of IDH2 S-acylation suppresses tumor growth in vitro and in vivo. Our work establishes dynamic S-acylation of IDH2 as an essential regulator of mitochondrial redox homeostasis, thereby revealing a potential metabolic vulnerability in cancer.

Source: Cell Reports

DOI: 10.1016/j.celrep.2026.117876

Authors: Chen Miao, Zhen Wang, Jian Lin, Ziye Zhu, Jinan Wang, Baoen Chen

Institution: Zhejiang University

Language: English

Topic: Redox biology and oxidative stress

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,620