SUMOylation targets OGA to mitochondria via PRKN for respiratory homeostasis

O-GlcNAcylation is a dynamic post-translational modification spatiotemporally orchestrated by OGA, the sole O-GlcNAcase, and OGT, the sole O-GlcNAc transferase. However, the mechanisms that control their enzymatic activity and subcellular deployment remain poorly understood. Here, we identify SUMOylation as a critical regulator of this process. SUMOylation elevates global O-GlcNAcylation levels by reducing OGA abundance while increasing that of OGT. Additionally, SUMO conjugates to the catalytic domain of OGA, a modification associated with its hydrolytic activity. SUMOylation also promotes OGA binding to the mitochondrial E3 ubiquitin ligase PRKN, facilitating its turnover and driving its translocation to mitochondria. Mutation of K358, which abolished detectable OGA SUMOylation, impaired mitochondrial respiration and cell proliferation and markedly reduced xenograft tumor growth. Together, our findings establish SUMOylation as a key regulator that coordinates both the enzymatic activity and subcellular localization of OGA, with functional consequences for cellular energetics and malignant fitness.