Regulation of PDH via cysteine oxidation on DLAT.

Cysteine oxidation of DLAT inhibits PDH activity and promotes a Warburg-like metabolic shift under oxidative stress in mouse and human tissues.

• Why it matters: Dysregulation of PDH is linked to metabolic diseases and cancer, but the mechanisms beyond phosphorylation are not fully understood. Understanding redox regulation of PDH could reveal new targets for therapy.
• What they did: The study identified that oxidation of three cysteines (Cys488, Cys586, Cys618) on DLAT inhibits PDH activity, with oxidation increasing under oxidative stress in tissues, and used mutations to show this regulation affects NADPH production and cell survival.
• The result: DLAT oxidation is essential for antioxidant responses, and its regulation of PDH promotes a metabolic phenotype characterized by increased glucose uptake and lactate secretion, enabling cells to better manage oxidative damage.