Lactate drives maladaptive metabolic reprogramming via MRS2 inischemia–reperfusion-induced acute kidney injury

Background Ischemia–reperfusion–induced acute kidney injury (I/R-AKI) causes profound bioenergetic collapse in renal proximal tubular epithelial cells, triggering a sustained shift from mitochondrial oxidative metabolism to glycolysis. Although lactate accumulation is a hallmark of this metabolic state, whether lactate actively drives mitochondrial dysfunction and enforces persistent metabolic reprogramming remains unclear. Methods Human renal biopsy specimens, murine I/R-AKI, and hypoxia/reoxygenation–challenged proximal tubular epithelial cells were used to investigate the lactate–MRS2 axis in I/R-AKI. Lactate signaling was inhibited by sodium oxamate, while MRS2 was suppressed using CPACC or siRNA-based approaches, including lipid nanoparticle–mediated siMRS2 delivery. Mitochondrial function and oxidative metabolism were assessed by oxygen consumption rate, ATP production, mitochondrial membrane potential, and tricarboxylic acid cycle (TCA) gene expression. Results I/R-AKI induced a pronounced bioenergetic deficit in proximal tubules, marked by disrupted mitochondrial homeostasis, suppressed TCA cycle activity and enhanced aerobic glycolysis. Glycolysis-derived lactate accumulated during reperfusion, disrupting mitochondrial oxidative metabolism, whereas inhibition of lactate production with sodium oxamate attenuated tubular injury and restored mitochondrial metabolic function. Mechanistically, lactate activated the mitochondrial Mg²⁺ channel MRS2, causing mitochondrial Mg²⁺ overload and sustained reliance on inefficient glycolysis. Targeting MRS2, either pharmacologically or via lipid nanoparticle–mediated siRNA delivery, normalized mitochondrial Mg²⁺ homeostasis, improved mitochondrial function and reinstated oxidative metabolism following I/R-AKI. Conclusion This study identifies a previously unrecognized lactate–MRS2 signaling axis that drives maladaptive metabolic reprogramming in ischemic AKI. Targeting MRS2 to restore mitochondrial Mg²⁺ homeostasis reinstates oxidative metabolism, breaks maladaptive metabolic reprogramming, and promotes renal recovery.