Lactate drives maladaptive metabolic reprogramming via MRS2 in ischemia/reperfusion-induced acute kidney injury

Ischemia/reperfusion (I/R) triggers profound bioenergetic collapse in renal proximal tubular epithelial cells (PTECs), inducing acute kidney injury (AKI) and forcing a sustained shift from mitochondrial oxidative metabolism to glycolysis. Lactate accumulation is a hallmark of this metabolic switch, yet it remains unknown whether lactate actively drives mitochondrial dysfunction and enforces persistent maladaptive metabolic reprogramming. We hypothesized that hypoxia-driven lactate overproduction sustains maladaptive metabolic reprogramming through an MRS2-dependent mechanism in PTECs. To test this hypothesis, human renal biopsy specimens, murine I/R-AKI, and hypoxia/reoxygenation (H/R)–challenged PTECs were used. Lactate signaling was inhibited by sodium oxamate, and MRS2 was suppressed pharmacologically (CPACC) or via siRNA, including lipid nanoparticle–mediated delivery of siMRS2. Mitochondrial function and oxidative metabolism were assessed by oxygen consumption rate (OCR), ATP production, mitochondrial membrane potential, and expression of tricarboxylic acid (TCA) cycle genes. I/R induced a pronounced bioenergetic deficit in proximal tubules, characterized by disrupted mitochondrial homeostasis, suppressed TCA cycle activity, and enhanced aerobic glycolysis. Lactate accumulation derived from glycolysis during reperfusion impaired mitochondrial oxidative metabolism, whereas inhibition of lactate production with sodium oxamate attenuated tubular injury and restored oxidative metabolism. In AKI patients, serum lactate levels were positively correlated with renal MRS2 expression. Lactate accumulation increased mitochondrial Mg 2+ uptake in an MRS2-dependent manner, resulting in mitochondrial Mg 2+ overload and inhibition of citrate synthase (CS). Pharmacological inhibition or lipid nanoparticle-mediated siRNA delivery targeting MRS2 restored mitochondrial oxidative metabolism, reduced lactate accumulation, and attenuated renal injury following I/R injury. This study identifies a previously unrecognized lactate–MRS2 pathway that contributes to maladaptive metabolic reprogramming in ischemic AKI. MRS2 functions as a key mediator linking lactate accumulation to impaired metabolic adaptation during reperfusion. These findings highlight the lactate–MRS2 pathway as a mechanistically defined target for future metabolism-based intervention in AKI.