Acute kidney injury, or AKI, affects a substantial share of hospitalized patients and carries significant short-term mortality and long-term risk of chronic kidney disease. At the cellular level, the damage concentrates in the proximal tubular epithelial cells, the workhorse cells of the nephron that normally rely overwhelmingly on mitochondrial oxidative phosphorylation to power massive reabsorption of solutes. When ischemia cuts off oxygen, these cells suffer a bioenergetic collapse: ATP production plummets, mitochondrial homeostasis is disrupted, and the tricarboxylic acid cycle, the central hub of oxidative metabolism, grinds toward inactivity. In a desperate bid to survive, the cells pivot to glycolysis, generating ATP from glucose without oxygen. That metabolic switch produces lactate as its signature byproduct, and lactate accumulation has long been regarded as a passive marker of the injury. The new study asks a sharper question: is lactate merely a bystander, or is it an active driver of the mitochondrial failure that follows?

To answer it, the researchers assembled evidence from three complementary systems: human renal biopsy specimens from patients with AKI, a murine model of ischemia/reperfusion-induced AKI, and proximal tubular epithelial cells challenged in vitro with hypoxia followed by reoxygenation. Across all three, they documented the same sequence. Ischemia/reperfusion inflicted a pronounced bioenergetic deficit in the proximal tubules, characterized by disrupted mitochondrial homeostasis, suppressed activity of TCA cycle genes, and enhanced aerobic glycolysis. Crucially, the lactate that accumulated during reperfusion was not inert. When the team blocked lactate production with sodium oxamate, a well-established inhibitor of lactate dehydrogenase, tubular injury was attenuated and oxidative metabolism was partially restored, indicating that lactate actively impairs mitochondrial oxidative metabolism rather than simply reflecting it.

The mechanistic trail then led to an unexpected player: MRS2, the mitochondrial RNA splicing 2 protein, which functions as the dominant channel for magnesium uptake into mitochondria. In the patient biopsies, serum lactate levels were positively correlated with renal MRS2 expression, hinting that the metabolic waste product and the magnesium channel were linked in human disease. Follow-up experiments in cells and mice confirmed the connection. Lactate accumulation increased mitochondrial magnesium uptake in an MRS2-dependent manner, driving an overload of magnesium ions inside the organelles. That overload, the study found, inhibits citrate synthase, the enzyme that catalyzes the first committed step of the TCA cycle. The consequence is a vicious loop: glycolysis generates lactate, lactate triggers MRS2-mediated magnesium influx, magnesium excess throttles the TCA cycle, and the crippled oxidative machinery forces the cell to lean even harder on glycolysis, producing more lactate.

Technical measurements anchored the claim. The team assessed mitochondrial function and oxidative metabolism using oxygen consumption rate assays, which quantify how efficiently mitochondria consume oxygen to generate ATP, alongside direct measurements of ATP production, mitochondrial membrane potential, and expression of TCA cycle genes. In the injured tubules, these readouts collapsed in parallel with rising lactate and rising MRS2 activity. When MRS2 was suppressed, either pharmacologically with the inhibitor CPACC or genetically with siRNA, mitochondrial oxidative metabolism rebounded, lactate accumulation fell, and renal injury following ischemia/reperfusion was attenuated. The genetic approach was delivered in vivo using lipid nanoparticles, the same class of delivery vehicles that carried mRNA vaccines into clinical use, encapsulating siMRS2 and silencing the channel in kidney tissue.

The therapeutic implications are striking because MRS2 offers a defined molecular handle on a process that has resisted intervention. Current management of ischemic AKI remains largely supportive, centered on hemodynamic optimization, avoidance of nephrotoxins, and, in severe cases, dialysis, while the underlying metabolic failure runs its course. A metabolism-based strategy that interrupts the lactate–MRS2 axis could, in principle, preserve mitochondrial function during the vulnerable reperfusion window and prevent the transition from reversible injury to established organ damage. The lipid nanoparticle delivery of siMRS2 demonstrated in this study provides a proof of concept that the target is druggable in living animals, and CPACC offers a small-molecule starting point for medicinal chemistry.

The study also reframes lactate itself. Long treated as a metabolic waste product or, in the Warburg tradition of cancer biology, as a hallmark of deranged metabolism, lactate is increasingly recognized as a signaling molecule with receptor-mediated and epigenetic effects. This work adds a subcellular dimension to that picture: lactate acting on the mitochondrial magnesium channel to reshape bioenergetics from within. In the kidney, where proximal tubular cells have minimal glycolytic capacity relative to their oxidative demands, such signaling may be particularly consequential, explaining why the glycolytic shift that sustains other cell types during hypoxia becomes maladaptive in the tubule.

Important caveats remain. The findings derive from biopsy specimens, a mouse model, and cell culture, and the translation of MRS2 inhibition to human therapy will require safety evaluation, since mitochondrial magnesium handling is fundamental to organelle function throughout the body. The timing of any intervention also matters, because reperfusion injury unfolds over hours and the therapeutic window must be defined precisely. The authors note that the article was shared early as a citable, peer-reviewed accepted version subject to further edits, and the work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, and Shanghai municipal science programs. Corresponding authors Yiqin Shi, Xiaoqiang Ding, and Nana Song led the collaboration, with Zhixin Yan, Annan Chen, and Fang Li as co-first authors.

Even with those qualifications, the study delivers a coherent and clinically resonant mechanism: hypoxia-driven lactate overproduction sustains maladaptive metabolic reprogramming through MRS2-dependent mitochondrial magnesium overload and citrate synthase inhibition. It explains why the kidney’s metabolic switch after ischemia becomes a trap rather than a rescue, and it converts that explanation into testable targets. If subsequent work confirms that blunting the lactate–MRS2 pathway protects human kidneys during surgery, transplantation, and shock, the humble end product of glycolysis may graduate from biomarker to bullseye, and the mitochondria of the proximal tubule may finally get the chance to resume the oxidative work upon which the entire organ depends.

Subject of Research: The lactate–MRS2 pathway driving maladaptive metabolic reprogramming in ischemia/reperfusion-induced acute kidney injury

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

Article References: Yan, Z., Chen, A., Li, F., Zhang, J., Xie, Q., Han, G., Zhou, W., Yusufu, A., Chen, W., Gu, Q., Zhao, S., Yang, Y., Wang, J., Fang, Y., Li, Y., Dai, Y., Jin, S., Shi, Y., Ding, X., & Song, N. (2026). Lactate drives maladaptive metabolic reprogramming via MRS2 in ischemia/reperfusion-induced acute kidney injury. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06402-y

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06402-y

Keywords: acute kidney injury, ischemia/reperfusion, lactate, MRS2, mitochondrial magnesium overload, metabolic reprogramming, citrate synthase, proximal tubular epithelial cells, TCA cycle, lipid nanoparticle siRNA, mitochondrial dysfunction, sodium oxamate