The research, led by Scott L. Weiss of the Critical Care Mitochondrial Unit at Nemours Biomedical Research and colleagues at the University of California, Davis, and Children’s National Hospital, was built around a simple but consequential hypothesis: mitochondrial function is impaired during diabetic ketoacidosis, and that impairment may be a mechanism driving acute kidney injury. Mitochondria are the organelles responsible for converting nutrients into adenosine triphosphate, the chemical currency that cells spend to fuel everything from ion pumps to protein synthesis. Kidney tissue is particularly dependent on this energy supply. The proximal tubules, which reclaim the vast majority of the glomerular filtrate every day, are packed with mitochondria and are among the most energy-hungry cells in the body, making them exquisitely vulnerable when oxidative phosphorylation falters.

To test the hypothesis, the team studied juvenile rats aged four to five weeks, an age chosen because it mirrors the pediatric population in which diabetic ketoacidosis most often announces a new diagnosis of type 1 diabetes. The animals were divided into four groups: normoglycemic controls with seven animals; a hyperglycemic group with five; an acute diabetic ketoacidosis group with five; and a fifth group examined twenty-four hours after treatment of diabetic ketoacidosis, also with five animals. This design allowed the investigators to separate the effects of high blood sugar alone from the full metabolic storm of ketoacidosis, and then to ask whether the changes they observed could be rolled back by standard treatment.

The team prepared homogenates from frozen kidney tissue and measured the activity of the mitochondrial electron transport system, the chain of protein complexes embedded in the inner mitochondrial membrane that shutters electrons from nutrients to oxygen while pumping protons to power ATP synthesis. Using spectrophotometric assays, they quantified the coupled activity of complexes I plus III, complexes II plus III, and complex IV, along with citrate synthase activity, a standard surrogate for mitochondrial content. In parallel, Western blots quantified the expression of the electron transport system complex proteins themselves, giving the researchers two independent windows on mitochondrial health: one biochemical, one structural.

The central finding was strikingly clean. The coupled activity of complexes I plus III, which reflects the ability of the first and third links in the respiratory chain to work together, showed a stepwise decline as glycemic stress deepened. Hyperglycemic animals averaged 113 plus or minus 54 nanomoles per minute per milligram of tissue protein, while animals in acute diabetic ketoacidosis dropped to 64 plus or minus 32, a value significantly lower than the normoglycemic controls. When the researchers treated the diabetic ketoacidosis animals and re-examined their kidneys twenty-four hours later, activity had rebounded to 135 plus or minus 39, essentially indistinguishable from the control level of 143 plus or minus 37. In other words, the enzyme defect was not a fixed injury but a reversible functional derangement that tracked the severity of the metabolic crisis.

Equally important was what did not change. Citrate synthase activity and the expression of electron transport system complex proteins I, II, IV, and V did not differ between the groups, indicating that the total number of mitochondria in the kidney tissue was preserved throughout the experiment. The single exception was complex III, whose protein expression rose in both the hyperglycemic and diabetic ketoacidosis groups and then fell back after treatment. This dissociation between mitochondrial quantity and mitochondrial quality is the study’s most technically significant contribution. It suggests that during diabetic ketoacidosis, the kidney’s problem is not a loss of mitochondria but a loss of function within the ones it already has, a subtle but clinically meaningful distinction that changes what kinds of therapies might help.

Why would complex I be particularly susceptible? Complex I, or NADH:ubiquinone oxidoreductase, is the largest and most structurally elaborate of the respiratory chain complexes, the entry point for electrons donated from the Krebs cycle, and a well-known site of vulnerability under metabolic stress. Prior work in other contexts has shown that complex I dysfunction can promote the generation of reactive oxygen species, disrupt the proton gradient, and sensitize cells to inflammatory signaling. The reversible nature of the defect observed here points toward regulatory or post-translational mechanisms, such as oxidative modification of complex I subunits, changes in the assembly of respiratory supercomplexes, or alterations in the mitochondrial redox environment, rather than wholesale destruction of the organelles. Complex III upregulation during hyperglycemia and ketoacidosis may represent a compensatory attempt to maintain electron flux when the upstream entry point is compromised.

The findings dovetail with a broader body of evidence linking mitochondrial dysfunction to organ injury in critical illness. Weiss and colleagues have previously shown that persistent mitochondrial dysfunction is associated with prolonged organ dysfunction in pediatric sepsis, and other groups have documented renal mitochondrial impairment in experimental sepsis-associated acute kidney injury and in models of early diabetes affecting the heart. Diabetic ketoacidosis brings together several of the same stressors: severe hyperglycemia, acidosis, dehydration and shock, and a surge of circulating inflammatory cytokines. Mitochondrial damage-associated molecular patterns released from injured cells are known to amplify inflammatory responses, raising the possibility that kidney mitochondrial dysfunction during diabetic ketoacidosis is not merely a victim of the crisis but an active contributor to the inflammatory cascade and the clinical kidney injury that follows.

The clinical stakes are considerable. Acute kidney injury complicates a substantial fraction of pediatric diabetic ketoacidosis episodes, and follow-up data from children with type 1 diabetes have associated such injury with later microalbuminuria, an early marker of diabetic kidney disease. If the mitochondrial defect demonstrated here proves to be mechanistically involved, it opens a therapeutic window: strategies aimed at preserving respiratory chain function, buffering oxidative stress, or supporting mitochondrial biogenesis during and after diabetic ketoacidosis could conceivably blunt both the acute injury and its long-term renal consequences. The reversibility observed in the rat model after only twenty-four hours of treatment is encouraging on this front, though the authors are careful to frame it as support for further investigation rather than proof of causation.

Limitations remain. The study was conducted in tissue homogenates from a rodent model with relatively small group sizes, and homogenate assays measure maximal enzymatic capacity rather than respiration in intact cells. Whether the same complex I defect occurs in the kidneys of children with diabetic ketoacidosis, and whether it predicts the severity of acute kidney injury or later albuminuria, will require translational studies in human patients. Still, by isolating a specific, reversible molecular lesion, complex I dysfunction with altered complex III expression, within preserved mitochondrial content, the study gives investigators a concrete target and a testable mechanism for one of the most feared complications of childhood diabetes, and it strengthens the growing argument that mitochondria sit at the crossroads of metabolic crisis, inflammation, and organ injury.

Subject of Research: Kidney mitochondrial complex I dysfunction during diabetic ketoacidosis in a juvenile rat model

Article Title: Kidney mitochondrial complex I dysfunction in a juvenile rat model of diabetic ketoacidosis

Article References: Kidney mitochondrial complex I dysfunction in a juvenile rat model of diabetic ketoacidosis. (n.d.). https://doi.org/10.1038/s41390-026-05499-y

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05499-y

Keywords: diabetic ketoacidosis, acute kidney injury, mitochondrial dysfunction, complex I, electron transport chain, complex III, citrate synthase, juvenile rat model, type 1 diabetes, pediatric research, oxidative phosphorylation, kidney injury

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