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