The Warburg Effect Promotes Mitochondrial Injury Regulated by Uncoupling Protein-2 in Septic Acute Kidney Injury

Background: Evidence implying that metabolism reprogramming plays an important role in the regulation of sepsis is increasing; however, whether it has a similar role in septic organ dysfunction remains unclear. Here, we provide evidence to support a new role of uncoupling protein-2 (UCP2)-regulated Warburg effect, i.e., aerobic glycolysis, in promoting mitochondrial injury in the kidney. Methods: To imitate sepsis condition, male C57BL/6 mice were operated by the cecal ligation puncture in vivo, whereas a normal human kidney cell line (HK-2) was treated with lipopolysaccharide in vitro. UCP2 small interfering RNA pretreatment was performed to knock down UCP2 expression in vitro. The glycolysis metabolite was detected by liquid chromatography/tandem mass spectrometry in vivo and detected by commercial kits in vitro. Oxidative phosphorylation level and glycolysis level were monitored by measuring the oxygen consumption rate (indicative of respiration) and extracellular acidification rate (indicative of glycolysis) in vitro. Exogenous lactate was supplied to stimulate HK-2 cells and indicators of mitochondrial dysfunction were also assessed. Results: Aerobic glycolysis is enhanced in septic tubular epithelial cells, and the glycolysis inhibitor 2-deoxyglucose can partially restore mitochondrial membrane potential and decrease the reactive oxygen species production. With the knockdown of UCP2, the aerobic glycolysis level upregulates, and mitochondrial injury increases. Conclusions: These results provide insights on a new mechanism of metabolic regulation of mitochondrial injury and the importance of targeting aerobic glycolysis for the treatment of septic acute kidney injury.

Automated summary

The study demonstrates that aerobic glycolysis is enhanced in septic tubular epithelial cells and inhibition of glycolysis can partially restore mitochondrial function. Knockdown of UCP2 results in increased aerobic glycolysis and mitochondrial injury. Targeting aerobic glycolysis may be important in the treatment of septic acute kidney injury.