Mitochondrial Complex I Inhibition Is Associated with Macrophage Metabolic Reprogramming and Impaired Chronic Diabetic Wound Healing

Abstract Aim To investigate the association of macrophage metabolic reprogramming with wound healing and angiogenesis in a murine model of chronic diabetic wounds. Methods Diabetes was induced in mice using a high-fat diet combined with streptozotocin (STZ). Successful induction was defined as a fasting blood glucose level ≥ 16.7 mmol/L on two separate days. Mice were randomly allocated to normal control, diabetic, vehicle, and rotenone groups. A full-thickness excisional wound approximately 2 cm in diameter was created on the dorsum of each mouse. The rotenone group received daily intraperitoneal rotenone (1 mg/kg), whereas the vehicle group received an equivalent volume of vehicle; the normal control and diabetic groups received no additional treatment. Wound closure was evaluated on days 4, 8, 12, and 16. Histological changes were assessed by hematoxylin and eosin staining; LDHA, PKM2, and CS expression by immunohistochemistry; and iNOS and Arg-1 mRNA expression by RT-qPCR. Results Compared with the normal control group, the diabetic, vehicle, and rotenone groups showed delayed wound closure. On days 8, 12, and 16, wound closure rates were lower in all three groups than in normal controls, with the rotenone group showing the lowest rates at each time point. Histological examination further revealed greater inflammatory cell infiltration and delayed re-epithelialization in the rotenone group. In this group, LDHA and PKM2 expression began to increase on day 8. Relative to normal controls, LDHA expression was significantly higher on days 8 and 16, PKM2 expression was significantly higher on days 8, 12, and 16, and CS expression was lower at all assessed time points. In addition, iNOS mRNA expression was increased on days 4, 8, and 12, whereas Arg-1 mRNA expression was decreased on days 4 and 8 but increased on day 12. Conclusions Rotenone further delayed chronic wound healing in diabetic mice, accompanied by changes consistent with enhanced glycolysis, impaired oxidative metabolism, and an imbalance between M1- and M2-associated macrophage phenotypes. These findings suggest that macrophage metabolic reprogramming may contribute to impaired repair of chronic diabetic wounds and may represent a potential target for future intervention.