Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db/db mice against progression of diabetic kidney disease

Chronic hyperglycemia caused by diabetes mellitus can contribute to the development and progression of diabetic kidney disease (DKD). In a previous study, we reported that reduced superoxide production is linked to mitochondrial dysfunction in the kidneys of mouse models with type 1 DKD. Additionally, we showed that individuals with DKD have significantly lower levels of mitochondrion-derived metabolites in their urine. In this study, we investigated renal superoxide production in a type 2 diabetes animal model, the db/db mouse, and explored the role of the mitochondrial protectant MTP-131 (also known as elamipretide, SS-31, or Bendavia) in restoring renal superoxide levels and alleviating DKD. We found that 18-week-old db/db mice exhibited reduced renal and cardiac superoxide levels, as assessed by dihydroethidium oxidation, alongside increased albuminuria, mesangial matrix accumulation, and urinary H2O2. Treatment with MTP-131 significantly reduced albuminuria, urinary H2O2, and mesangial matrix accumulation in db/db mice, while fully preserving renal superoxide production. Additionally, MTP-131 lowered total renal lysocardiolipin and its major subspecies, while maintaining lysocardiolipin acyltransferase 1 expression in the kidneys of db/db mice. These findings suggest that in type 2 diabetes, DKD is associated with decreased renal and cardiac superoxide levels, and that MTP-131 protects against DKD by preserving physiological superoxide levels, potentially through the regulation of cardiolipin remodeling.