Mitochondria-targeted Antioxidant Therapy MitoTempo Attenuates Renal Injury in a Mouse Model of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and polycystic ovaries. Renal injury in the form of albuminuria is prevalent in PCOS, yet the molecular mechanisms are poorly understood. Both animal models and women with PCOS exhibit chronic systemic low-grade inflammation. Inflammation impairs renal mitochondrial function, leading to oxidative stress and renal injury. Hyperandrogenemia negatively impacts mitochondrial structure and function in extra-renal tissues in PCOS. However, the role of mitochondrial dysfunction in androgen excess-induced renal injury in PCOS remains elusive. We aimed to test the hypothesis that androgen excess induces renal inflammation, mitochondrial reactive oxygen species (ROS) generation, and mitochondrial dysfunction, leading to renal injury, and that mitochondria-targeted antioxidant therapy can ameliorate this injury in a well-established mouse model of PCOS. Methods: PCOS was induced in 3-week-old female mice by the non-aromatizable androgen dihydrotestosterone Silastic Tube implantation (DHT, 8 mg, 12 weeks). Eight weeks later, the mice were given the mitochondria-targeted antioxidant therapy MitoTEMPO (1 mg/kg/d, i.p.) or vehicle for 4 weeks. Kidney weight was measured and normalized by tibia length (TL). Urinary albumin to creatinine ratio (UACR) was assessed using a clinical chemistry analyzer. The inflammatory (IL-6, IL-β, and TNF-α) markers were quantified by RT-qPCR. Renal mitochondrial markers (cytochrome C, succinate dehydrogenase A, and stress protein HSP60) were measured by Western blot. Mitochondrial reactive oxygen species (mtROS) was detected by the Amplex Red assay. Moreover, complex I and II-driven respiration and complex IV activity (Oroboros FluoRespirometer), as well as medium (MCFA) and long chain fatty acid (LCFA) oxidation, were measured in freshly-isolated kidney mitochondria. Results: DHT significantly (p<0.05) increased kidney weight/TL (28.49±1.01 vs. 18.16±1.26 g/mm), UACR (1.7-fold), and renal IL-6, IL-β, and TNF-α levels (1.5-fold). PCOS mice have higher renal complex I-driven (4.60±0.79 vs. 1.61±0.23% electron leak), as well as maximal mtROS production (3.5-fold) compared to the control mice. Moreover, PCOS mice have lower complexes I, II, III, and IV-driven respiration (43-71%), along with lower cytochrome c (32%), and higher HSP60 (4-fold) levels. MCFA and LCFA levels were similar among PCOS and control mice. Targeting mtROS with MitoTEMPO didn’t affect kidney weight and had no significant changes on complexes I, II, III, and IV-derived respiration. Enhancing fatty acid oxidation can be targeted to ameliorate renal injury. Interestingly, PCOS mice treated with MitoTEMPO have a significant increase in both MCFA (1.8-fold) and LCFA (1.5-fold) oxidation, indicating enhanced fatty acid metabolism when compared to vehicle-treated PCOS mice. Conclusion and significance: Our findings suggest that renal mitochondrial function plays a significant role in the renal outcomes in PCOS, and its targeting could be a novel therapeutic approach to ameliorate renal injury in PCOS. Supported by NIH grants NIGMS P20GM121334 (SR, KSE, and DGR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.