From antioxidant hype to mitochondrial reality: Quercetin modulates cardiac redox balance but fails to restore mitochondrial respiration parameters in Zucker diabetic fatty rats

Cardiovascular diseases are strongly associated with metabolic disorders; particularly type 2 diabetes mellitus (T2DM), which profoundly alters cardiac energy metabolism. Quercetin (QCT), a dietary polyphenol with antioxidant and cardioprotective properties, has been shown to improve mitochondrial function in various disease settings. This study evaluated the effects of chronic QCT supplementation (20 mg/kg/day for 6 weeks) on antioxidant capacity and bioenergetic parameters in cardiac tissue of 6-month-old male Zucker Diabetic Fatty (ZDF) rats. As expected, T2DM caused significant hyperglycaemia and increased body weight in ZDF rats. This was accompanied by decreased plasma superoxide dismutase (SOD) and catalase (CAT) activity, together with increased lactate dehydrogenase (LDH) activity. Our observations revealed significant upregulation of Nrf2/Keap1 pathway and higher lipid peroxidation in response to T2DM. In isolated cardiac mitochondria, T2DM reduced oxygen consumption under States 2-4 respiration, as well as during respiration induced through complexes I and II. Chronic QCT supplementation significantly increased glutathione peroxidase (GPx4) expression and favourably modulated Bax/Bcl2 ratio, indicating anti-apoptotic, anti-ferroptotic, and antioxidant properties. Additionally, QCT administration reversed the effects of T2DM, increasing SOD and CAT activities and decreasing LDH activity. However, chronic QCT administration did not normalize respiration rates measured in isolated mitochondria. These findings indicate that T2DM is associated with alterations in cardiac bioenergetic parameters while QCT enhanced antioxidant defenses but did not normalize respiration measured in isolated mitochondria. The results suggest antioxidant therapy alone may by insufficient to normalize cardiac bioenergetic alterations associated with T2DM, highlighting the need for further studies targeting mitochondrial-related mechanisms.