Interplay between NADH oxidation by complex I, glutathione redox state and sirtuin-3, and its role in the development of insulin resistance

Metabolic diseases are characterized by high NADH/NAD(+) ratios due to excessive electron supply, causing defective mitochondrial function and impaired sirtuin-3 (SIRT-3) activity, the latter driving to oxidative stress and altered fatty acid beta-oxidation. NADH is oxidized by the complex I in the electron transport chain, thereby factors inhibiting complex I like acetylation, cardiolipin peroxidation, and glutathionylation by low GSH/GSSG ratios affects SIRT3 function by increasing the NADH/NAD(+) ratio. In this review, we summarized the evidence supporting a role of the above events in the development of insulin resistance, which is relevant in the patho-genesis of obesity and diabetes. We propose that maintenance of proper NADH/NAD(+) and GSH/GSSG ratios are central to ameliorate insulin resistance, as alterations in these redox couples lead to complex I dysfunction, disruption of SIRT-3 activity, ROS production and impaired beta-oxidation, the latter two being key effectors of insulin resistance.