Mitochondrial Bioenergetics, Diabetes, and Aging: Top-Down Analysis Using the Diabetic Goto-Kakizaki (GK) Rat as a Model.

In the present study we investigated the changes in the oxidative phosphorylation system of liver mitochondria, isolated from diabetic Goto-Kakizaki (GK) and Wistar (control) rats with different ages (6, 12, 26, and 52 weeks). We used a kinetic approach known as "top-down" analysis, which conceptually divides the oxidative phosphorylation system into two subsystems: one producing the protonmotive force (Deltap) and another that consumes Deltap. The overall response of the Deltap generators to Deltap was obtained from an uncoupler titration of respiration rate versus Deltap, while the overall response of Deltap consumers to Deltap was obtained from an inhibitor titration of respiration rate versus Deltap. Our results showed that GK liver mitochondrial preparations presented an increase in Deltap production and phosphorylative subsystems (using succinate as respiratory substrate). The alterations observed may suggest the existence of biochemical compensatory mechanisms to type 2 diabetes mellitus in GK rats during their first year of life, in order to reduce the injury associated with the disease. Furthermore, we observed that liver metabolic efficiency of mitochondrial respiration declined with age, this decrease in respiratory activity being visible both in control and diabetic rats.