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

Abstract

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 (Δp) and another that consumes Δp. The overall response of the Δp generators to Δp was obtained from an uncoupler titration of respiration rate versus Δp, while the overall response of Δp consumers to Δp was obtained from an inhibitor titration of respiration rate versus Δp. Our results showed that GK liver mitochondrial preparations presented an increase in Δp 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.