Mitochondrial ROS deficiency and diabetic complications: AMP[K]-lifying the adaptation to hyperglycemia

Abstract

Global, sustained production of ROS has deleterious effects on tissue structure and function and gives rise to biochemical and physiological changes associated with organ senescence. Specific, localized ROS metabolites generated by mitochondria and NADPH oxidases also transduce homeostatic information in response to metabolic, mechanical, and inflammatory cues. In this issue of the JCI, Dugan and colleagues demonstrate that mitochondrial-derived ROS, which is maintained by a feed-forward AMP kinase activation cascade, is reduced in diabetes and plays an adaptive role in preserving renal glomerular function during hyperglycemia. This enlightened view of mitochondrial ROS biology forces us to reconsider therapeutic approaches to metabolic disease complications such as diabetic nephropathy.

Figure 1. A feed-forward cycle of AMPK-activated mitochondrial metabolism and ROS generation by the kidney reduces diabetes-induced albuminuria.

(A) Diabetes results in decreased renal mitochondrial superoxide production, which is associated with decreased AMPK and PDH activity. Decreases in AMPK and PDH activity further reduce mitochondrial ROS production directly and through decreased PGC1α, which promotes decreased mitochondrial density, ultimately resulting in impaired renal podocyte function and albuminuria. Decreased AMPK also results in increased NADPH oxidase–dependent ROS production. (B) Restoration of renal mitochondrial ROS production by treatment with the AMPK activator AICAR reduces albuminuria and total renal oxidative stress. Mitochondrially derived ROS, which is stimulated by AICAR and amplified by a feedforward AMPK cascade, is protective in the setting of hyperglycemia. The failure of mitochondrial ROS generation contributes to diabetic kidney disease. Furthermore, AMPK activation reduces NADPH oxidase–dependent ROS formation.