Abstract

Objective: To elucidate the molecular basis for mitochondrial dysfunction, which has been implicated in the pathogenesis of diabetic complications.

Research Design and Methods: Mitochondrial matrix and membrane fractions were generated from liver, brain, heart, and kidney of wildtype and type 1 diabetic Akita mice. Comparative proteomics was performed using label-free proteome expression analysis. Mitochondrial state 3 respirations and ATP synthesis were measured, and mitochondrial morphology was evaluated by electron microscopy. Expression of genes that regulate mitochondrial biogenesis, substrate utilization and oxidative phosphorylation (OXPHOS) were determined.

Results: In diabetic mice, fatty acid oxidation (FAO) proteins were less abundant in liver mitochondria, whereas in mitochondria from all other tissues FAO protein content was induced. Kidney mitochondria showed coordinate induction of tricarboxylic acid (TCA) cycle enzymes, whereas TCA cycle proteins were repressed in cardiac mitochondria. Levels of OXPHOS subunits were coordinately increased in liver mitochondria, whereas mitochondria of other tissues were unaffected. Mitochondrial respiration, ATP synthesis, and morphology were unaffected in liver and kidney mitochondria. In contrast, state 3 respirations, ATP synthesis, and mitochondrial cristae density were decreased in cardiac mitochondria and were accompanied by coordinate repression of OXPHOS and PGC-1α transcripts.

Conclusions: Type 1 diabetes causes tissue-specific remodeling of the mitochondrial proteome. Preservation of mitochondrial function in kidney, brain and liver, versus mitochondrial dysfunction in the heart, supports a central role for mitochondrial dysfunction in diabetic cardiomyopathy.