Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice

Heiko Bugger, Chen Dong, Christian Riehle, Jamie Soto, Heather A. Theobald, Xiao Hu, Balasubramanian Ganesan, Bart C. Weimer, E. Dale Abel

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122 Scopus citations

Abstract

OBJECTIVE - To elucidate the molecular basis for mitochondrial dysfunction, which has been implicated in the pathogenesis of diabetes complications. RESEARCH DESIGN AND METHODS - Mitochondrial matrix and membrane fractions were generated from liver, brain, heart, and kidney of wild-type 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 FAO protein content was induced in mitochondria from all other tissues. 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 peroxisome proliferator-activated receptor (PPAR)-γ coactivator (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.

Original languageEnglish (US)
Pages (from-to)1986-1997
Number of pages12
JournalDiabetes
Volume58
Issue number9
DOIs
StatePublished - Sep 2009

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Bugger, H., Dong, C., Riehle, C., Soto, J., Theobald, H. A., Hu, X., Ganesan, B., Weimer, B. C., & Abel, E. D. (2009). Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice. Diabetes, 58(9), 1986-1997. https://doi.org/10.2337/db09-0259