title: Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice.
abstract: OBJECTIVE
  To elucidate the molecular basis for mitochondrial dysfunction, which has been implicated in the pathogenesis of diabetes complications.
  
  
  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)-gamma coactivator (PGC)-1alpha 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.
authors: Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors: Heiko
authors: H
authors: Bugger
authors: Dong
authors: D
authors: Chen
authors: Christian
authors: C
authors: Riehle
authors: Jamie
authors: J
authors: Soto
authors: Heather A
authors: HA
authors: Theobald
authors: Xiao X
authors: XX
authors: Hu
authors: Balasubramanian
authors: B
authors: Ganesan
authors: Bart C
authors: BC
authors: Weimer
authors: E Dale
authors: ED
authors: Abel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D019069:Cell Respiration; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D020543:Proteome / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D020543:Proteome; D000255:Adenosine Triphosphate