Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice.
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.
Bugger
Heiko
H
Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Chen
Dong
D
Riehle
Christian
C
Soto
Jamie
J
Theobald
Heather A
HA
Hu
Xiao X
XX
Ganesan
Balasubramanian
B
Weimer
Bart C
BC
Abel
E Dale
ED
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*
D005227:Fatty Acids; D020543:Proteome; D000255:Adenosine Triphosphate