Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Sep;58(9):1986-97.
doi: 10.2337/db09-0259. Epub 2009 Jun 19.

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

Heiko Bugger  1 , Dong Chen, Christian Riehle, Jamie Soto, Heather A Theobald, Xiao X Hu, Balasubramanian Ganesan, Bart C Weimer, E Dale Abel
Affiliations

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

Heiko Bugger et al. Diabetes. 2009 Sep.

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)-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.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
GO enrichment analysis. Simplified hierarchical trees of selected GO terms (boxes) of the “biological process” category that are enriched to the greatest extent in matrix (A) or membrane (B) fractions of Akita mitochondria using pooled proteomic data from all tissues (complete GO enrichment analyses are presented in online appendix Tables S4 and S5). Significantly enriched GO terms (P < 0.05) are highlighted, and the degree of color saturation of each node positively correlates with the enrichment significance of the corresponding GO term (red = most significant enrichment).
FIG. 2.
FIG. 2.
Gene expression. Gene expression in liver (A), heart (B), brain (C), and kidney (D) tissue of 12-week-old wild-type and Akita mice normalized to 16S RNA transcript levels (n = 6–8). Values represent fold change in mRNA transcript levels relative to wild type, which was assigned as one (dashed line).
FIG. 3.
FIG. 3.
Mitochondrial function in the liver. Respiration rates (A, B, D, E, and G) and ATP synthesis rates (C, F, and H) of mitochondria isolated from livers of 12-week-old wild-type (WT) (■) and Akita (□) mice, measured in the presence of succinate/rotenone (A–C) or glutamate/malate (D–F) or palmitoyl-carnitine/malate (G and H) as a substrate (n = 5–7). I: State 3 respiration and ATP synthesis rates were used to calculate ATP-to-O ratios for each substrate. There were no significant differences in any parameter. glu, glutamate; pc, palmitoyl-carnitine; suc, succinate.
FIG. 4.
FIG. 4.
Mitochondrial function in the kidney. Respiration rates (A, B, D, E, and G) and ATP synthesis rates (C, F, and H) of mitochondria isolated from kidneys of 12-week-old wild-type (WT) (■) and Akita (□) mice, measured in the presence of succinate/rotenone (A–C) or glutamate/malate (D–F) or palmitoyl-carnitine/malate (G and H) as a substrate (n = 5–7). I: State 3 respiration and ATP synthesis rates were used to calculate ATP-to-O ratios for each substrate. *P < 0.05 vs. wild type. glu, glutamate; pc, palmitoyl-carnitine; suc, succinate.
FIG. 5.
FIG. 5.
Mitochondrial function in the heart. Respiration rates (A, B, D, and E) and ATP synthesis rates (C and F) of mitochondria isolated from hearts of 12-week-old wild-type (WT) (■) and Akita (□) mice, measured in the presence of succinate/rotenone (A–C) or glutamate/malate (D–F) as a substrate (n = 5–7). G: State 3 respiration and ATP synthesis rates were used to calculate ATP-to-O ratios for each substrate. *P < 0.05 vs. wild type. glu, glutamate; suc, succinate.
FIG. 6.
FIG. 6.
Mitochondrial morphology. Representative longitudinal electron microscopy images of liver (A), kidney (B), brain (C), and heart (D) at a magnification of ×40,000 and quantification of mitochondrial volume density (E) and mitochondrial number (F), in liver, kidney, and heart tissue of 12-week-old wild-type (WT) (■) and Akita (□) mice (n = 4).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Borch-Johnsen K: The prognosis of insulin-dependent diabetes mellitus. An epidemiological approach. Dan Med Bull 1989; 36: 336– 348 - PubMed
    1. Dorman JS, Laporte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL: The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study: mortality results. Diabetes 1984; 33: 271– 276 - PubMed
    1. Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, Theobald HA, Yun UJ, McQueen AP, Wayment B, Litwin SE, Abel ED: Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 2008; 57: 2924– 2932 - PMC - PubMed
    1. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM: Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413: 131– 138 - PubMed
    1. de Cavanagh EM, Ferder L, Toblli JE, Piotrkowski B, Stella I, Fraga CG, Inserra F: Renal mitochondrial impairment is attenuated by AT1 blockade in experimental type I diabetes. Am J Physiol Heart Circ Physiol 2008; 294: H456– H465 - PubMed

Publication types

MeSH terms