Mitochondrial energetics in the heart in obesity-related diabetes: Direct evidence for increased uncoupled respiration and activation of uncoupling proteins

Sihem Boudina, Sandra Sena, Heather Theobald, Xiaoming Sheng, Jordan J. Wright, Xuan Hu Xia, Salwa Aziz, Josie I. Johnson, Heiko Bugger, Vlad G. Zaha, E. Dale Abel

Research output: Contribution to journalArticle

384 Scopus citations

Abstract

OBJECTIVE - In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVO2) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated. RESEARCH DESIGN AND METHODS - Oxygen consumption and cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H2O2 generation determined in isolated mitochondria. RESULTS - db/db hearts exhibited reduced cardiac function and increased MVO2. Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H2O2 production was increased. Mitochondria from db/db mice exhibited fatty acid-induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 α-subunit of ATP synthase was reduced. CONCLUSIONS - These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from β-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.

Original languageEnglish (US)
Pages (from-to)2457-2466
Number of pages10
JournalDiabetes
Volume56
Issue number10
DOIs
StatePublished - Oct 1 2007

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Boudina, S., Sena, S., Theobald, H., Sheng, X., Wright, J. J., Xia, X. H., Aziz, S., Johnson, J. I., Bugger, H., Zaha, V. G., & Abel, E. D. (2007). Mitochondrial energetics in the heart in obesity-related diabetes: Direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes, 56(10), 2457-2466. https://doi.org/10.2337/db07-0481