Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure

San Pin Wu, Chung Yang Kao, Leiming Wang, Chad J. Creighton, Jin Yang, Taraka R. Donti, Romain Harmancey, Hernan G. Vasquez, Brett H. Graham, Hugo J. Bellen, Heinrich Taegtmeyer, Ching Pin Chang, Ming Jer Tsai, Sophia Y. Tsai

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy. Here, we show that myocardial COUP-TFII overexpression causes heart failure in mice, suggesting a causal effect of elevated COUP-TFII levels on development of dilated cardiomyopathy. COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification and mitochondrial dynamics, resulting in increased levels of reactive oxygen species and lower rates of oxygen consumption in mitochondria. COUP-TFII also suppresses the metabolic regulator PGC-1 network and decreases the expression of key glucose and lipid utilization genes, leading to a reduction in both glucose and oleate oxidation in the hearts. These data suggest that COUP-TFII affects mitochondrial function, impairs metabolic remodelling and has a key role in dilated cardiomyopathy. Last, COUP-TFII haploinsufficiency attenuates the progression of cardiac dilation and improves survival in a calcineurin transgenic mouse model, indicating that COUP-TFII may serve as a therapeutic target for the treatment of dilated cardiomyopathy.

Original languageEnglish (US)
Article number8245
JournalNature communications
Volume6
DOIs
StatePublished - Sep 10 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Wu, S. P., Kao, C. Y., Wang, L., Creighton, C. J., Yang, J., Donti, T. R., Harmancey, R., Vasquez, H. G., Graham, B. H., Bellen, H. J., Taegtmeyer, H., Chang, C. P., Tsai, M. J., & Tsai, S. Y. (2015). Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nature communications, 6, [8245]. https://doi.org/10.1038/ncomms9245