Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the AktmTOR-NFkB-Opa-1 signaling pathway

Valentina Parra, Hugo E. Verdejo, Myriam Iglewski, Andrea Del Campo, Rodrigo Troncoso, Deborah Jones, Yi Zhu, Jovan Kuzmicic, Christian Pennanen, Camila Lopez-Crisosto, Fabián Jaña, Jorge Ferreira, Eduard Noguera, Mario Chiong, David A. Bernlohr, Amira Klip, Joseph A Hill, Beverly A Rothermel, Evan Dale Abel, Antonio ZorzanoSergio Lavandero

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFkB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFkB pathway.

Original languageEnglish (US)
Pages (from-to)75-88
Number of pages14
JournalDiabetes
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Parra, V., Verdejo, H. E., Iglewski, M., Del Campo, A., Troncoso, R., Jones, D., Zhu, Y., Kuzmicic, J., Pennanen, C., Lopez-Crisosto, C., Jaña, F., Ferreira, J., Noguera, E., Chiong, M., Bernlohr, D. A., Klip, A., Hill, J. A., Rothermel, B. A., Abel, E. D., ... Lavandero, S. (2014). Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the AktmTOR-NFkB-Opa-1 signaling pathway. Diabetes, 63(1), 75-88. https://doi.org/10.2337/db13-0340