Insulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 Signaling Pathway
- Valentina Parra1,2,3,
- Hugo E. Verdejo1,4,
- Myriam Iglewski3,
- Andrea del Campo1,2,
- Rodrigo Troncoso1,2,
- Deborah Jones5,
- Yi Zhu5,
- Jovan Kuzmicic1,2,
- Christian Pennanen1,2,
- Camila Lopez‑Crisosto1,2,
- Fabián Jaña6,
- Jorge Ferreira6,
- Eduard Noguera7,
- Mario Chiong1,2,
- David A. Bernlohr8,
- Amira Klip9,
- Joseph A. Hill3,
- Beverly A. Rothermel3,
- Evan Dale Abel5,
- Antonio Zorzano7 and
- Sergio Lavandero1,2,3,10⇑
- 1Advanced Center for Chronic Diseases (ACCDIS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
- 2Departamento de Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- 3Department of Internal Medicine (Cardiology) and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
- 4Departamento Enfermedades Cardiovasculares, Facultad Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- 5Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UT
- 6Programa de Farmacología Molecular y Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- 7Institute for Research in Biomedicine, Barcelona, Spain
- 8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota: Twin Cities, Minneapolis, MN
- 9The Hospital for Sick Children, Toronto, Ontario, Canada
- 10Programa de Biología Molecular y Celular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Corresponding author: Sergio Lavandero, .
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-NFκB 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-NFκB pathway.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0340/-/DC1.
- Received February 27, 2013.
- Accepted August 23, 2013.
- © 2014 by the American Diabetes Association.
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