GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice

  1. Miguel A. Aon1
  1. 1Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  2. 2Cardiovascular Research Center, Division of Cardiology, Mount Sinai School of Medicine, New York, New York
  3. 3Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, Kentucky
  4. 4Dipartimento di Medicina Clinica e Sperimentale, Universita di Perugia, Perugia, Italy
  1. Corresponding author: Miguel A. Aon, maon1{at}jhmi.edu.
  1. C.G.T., V.C., N.P., and M.A.A. contributed equally to this work.

Abstract

In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle’s functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the β-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and β-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient’s inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0072/-/DC1.

  • C.G.T. is currently affiliated with the Division of Cardiology, National Cancer Institute, Pascale Foundation, Naples, Italy.

  • V.C. is currently affiliated with the Departamento de Farmacologia, Universidade Federal de Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil.

  • S.S. is currently affiliated with the Department of Pathophysiology, Harbin Medical University, Harbin, China.

  • R.C.S.-B. is currently affiliated with the Departamento de Biociencias, Campus Baixada Santista-UNIFESP, Sao Paulo, Brazil.

  • Received January 19, 2012.
  • Accepted May 31, 2012.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 61 no. 12 3094-3105
  1. Supplementary Data
  2. All Versions of this Article:
    1. db12-0072v1
    2. 61/12/3094 most recent