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GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501888/ https://www.ncbi.nlm.nih.gov/pubmed/22807033 http://dx.doi.org/10.2337/db12-0072 |
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author | Tocchetti, Carlo G. Caceres, Viviane Stanley, Brian A. Xie, Chaoqin Shi, Sa Watson, Walter H. O’Rourke, Brian Spadari-Bratfisch, Regina C. Cortassa, Sonia Akar, Fadi G. Paolocci, Nazareno Aon, Miguel A. |
author_facet | Tocchetti, Carlo G. Caceres, Viviane Stanley, Brian A. Xie, Chaoqin Shi, Sa Watson, Walter H. O’Rourke, Brian Spadari-Bratfisch, Regina C. Cortassa, Sonia Akar, Fadi G. Paolocci, Nazareno Aon, Miguel A. |
author_sort | Tocchetti, Carlo G. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3501888 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-35018882013-12-01 GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice Tocchetti, Carlo G. Caceres, Viviane Stanley, Brian A. Xie, Chaoqin Shi, Sa Watson, Walter H. O’Rourke, Brian Spadari-Bratfisch, Regina C. Cortassa, Sonia Akar, Fadi G. Paolocci, Nazareno Aon, Miguel A. Diabetes Metabolism 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. American Diabetes Association 2012-12 2012-11-15 /pmc/articles/PMC3501888/ /pubmed/22807033 http://dx.doi.org/10.2337/db12-0072 Text en © 2012 by the American Diabetes Association. 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. |
spellingShingle | Metabolism Tocchetti, Carlo G. Caceres, Viviane Stanley, Brian A. Xie, Chaoqin Shi, Sa Watson, Walter H. O’Rourke, Brian Spadari-Bratfisch, Regina C. Cortassa, Sonia Akar, Fadi G. Paolocci, Nazareno Aon, Miguel A. GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice |
title | GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice |
title_full | GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice |
title_fullStr | GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice |
title_full_unstemmed | GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice |
title_short | GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice |
title_sort | gsh or palmitate preserves mitochondrial energetic/redox balance, preventing mechanical dysfunction in metabolically challenged myocytes/hearts from type 2 diabetic mice |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501888/ https://www.ncbi.nlm.nih.gov/pubmed/22807033 http://dx.doi.org/10.2337/db12-0072 |
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