Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
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
_version_ 1782250239134007296
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
work_keys_str_mv AT tocchetticarlog gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT caceresviviane gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT stanleybriana gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT xiechaoqin gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT shisa gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT watsonwalterh gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT orourkebrian gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT spadaribratfischreginac gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT cortassasonia gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT akarfadig gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT paoloccinazareno gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice
AT aonmiguela gshorpalmitatepreservesmitochondrialenergeticredoxbalancepreventingmechanicaldysfunctioninmetabolicallychallengedmyocytesheartsfromtype2diabeticmice