Open AccessEnergetic Dysfunction Is Mediated by Mitochondrial Reactive Oxygen Species and Precedes Structural Remodeling in Metabolic Heart Disease
Author(s) -
Ivan Luptak,
Fuzhong Qin,
Aaron L. Sverdlov,
David R. Pimentel,
Marcello Panagia,
Dominique Croteau,
Deborah A. Siwik,
Markus Bachschmid,
Hui He,
James A. Balschi
Publication year - 2019
Publication title -
antioxidants and redox signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.277
H-Index - 190
eISSN - 1557-7716
pISSN - 1523-0864
DOI - 10.1089/ars.2018.7707
Subject(s) - mitochondrion , reactive oxygen species , phosphocreatine , medicine , mitochondrial ros , endocrinology , bioenergetics , catalase , adenosine triphosphate , myocyte , fibrosis , muscle hypertrophy , oxidative stress , mitochondrial matrix , biology , ventricular remodeling , microbiology and biotechnology , biochemistry , heart failure , enzyme , cytosol , energy metabolism
Aims: Metabolic syndrome is associated with metabolic heart disease (MHD) that is characterized by left ventricular (LV) hypertrophy, interstitial fibrosis, contractile dysfunction, and mitochondrial dysfunction. Overexpression of catalase in mitochondria (transgenic expression of catalase targeted to the mitochondria [mCAT]) prevents the structural and functional features of MHD caused by a high-fat, high-sucrose (HFHS) diet for ≥4 months. However, it is unclear whether the effect of mCAT is due to prevention of reactive oxygen species (ROS)-mediated cardiac remodeling, a direct effect on mitochondrial function, or both. To address this question, we measured myocardial function and energetics in mice, with or without mCAT, after 1 month of HFHS, before the development of cardiac structural remodeling. Results: HFHS diet for 1 month had no effect on body weight, heart weight, LV structure, myocyte size, or interstitial fibrosis. Isolated cardiac mitochondria from HFHS-fed mice produced 2.2- to 3.8-fold more H 2 O 2 , and 16%-29% less adenosine triphosphate (ATP). In isolated beating hearts from HFHS-fed mice, [phosphocreatine (PCr)] and the free energy available for ATP hydrolysis (ΔG ∼ATP ) were decreased, and they failed to increase with work demands. Overexpression of mCAT normalized ROS and ATP production in isolated mitochondria, and it corrected myocardial [PCr] and ΔG ∼ATP in the beating heart. Innovation: This is the first demonstration that in MHD, mitochondrial ROS mediate energetic dysfunction that is sufficient to impair contractile function. Conclusion: ROS produced and acting in the mitochondria impair myocardial energetics, leading to slowed relaxation and decreased contractile reserve. These effects precede structural remodeling and are corrected by mCAT, indicating that ROS-mediated energetic impairment, per se , is sufficient to cause contractile dysfunction in MHD.