Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of
Aaron L Sverdlov1, Aly Elezaby1, Fuzhong Qin1
1Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
Background:
Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD.
Methods And Results:
Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild-type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium.
Conclusion:
Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103.
Insights
Mitochondrial reactive oxygen species (ROS) drive metabolic heart disease (MHD) by damaging proteins in mitochondria. Antioxidant therapy targeting these ROS ameliorates cardiac dysfunction.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Oxidative Stress
Background:
- Mitochondrial reactive oxygen species (ROS) are implicated in metabolic heart disease (MHD).
- The precise mechanisms linking ROS to MHD pathogenesis remain unclear.
- This study investigated the role of mitochondrial ROS as a key mediator in MHD.
Purpose of the Study:
- To determine if mitochondrial ROS are a key mediator of metabolic heart disease (MHD).
- To elucidate the molecular mechanisms by which ROS contribute to cardiac dysfunction in MHD.
- To evaluate the therapeutic potential of mitigating mitochondrial ROS in MHD.
Main Methods:
- Mice were fed a high-fat high-sucrose (HFHS) diet to induce MHD.
- Mitochondrial function, including ROS production and ATP synthesis, was assessed.
- Transgenic mice with mitochondrial catalase expression were used to test ROS mitigation.
- Protein modifications, specifically oxidative posttranslational modifications, were analyzed.
- In vitro studies with site-directed mutagenesis were performed on key mitochondrial proteins.
Main Results:
- HFHS diet induced cardiac and mitochondrial dysfunction, with increased ROS production in wild-type mice.
- Mitochondrial complex II activity and ATP synthesis were significantly reduced in HFHS-fed mice.
- Mitochondrial abnormalities and cardiac dysfunction were ameliorated in transgenic mice expressing mitochondrial catalase.
- Restoration of complex II function ex vivo by dithiothreitol suggested reversible oxidative modifications.
- Specific cysteine residues (Cys100, Cys103) in complex II subunit B were identified as targets of ROS-induced dysfunction.
Conclusions:
- Mitochondrial ROS are pathogenic drivers of metabolic heart disease (MHD).
- ROS contribute to mitochondrial dysfunction in MHD via oxidative posttranslational modifications of mitochondrial proteins.
- Reversible oxidative modifications of complex II subunit B (Cys100, Cys103) are a key mechanism in ROS-induced cardiac pathology.
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