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Published on: July 13, 2018
Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling
Yohan Santin1, Loubina Fazal1, Yannis Sainte-Marie1
1Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM, Université de Toulouse, Toulouse, France.
Insights
Monoamine oxidase-A (MAO-A) activation drives heart failure by increasing mitochondrial 4-hydroxynonenal (4-HNE) and calcium overload. Inhibiting MAO-A protects against cardiac dysfunction and remodeling post-myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Cardiac Pathophysiology
Background:
- Chronic post-myocardial infarction remodeling involves fibrosis, cardiomyocyte death, and mitochondrial dysfunction, leading to heart failure (HF).
- Reactive aldehydes like 4-hydroxynonenal (4-HNE) mediate mitochondrial dysfunction, but their cardiac sources and mechanisms are unclear.
- Monoamine oxidase-A (MAO-A) produces hydrogen peroxide (H2O2), a potential precursor to harmful aldehydes.
Purpose of the Study:
- To investigate if MAO-A is a source of mitochondrial 4-HNE in heart failure.
- To elucidate the mechanisms by which MAO-A contributes to cardiac dysfunction.
- To assess the therapeutic potential of targeting MAO-A in post-ischemic remodeling.
Main Methods:
- Primary cardiomyocyte cultures and a chronic mouse model of ischemic remodeling.
- Assessment of mitochondrial reactive oxygen species (ROS), 4-HNE production, cardiolipin peroxidation, and aldehyde dehydrogenase 2 (ALDH2) activity.
- Analysis of VDAC and MCU protein interactions, mitochondrial calcium (Ca2+) levels, membrane potential, and respiratory function.
- Evaluation of MAO-A inhibition (pharmacological/genetic) effects on cardiac remodeling and function.
Main Results:
- MAO-A activation increased mitochondrial ROS and 4-HNE production via cardiolipin peroxidation in cardiomyocytes.
- MAO-A-derived 4-HNE targeted VDAC and MCU, promoting ER-mitochondria contacts and MCU complex formation, leading to mitochondrial Ca2+ overload.
- Inhibition of MAO-A or activation of ALDH2 protected against 4-HNE accumulation and cardiac dysfunction in vitro and in vivo.
- MAO-A inhibition mitigated MCU oligomerization, Ca2+ overload, and ventricular dysfunction in a chronic ischemic remodeling model.
Conclusions:
- MAO-A is a significant source of mitochondrial 4-HNE in heart failure, contributing to cardiac dysfunction.
- MAO-A-induced 4-HNE promotes mitochondrial Ca2+ mishandling by targeting VDAC and MCU, impairing cardiac energetics.
- Targeting MAO-A represents a promising therapeutic strategy for mitigating post-ischemic cardiac remodeling and heart failure.
Abstract:
Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2 as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa2+ mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling.
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