title: Oxidative Stress by Monoamine Oxidase-A Impairs Transcription Factor EB Activation and Autophagosome Clearance, Leading to Cardiomyocyte Necrosis and Heart Failure.
abstract: In heart failure (HF), mitochondrial quality control and autophagy are progressively impaired, but the role of oxidative stress in this process and its underlying mechanism remain to be defined. By degrading norepinephrine and serotonin, the mitochondrial enzyme, monoamine oxidase-A (MAO-A), is a potent source of reactive oxygen species (ROS) in the heart and its activation leads to the persistence of mitochondrial damage. In this study, we analyzed the consequences of ROS generation by MAO-A on the autophagy-lysosome pathway in the heart.
  
  
  
  Cardiomyocyte-driven expression of MAO-A in mice led to mitochondrial fission and translocation of Drp1 and Parkin in the mitochondrial compartment. Ventricles from MAO-A transgenic mice displayed accumulation of LC3-positive autophagosomes, together with p62 and ubiquitylated proteins, indicating impairment of autophagy. In vitro adenoviral delivery of MAO-A in cardiomyocytes and the consequent generation of ROS blocked autophagic flux with accumulation of LC3II, p62, and ubiquitylated proteins, leading to mitochondrial fission and cell necrosis. In addition, MAO-A activation induced accumulation of lysosomal proteins, cathepsin D and Lamp1, reduced lysosomal acidification, and blocked the nuclear translocation of transcription factor-EB (TFEB), a master regulator of autophagy and lysosome biogenesis. Most interestingly, overexpression of TFEB attenuated autophagosome buildup, mitochondrial fission, cardiomyocyte death, and HF associated with MAO-A activation.
  
  
  
  This study unravels a new link between MAO-dependent H2O2 production and lysosomal dysfunction. Altogether, our findings demonstrate that the MAO-A/H2O2 axis has a negative impact on the elimination and recycling of mitochondria through the autophagy-lysosome pathway, which participates in cardiomyocyte death and HF. Antioxid. Redox Signal. 25, 10-27.
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Yohan
authors.initials: Y
authors.lastname: Santin
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Pierre
authors.initials: P
authors.lastname: Sicard
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: François
authors.initials: F
authors.lastname: Vigneron
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Céline
authors.initials: C
authors.lastname: Guilbeau-Frugier
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Marianne
authors.initials: M
authors.lastname: Dutaur
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Olivier
authors.initials: O
authors.lastname: Lairez
authors.affiliation: 2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Bettina
authors.initials: B
authors.lastname: Couderc
authors.affiliation: 3 Institute for Cell and Molecular Biosciences and Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University , Newcastle upon Tyne, United Kingdom .
authors.forename: Diego
authors.initials: D
authors.lastname: Manni
authors.affiliation: 3 Institute for Cell and Molecular Biosciences and Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University , Newcastle upon Tyne, United Kingdom .
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.affiliation: 1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .|2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D000071182:Autophagosomes / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D008995:Monoamine Oxidase / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000473:pathology; D009336:Necrosis / Q000378:metabolism* / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017382:Reactive Oxygen Species; C064972:TFEB protein, human; D012701:Serotonin; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D009638:Norepinephrine