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Oxidative Stress by Monoamine Oxidase-A Impairs Transcription Factor EB Activation and Autophagosome Clearance, Leading to Cardiomyocyte Necrosis and Heart Failure

Lookup NU author(s): Diego Manni, Dr Viktor Korolchuk


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Aims: 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. Results: 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. Innovation and Conclusion: 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.

Publication metadata

Author(s): Santin Y, Sicard P, Vigneron F, Guilbeau-Frugier C, Dutaur M, Lairez O, Couderc B, Manni D, Korolchuk VI, Lezoualc'h F, Parini A, Mialet-Perez J

Publication type: Article

Publication status: Published

Journal: Antioxidants & Redox Signaling

Year: 2016

Volume: 25

Issue: 1

Pages: 10-27

Print publication date: 05/07/2016

Online publication date: 09/03/2016

Acceptance date: 08/03/2016

ISSN (print): 1523-0864

ISSN (electronic): 1557-7716

Publisher: Mary Ann Liebert, Inc. Publishers


DOI: 10.1089/ars.2015.6522


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Funder referenceFunder name
Cellular Imaging Facility I2MC
INSERM (Institut National pour la Sante Et la Recherche Medicale)
Region Midi-Pyrenees
ANR (Agence Nationale pour la Recherche)
Biotechnology and Biological Sciences Research Council
Cell Protein Analysis platform
Histology platform
NIHR Newcastle Biomedical Research Centre
Transcriptomic platform
UMS006Animal Facility