Santin Yohan, Sicard Pierre, Vigneron François, Guilbeau-Frugier Céline, Dutaur Marianne, Lairez Olivier, Couderc Bettina, Manni Diego, Korolchuk Viktor I, Lezoualc'h Frank, Parini Angelo, Mialet-Perez Jeanne
1 INSERM, I2MC, Institut des Maladies Métaboliques et Cardiovasculaires , Toulouse, France .
2 CHU de Toulouse, Institut Claudius Regaud , Université de Toulouse, France .
Antioxid Redox Signal. 2016 Jul 1;25(1):10-27. doi: 10.1089/ars.2015.6522. Epub 2016 Apr 22.
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.
在心力衰竭（HF）中，线粒体质量控制和自噬逐渐受损，但氧化应激在此过程中的作用及其潜在机制仍有待明确。线粒体酶单胺氧化酶A（MAO-A）通过降解去甲肾上腺素和血清素，是心脏中活性氧（ROS）的一个重要来源，其激活会导致线粒体损伤的持续存在。在本研究中，我们分析了MAO-A产生的ROS对心脏自噬-溶酶体途径的影响。
小鼠心肌细胞驱动的MAO-A表达导致线粒体分裂以及动力相关蛋白1（Drp1）和帕金森蛋白（Parkin）在线粒体区室中的转位。MAO-A转基因小鼠的心室显示LC3阳性自噬体积累，同时伴有p62和泛素化蛋白，表明自噬受损。在体外，将MAO-A通过腺病毒递送至心肌细胞并随之产生ROS，会阻断自噬流，导致LC3II、p62和泛素化蛋白积累，进而导致线粒体分裂和细胞坏死。此外，MAO-A激活诱导溶酶体蛋白组织蛋白酶D和溶酶体相关膜蛋白1（Lamp1）积累，降低溶酶体酸化，并阻断自噬和溶酶体生物发生的主要调节因子转录因子EB（TFEB）的核转位。最有趣的是，TFEB的过表达减弱了与MAO-A激活相关的自噬体积累、线粒体分裂、心肌细胞死亡和心力衰竭。
本研究揭示了MAO依赖性过氧化氢产生与溶酶体功能障碍之间的新联系。总之，我们的研究结果表明，MAO-A/H2O2轴通过自噬-溶酶体途径对线粒体的清除和再循环产生负面影响，这参与了心肌细胞死亡和心力衰竭。《抗氧化与氧化还原信号》25卷，第10 - 27页。
