Jiménez Ray, Zúñiga-Muñoz Alejandra, Álvarez-León Edith, García-Niño Wylly Ramsés, Navarrete-Anastasio Gabriela, Soria-Castro Elizabeth, Pérez-Torres Israel, Lira-Silva Elizabeth, Pavón Natalia, Cruz-Gregorio Alfredo, López-Marure Rebeca, Zazueta Cecilia, Silva-Palacios Alejandro
Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Col. Belisario Domínguez-Sección XVI, Tlalpan, 14080, Mexico City, Mexico.
Basic and Technological Research Subdirection, Instituto Nacional de Cardiología Ignacio Chávez, 14080, Mexico City, Mexico.
Biogerontology. 2024 Dec 20;26(1):29. doi: 10.1007/s10522-024-10174-y.
Cardiomyocyte senescence plays a crucial role in the pathophysiology of age-related cardiovascular disease. Senescent cells with impaired contractility, mitochondrial dysfunction, and hypertrophic growth accumulate in the heart during aging, contributing to cardiac dysfunction and remodeling. Mitochondrial dynamics is altered in aging cells, leading to changes in their function and morphology. Such rearrangements can affect the spatially restricted region of the mitochondrial membrane that interacts with reticulum membrane fragments, termed mitochondria-endoplasmic reticulum (ER) contact sites (MERCs). Besides, oxidative stress associated with inefficient organelle turnover can drive cellular senescence. Therefore, in this study, we evaluated the possible association between the senolytic effect of the antioxidant quercetin (Q) and MERCs preservation in a D-galactose-induced cellular senescence model. We found that Q ameliorates the senescent phenotype of H9c2 cells in association with increased mitochondria-ER colocalization, reduced distance between both organelles, and lower ROS production. Moreover, regulation of fusion and fission processes was related with increased mitochondrial ATP production and enhanced transmembrane potential. Overall, our data provide evidence that the inhibitory effect of Q on cellular senescence is associated with preserved MERCs and improved mitochondrial function and morphology, which might contribute to the attenuation of cardiac dysfunction.
心肌细胞衰老在年龄相关性心血管疾病的病理生理学中起着关键作用。随着年龄增长，心脏中收缩力受损、线粒体功能障碍和肥大生长的衰老细胞会逐渐积累，导致心脏功能障碍和重塑。衰老细胞中线粒体动力学发生改变，导致其功能和形态发生变化。这种重排会影响线粒体膜与内质网（ER）膜片段相互作用的空间受限区域，即线粒体-内质网（ER）接触位点（MERC）。此外，与细胞器周转效率低下相关的氧化应激会驱动细胞衰老。因此，在本研究中，我们在D-半乳糖诱导的细胞衰老模型中评估了抗氧化剂槲皮素（Q）的溶衰老作用与MERC保存之间的可能关联。我们发现，Q改善了H9c2细胞的衰老表型，同时线粒体-内质网共定位增加、两个细胞器之间的距离缩短以及活性氧生成减少。此外，融合和裂变过程的调节与线粒体ATP生成增加和跨膜电位增强有关。总体而言，我们的数据表明，Q对细胞衰老的抑制作用与MERC的保存以及线粒体功能和形态的改善有关，这可能有助于减轻心脏功能障碍。
