Ahumada-Castro Ulises, Puebla-Huerta Andrea, Cuevas-Espinoza Victor, Lovy Alenka, Cardenas J Cesar
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile.
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Department of Neuroscience, Center for Neuroscience Research, Tufts School of Medicine, Boston, MA, USA.
Biochim Biophys Acta Mol Cell Res. 2021 Oct;1868(11):119099. doi: 10.1016/j.bbamcr.2021.119099. Epub 2021 Jul 16.
Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca release channels activated by a ligand (IP3). IP3R-mediated Ca release is transferred to mitochondria through the mitochondrial Ca uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca transfer and senescence. Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.
细胞衰老会导致永久性细胞周期停滞，其特征为抗凋亡和促炎的衰老相关分泌表型（SASP）。在生理状态下，衰老细胞在发育过程中和损伤后促进组织重塑。然而，当衰老细胞像在衰老过程中或细胞应激后那样累积超过一定阈值时，它们会导致组织功能衰退，参与多种疾病的发生。细胞衰老伴随着线粒体代谢增加。线粒体功能如何被调节以及它在衰老细胞稳态中发挥何种作用，目前还知之甚少。线粒体在功能和物理上通过称为线粒体-内质网接触（MERC）的特殊结构域与内质网（ER）相连，内质网是哺乳动物细胞中主要的钙（Ca）储存细胞器。在这个结构域中，内质网中钙的释放主要由肌醇1,4,5-三磷酸受体（IP3R）调节，IP3R是一个由三个钙释放通道组成的家族，由配体（IP3）激活。IP3R介导的钙释放通过线粒体钙单向转运体（MCU）传递到线粒体，在那里它调节几种酶和转运蛋白的活性，影响其生物能量和生物合成功能。在这里，我们综述内质网到线粒体的钙转运与衰老之间可能的联系。了解导致衰老的途径对于揭示新的治疗靶点至关重要，这些靶点可以延缓衰老细胞的积累或减轻衰老细胞负担以缓解多种疾病。
