Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence

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 2+ ) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca 2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca 2+ release channels activated by a ligand (IP3). IP3R-mediated Ca 2+ release is transferred to mitochondria through the mitochondrial Ca 2+ 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 2+ 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. • The basic concepts of cellular senescence • The role of Ca 2+ transfer between the endoplasmic reticulum and mitochondria through the IP3R in cellular senescence • The relationship between mitochondria-ER contact sites (MERCs) and cellular senescence • The role of cellular senescence in age-related diseases as well as the drugs available to counter their effects