ABSTRACT
Excessive amounts of reactive oxygen species (ROS) lead to macromolecular damage and high levels of cell death with consequent pathological sequelae. We hypothesized that switching cell death to a tissue regenerative state could potentially improve the short-term and long-term detrimental effects of ROS-associated acute tissue injury, although the mechanisms regulating oxidative stress-induced cell fate decisions and their manipulation for improving repair are poorly understood. Here, we show that cells exposed to high oxidative stress enter a poly (ADP-ribose) polymerase 1 (PARP1)-mediated regulated cell death, and that blocking PARP1 activation promotes conversion of cell death into senescence (CODIS). We demonstrate that this conversion depends on reducing mitochondrial Ca2+ overload as a consequence of retaining the hexokinase II on mitochondria. In a mouse model of kidney ischemia-reperfusion damage, PARP inhibition reduces necrosis and increases transient senescence at the injury site, alongside improved recovery from damage. Together, these data provide evidence that converting cell death into transient senescence can therapeutically benefit tissue regeneration.
Subject(s)
Cell Death , Cellular Senescence , Oxidative Stress , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Oxidative Stress/drug effects , Cellular Senescence/drug effects , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Mice , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Cell Death/drug effects , Reperfusion Injury/pathology , Reperfusion Injury/metabolism , Reperfusion Injury/drug therapy , Reactive Oxygen Species/metabolism , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Calcium/metabolism , Disease Models, AnimalABSTRACT
Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.
Subject(s)
Cellular Senescence/physiology , Endoplasmic Reticulum/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Longevity/physiology , Mitochondria/metabolism , Animals , Calcium/metabolism , Endoplasmic Reticulum/ultrastructure , Female , Fibroblasts , HEK293 Cells , Humans , Inositol 1,4,5-Trisphosphate Receptors/genetics , Male , Mice , Mice, Knockout , Microscopy, Confocal , Mitochondria/ultrastructure , RNA, Small Interfering , Refractory Period, Electrophysiological , Single-Cell AnalysisABSTRACT
Calcium is a universal messenger regulating many physiological functions, including the ability of the cell to undergo orderly self-destruction upon completion of its function, called apoptosis. In physiopathological conditions such as cancer, apoptotic processes become deregulated, leading to apoptosis-resistant phenotypes. Recently, perturbations of cellular calcium homeostasis have been described in apoptosis-resistant cell phenotypes. Thereby, new molecular actors have been identified, offering more accurate research possibilities in the field of apoptosis resistance and providing the bases for more rational approaches to cancer treatments. In this review, we focus on the calcium-transporting protein-dependent pathways involved in apoptosis, which are deregulated by cancer. We present the calcium-transporting proteins involved in the deregulation of apoptosis, and those chemotherapies that target actors in calcium-induced apoptosis.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Calcium/metabolism , Carrier Proteins/metabolism , Neoplasms/pathology , Animals , Humans , Ion Transport/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Signal Transduction/drug effectsABSTRACT
Prostate cancer is the second cancer-related cause of death. Nowadays, the aim of treatments is to decrease the effects of androgens on this organ. Unfortunately, over time, patients develop an androgen-independent cancer with a fatal outcome. The main features of late stage prostate cancer are an increased cell proliferation and apoptosis resistance. It is well known that calcium (Ca2+), a ubiquitous secondary messenger, is involved in several processes such as apoptosis and proliferation. In this mini review, we will focus on the changes in Ca2+ homeostasis of prostate cancer epithelial cells during prostate cancer evolution.
