PARP signaling regulates cell fate decision between senescence and death during oxidative stress events

Reactive oxygen species (ROS) are essential intracellular messengers, but large amounts can lead to high levels of macromolecular damage and activation of necrotic cell death. Excessive necrosis is normally associated with impaired ability to recover from injury and the subsequent development of pathological sequelae. ROS-induced irreversibly damaged cells can alternatively survive by entering senescence - a state of irreversible growth arrest characterized by a hypersecretory phenotype that can contribute to optimal repair of acute tissue damages. Interestingly, the mechanisms regulating the decision between oxidative stress-induced necrosis and senescence remain poorly understood, and the possibility to switch necrotic into senescent cells to promote tissue repair is completely unexplored. Here, we show that cells exposed to high oxidative stress enter a PARP-mediated cell death modality and that blocking PARP activation, either genetically or pharmacologically, promotes survival. Importantly, rescued cells enter a senescence state characterized by irreversible growth arrest and a hypersecretory phenotype. We demonstrate that the switch from death to senescence is dependent on a reduction of PARP-mediated and oxidative stress-induced mitochondrial Ca2+ overload. We also show that the amount of mitochondrial Ca2+ uptake is restricted upon PARP inhibition as a consequence of preventing the translocation of the hexokinase HKII from mitochondria to the cytoplasm. Using a mouse model of kidney ischemia/reperfusion (IR) damage, we observe that PARP inhibition reduces necrotic cell death and increases senescence, eventually leading to improved recovery from oxidative-stress induced renal damage. Our data suggest that PARP1 activity is essential to promote necrosis in high oxidative environments and that its inhibition can alleviate the detriment of acute tissue damage via switching necrosis into senescence.