PARP 1 inhibition mediates a switch from cell death to transient senescence improving repair from acute oxidative injury

Excessive amounts of Reactive Oxygen Species (ROS) lead to macromolecular damage and high levels of cell death and pathological sequelae. Switching cell death to a tissue regenerativestate can potentially improve short – and long-term consequences of ROS-associated acute tissueinjury. However, the mechanisms regulating oxidative stress-induced cell fate decision and their manipulation for improving repair remain poorly understood. Here, we show that cells exposed tohigh oxidative stress enter a PARP1-mediated regulated cell death, and that blocking PARP1activation promotes conversion of cell death into senescence (CODIS). We demonstrate that CODIS depends on reducing mitochondrial Ca2+ overload as a consequence of retaining thehexokinase HKII onto mitochondria. In a mouse model of kidney ischemia/reperfusion damage,PARP1 inhibition lowers necrosis and increases acute and transient senescence at the injury site,leading to improved recovery from damage. For the first time, we provide evidence that strategiesconverting cell death into acute senescence can therapeutically reduce the detriment of accidental tissue damage. _x000B_ In this study, we showed that PARP inhibition (using PJ34) has a protective effect on tissue integrity and cellularity in the short term (3 days after IR). To evaluate the long-term effect, mice were divided in different groups : 2 Control groups which have received either vehicle (NV) or the PARP inhibitor PJ34 (NP) and 2 groups that have underwent ischemia reperfusion (IR) surgery, where one group received vehicle (IRV), and the other group received PJ34 (IRP).