2. Academic Validation
  3. Converting cell death into senescence by PARP1 inhibition improves recovery from acute oxidative injury

Converting cell death into senescence by PARP1 inhibition improves recovery from acute oxidative injury

  • Nat Aging. 2024 May 9. doi: 10.1038/s43587-024-00627-x.
Jamil Nehme 1 2,  Lina Mesilmany 2 3 4,  Marta Varela-Eirin 1,  Simone Brandenburg 1,  Abdullah Altulea 1,  Yao Lin 1,  Mariana Gaya da Costa 5,  Marc Seelen 5,  Jan-Luuk Hillebrands 6,  Harry van Goor 6,  Raya Saab 7,  Haidar Akl 2 8,  Natacha Prevarskaya 3 4,  Valerio Farfariello 3 4,  Marco Demaria 9
Affiliations

Affiliations

  • 1 European Research Institute for the Biology of Ageing (ERIBA), University of Groningen (RUG), University Medical Center Groningen, Groningen, the Netherlands.
  • 2 Department of Biology, Lebanese University, Beirut, Lebanon.
  • 3 Université de Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Lille, France.
  • 4 Laboratory of Excellence, Ion Channels Science and Therapeutics, Villeneuve d'Ascq, France.
  • 5 Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • 6 Department of Pathology & Medical Biology, Pathology Division, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 7 Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • 8 Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.
  • 9 European Research Institute for the Biology of Ageing (ERIBA), University of Groningen (RUG), University Medical Center Groningen, Groningen, the Netherlands. m.demaria@umcg.nl.
PMID: 38724734 DOI: 10.1038/s43587-024-00627-x
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.

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