Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion

TLDR

Cell death pathways, including apoptosis and necrosis, are regulated by intracellular ATP levels, and overactivation of the DNA‑repair enzyme PARP can deplete ATP and NAD⁺, triggering necrotic cell death. PARP‑deficient mouse fibroblasts are resistant to necrosis and ATP depletion but still undergo apoptosis, demonstrating that PARP activation actively triggers necrosis while apoptosis proceeds via other mechanisms.

Abstract

Apoptotic and necrotic cell death are well characterized and are influenced by intracellular ATP levels. Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by DNA strand breaks, physiologically participates in DNA repair. Overactivation of PARP after cellular insults can lead to cell death caused by depletion of the enzyme’s substrate β-nicotinamide adenine dinucleotide and of ATP. In this study, we have differentially elicited apoptosis or necrosis in mouse fibroblasts. Fibroblasts from PARP-deficient (PARP −/− ) mice are protected from necrotic cell death and ATP depletion but not from apoptotic death. These findings, together with cell death patterns in PARP −/− animals receiving other types of insults, indicate that PARP activation is an active trigger of necrosis, whereas other mechanisms mediate apoptosis.