Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?

Abstract

In contrast to apoptosis and autophagy, necrotic cell death was considered to be a random, passive cell death without definable mediators. However, this dogma has been challenged by recent developments suggesting that necrotic cell death can also be a regulated process. Regulated necrosis includes multiple cell death modalities such as necroptosis, parthanatos, ferroptosis, pyroptosis, and mitochondrial permeability transition pore (MPTP)-mediated necrosis. Several distinctive executive molecules, particularly residing on the mitochondrial inner and outer membrane, amalgamating to form the MPTP have been defined. The c-subunit of the F1F0ATP synthase on the inner membrane and Bax/Bak on the outer membrane are considered to be the long sought components that form the MPTP. Opening of the MPTP results in loss of mitochondrial inner membrane potential, disruption of ATP production, increased ROS production, organelle swelling, mitochondrial dysfunction and consequent necrosis. Cyclophilin D, along with adenine nucleotide translocator and the phosphate carrier are considered to be important regulators involved in the opening of MPTP. Increased production of ROS can further trigger other necrotic pathways mediated through molecules such as PARP1, leading to irreversible cell damage. This review examines the roles of PARP1 and cyclophilin D in necrotic cell death. The hierarchical role of p53 in regulation and integration of key components of signaling pathway to elicit MPTP-mediated necrosis and ferroptosis is explored. In the context of recent insights, the indistinct role of necroptosis signaling in tubular necrosis after ischemic kidney injury is scrutinized. We conclude by discussing the participation of p53, PARP1 and cyclophilin D and their overlapping pathways to elicit MPTP-mediated necrosis and ferroptosis in acute kidney injury.

Keywords: Bax; Cyclophilin D; Necroptosis; PARP1; Regulated necrosis; p53.

Fig. 1

A hypothetical scheme of the molecular hierarchy and cross talk characterizing regulated necrotic cell death in ischemic AKI. In the ischemic renal injury model, necrosis in proximal tubular cells is a common type of cell death. Initial injury results in DNA damage and rapid activation of p53 and PARP1. p53 induces the expression of Bax, which will facilitate the MOMP for necrosis [87]. Activated PARP1 will rapidly deplete intracellular NAD⁺ and ATP, and simultaneously inhibit GAPDH, which reduces glycolytic capacity in proximal tubules [55, 62]. p53-induced TIGAR expression inhibits the rate limiting PFK and the glycolytic pathway [125, 139]. The severe ATP depletion from glycolytic inhibition and PARP1 activation shuts down ion homeostasis resulting in Ca²⁺ influx and uptake into mitochondria. PARP1 as a transcriptional cofactor induces several cytokines and promote infiltration of inflammatory cells to the injured renal parenchyma, all leading to increased ROS production [55]. ROS and Ca²⁺, the most prominent mediators of permeability transition, increase the probability of MPTP opening via activation of CypD and the ATP synthasome complex [35]. Osmotic influx of water and solutes into the mitochondrial matrix leads to mitochondrial swelling and rupture of outer membrane, to elicit mitochondrial dysfunction and necrosis. Inhibition of ferroptosis can attenuate ischemic AKI. Although recent evidence suggests that p53 can mediate ferroptosis by regulating the expression of SLC7A11 [109], this pathway has not been tested in ischemic renal injury models. The contribution of necroptosis in proximal tubule cell death has recently been challenged and the mechanism by which RIP1 K blockade prevents renal injury remains to be elucidated [158]. Although, recent evidences suggest p53 translocation to mitochondrial matrix and activation of CypD [89], such a role for p53 is not established in kidney injury