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 (ANT) and the phosphate carrier (PiC) 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.

Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection

“…[12][13][14][15][16][17] This may be due to the fact that different cell types were used in different studies, and not all cells can undergo necroptosis, because parenchymal cells differ in gene expression and cellular signaling cascades. [12][13][14][15][16][17] This may be due to the fact that different cell types were used in different studies, and not all cells can undergo necroptosis, because parenchymal cells differ in gene expression and cellular signaling cascades.…”

“…10 Cyp-D mediates a conformational change of adenine nucleotide translocase, leading to mitochondrial swelling and release of apoptogenic effectors, which leads to cell death. [12][13][14] While it is well established that mitochondria are platforms for apoptosis execution, the prospect of direct mitochondrial involvement in programmed necrosis remains controversial, and contradictory experiments point toward either mitochondria-dependent or -independent forms of necrosis or necroptosis. [12][13][14] While it is well established that mitochondria are platforms for apoptosis execution, the prospect of direct mitochondrial involvement in programmed necrosis remains controversial, and contradictory experiments point toward either mitochondria-dependent or -independent forms of necrosis or necroptosis.…”

“…I G U R E 5 Cyclophilin-D (Cyp-D)-regulated necroptosis is linked to mixed-lineage kinase domain-like protein (MLKL) activation. This complex has then been proposed to induce necroptosis via MLKL-mediated cell membrane rupture (mitochondria independent)or, more recently, mitochondria-dependent pathways, including the production of mitochondrial ROS and increase in mitochondrial permeability [12][13][14]. MLKL inhibitor GW806742X (GW, 50-1000 nmol/L) was added.…”

“…11 The involvement of mitochondria and mPTPs as downstream necroptotic mediators is still a point of contention. [12][13][14] While it is well established that mitochondria are platforms for apoptosis execution, the prospect of direct mitochondrial involvement in programmed necrosis remains controversial, and contradictory experiments point toward either mitochondria-dependent or -independent forms of necrosis or necroptosis. [12][13][14][15][16][17] In our previous studies, we demonstrated that RIPK3mediated necroptosis in donor heart and kidney grafts can promote inflammatory injury and transplant rejection.…”

Urea transport B gene induces melanoma B16 cell death via activation of p53 and mitochondrial apoptosis

“…Various ROS are harmful byproducts of mitochondrial respiration. The formation of mitochondrial ROS is an important component of cell metabolism and plays an important role in cell physiology . Increased ROS is responsible for the accumulation of ROS‐related lesions in DNA, proteins and lipids, which may lead to progressive cell dysfunction, resulting in apoptosis.…”