Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?
Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?
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DOI：
10.1007/s00018-016-2202-5
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Padanilam BJ
中科院分区：
文献类型：
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作者：
Ying Y;Padanilam BJ
与细胞凋亡和自噬不同，坏死性细胞死亡被认为是一种随机的、被动的细胞死亡，没有明确的介体。然而，最近的发展表明，坏死性细胞死亡也可以是一个受调控的过程，这一教条受到了挑战。调节性坏死包括多种细胞死亡方式，如坏死性下垂、甲状旁腺、铁性下垂、下垂和线粒体通透性转换孔(MPTP)介导的坏死。几个独特的执行分子，特别是位于线粒体内膜和外膜上的执行分子，已经被定义为合并形成MPTP。内膜上的F1F0ATP合成酶的c-亚基和外膜上的Bax/Bak被认为是形成MPTP的长期寻找的成分。开放MPTP导致线粒体内膜电位丧失，ATP合成中断，ROS产生增加，细胞器肿胀，线粒体功能障碍，继而坏死。亲环素D与腺嘌呤核苷酸转运体(ANT)和磷酸载体(PIC)一起被认为是参与MPTP开放的重要调节因子。ROS的产生增加可以进一步触发通过PARP1等分子介导的其他坏死途径，导致不可逆转的细胞损伤。本文综述了PARP1和亲环素D在坏死性细胞死亡中的作用。探讨了P53在调节和整合信号通路关键成分以引起MPTP介导的坏死和铁性下垂中的分级作用。在最近的研究背景下，坏死性下垂信号在缺血性肾损伤后肾小管坏死中的模糊作用被仔细研究。我们通过讨论P53、PARP1和亲环素D的参与及其相互重叠的通路在急性肾损伤中引起MPTP介导的坏死和铁性下垂。
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.