缺血性卒中线粒体焦亡机制相关研究进展

蔡珂; 王钦鹏; 魏阳阳; 李婷婷; 王国娟; 梁成

doi:10.16766/j.cnki.issn.1674-4152.003518

缺血性卒中线粒体焦亡机制相关研究进展

doi: 10.16766/j.cnki.issn.1674-4152.003518

兰州大学第二医院神经内科ICU，甘肃兰州 730030

基金项目:

甘肃省自然科学基金项目 21JR11RA129

详细信息

通讯作者:
梁成，E-mail：hongyan200107@126.com

中图分类号: R743.33
计量
- 文章访问数: 34
- HTML全文浏览量: 31
- PDF下载量: 2
- 被引次数: 0
出版历程
- 收稿日期: 2024-01-25
- 网络出版日期: 2024-07-20

Research progress on mitochondrial pyroptosis mechanism in ischemic stroke

Department of Neurology ICU, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China

摘要

摘要: 缺血性卒中作为最常见的脑血管疾病，具有高发病率、高死亡率、高致残率、高复发率的特点，给患者、家庭及社会带来沉重的负担，其治疗的主要目的是及时开通血管恢复灌注、挽救缺血半暗带、改善神经功能。关于缺血性卒中的病理生理学机制以及其治疗的相关研究始终是一大热点，现已有大量研究表明，神经炎症是缺血性卒中的一个重要机制。细胞焦亡作为一种细胞的炎性死亡方式，与多种疾病及损伤机制密切相关，包括缺血性卒中的发生发展过程；细胞焦亡过程中有炎性小体、caspase-1、GSDMD等多种关键蛋白，而其中GSDMD作为细胞焦亡的执行蛋白，可在细胞膜上打孔，使得IL-1β、IL-18等炎性因子释放至胞外产生炎症反应；最新研究发现GSDMD不仅可在细胞膜上打孔，也可通过打孔破坏线粒体膜，导致线粒体功能受损、内容物释放，且线粒体膜受损先于细胞膜受损，既使得细胞焦亡过程被扩大，也可诱导其他途径的细胞死亡；因此抑制GSDMD的打孔功能、通过线粒体移植改善缺血细胞线粒体功能可有效抑制炎症反应，改善缺血半暗带功能，从而起到神经保护作用。本文简要介绍细胞焦亡的过程及GSDMD在焦亡过程中打孔的作用机制，重点阐述线粒体焦亡过程及其在缺血性卒中的相关研究进展，并为缺血性卒中的治疗找寻新的思路。
- 细胞焦亡 /
- 成孔蛋白D /
- 线粒体 /
- 缺血性卒中
Abstract: As the most common cerebrovascular disease, ischemic stroke has the characteristics of high incidence, high mortality, high disability rate, and high recurrence rate, which brings a heavy burden to patients, families, and society. The main purpose of its treatment is to timely open blood vessels to restore perfusion, rescue ischemic penumbra, and improve neurological function. Research on the pathophysiological mechanism and treatment of ischemic stroke has always been a hot spot. A large number of studies have shown that neuroinflammation is an important mechanism of ischemic stroke. As an inflammatory cell death mode, pyroptosis is closely related to a variety of diseases and injury mechanisms, including the occurrence and development of ischemic stroke. There are a variety of key proteins in the process of pyroptosis, such as inflammasome, caspase-1, and Gasdermin D (GSDMD). GSDMD, as the executive protein of pyroptosis, can punch holes in the cell membrane, causing inflammatory factors such as IL-1β and IL-18 to be released into the extracellular space to produce an inflammatory response. Recent studies have found that GSDMD can not only punch holes in the cell membrane but also destroy the mitochondrial membrane by punching holes, leading to impaired mitochondrial function and release of mitochondrial content. The mitochondrial membrane damage occurs before the cell membrane damage, which not only expands the pyroptosis process but also induces cell death through other pathways. Therefore, inhibiting the perforating function of GSDMD and improving the mitochondrial function of ischemic cells through mitochondrial transplantation can effectively inhibit the inflammatory response and improve the function of the ischemic penumbra, thus playing a neuroprotective role. In this review, we briefly introduce the process of pyroptosis and the mechanism of GSDMD drilling in the process of pyroptosis, focusing on the process of mitochondrial pyroptosis and its related research progress in ischemic stroke, and looking for new ideas for the treatment of ischemic stroke.
- Pyroptosis /
- Gasdermin D /
- Mitochondria /
- Ischemic stroke

HTML全文

参考文献(45)

[1]	张然, 田浩林, 王丽婷, 等. 静脉溶栓及血管内治疗急性脑梗死的国内研究进展[J]. 中华全科医学, 2020, 18(11): 1916-1920. doi: 10.16766/j.cnki.issn.1674-4152.001653 ZHANG R, TIAN H L, WANG L T, et al. Domestic research progress of intravenous thrombolysis and endovascular treatment of acute cerebral infarction[J]. Chinese Journal of General Practice, 2020, 18(11): 1916-1920. doi: 10.16766/j.cnki.issn.1674-4152.001653
[2]	MIAO R, JIANG C, CHANG W Y, et al. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis[J]. Immunity, 2023, 56(11): 2523-2541. doi: 10.1016/j.immuni.2023.10.004
[3]	RAO Z, ZHU Y, YANG P, et al. Pyroptosis in inflammatory diseases and cancer[J]. Theranostics, 2022, 12(9): 4310-4329. doi: 10.7150/thno.71086
[4]	ZHENG D, LIWINSKI T, ELINAV E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms[J]. Cell Discov, 2020, 6: 36.
[5]	LIAQAT A, ASAD M, SHOUKAT F, et al. A spotlight on the underlying activation mechanisms of the NLRP3 inflammasome and its role in atherosclerosis: a review[J]. Inflammation, 2020, 43(6): 2011-2020. doi: 10.1007/s10753-020-01290-1
[6]	SWANSON K V, DENG M, TING J P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics[J]. Nat Rev Immunol, 2019, 19(8): 477-489. doi: 10.1038/s41577-019-0165-0
[7]	QIAN Z, ZHAO Y, WAN C, et al. Pyroptosis in the initiation and progression of atherosclerosis[J]. Front Pharmacol, 2021, 12: 652963. DOI: 10.3389/FPHAR.2021.652963.
[8]	梅旦, 张玲玲, 魏伟. 细胞焦亡机制及与疾病的关系[J]. 生理科学进展, 2020, 51(2): 151-156. doi: 10.3969/j.issn.0559-7765.2020.02.018 MEI D, ZHANG L L, WEI W. Mechanism of pyroptosis and its relationship with diseases[J]. Progress in Physiological Sciences, 2020, 51(2): 151-156. doi: 10.3969/j.issn.0559-7765.2020.02.018
[9]	HU L, SHAO C Z, PAN L Y, et al. Lack of STAT6 enhances murine acute lung injury through NLRP3/ p38 MAPK signaling pathway in macrophages[J]. BMC Immunology, 2022, 23(1): 25. doi: 10.1186/s12865-022-00500-9
[10]	KAYAGAKI N, LEE B L, STOWE I B, et al. IRF2 transcriptionally induces GSDMD expression for pyroptosis[J]. Sci Signal, 2019, 12(582): eaax4917. DOI: 10.1126/scisignal.aax4917.
[11]	NIU X F, YAO Q, LI W F, et al. Harmine mitigates LPS-induced acute kidney injury through inhibition of the TLR4-NF-κB/NLRP3 inflammasome signalling pathway in mice[J]. Eur J Pharmacol, 2019, 849: 160-169. doi: 10.1016/j.ejphar.2019.01.062
[12]	XIA S, ZHANG Z, MAGUPALLI V G, et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1[J]. Nature, 2021, 593(7860): 607-611. doi: 10.1038/s41586-021-03478-3
[13]	LIU X, XIA S, ZHANG Z, et al. Channelling inflammation: gasdermins in physiology and disease[J]. Nat Rev Drug Discov, 2021, 20(5): 384-405. doi: 10.1038/s41573-021-00154-z
[14]	李陈广, 麦凤怡, 梁靖蓉, 等. Gasdermin D蛋白的研究进展[J]. 中国药理学通报, 2023, 39(5): 817-822. doi: 10.12360/CPB202202015 LI C G, MAI F Y, LIANG J R. Research progress of Gasdermin D protein[J]. Chinese Pharmacological Bulletin, 2023, 39(5): 817-822. doi: 10.12360/CPB202202015
[15]	RIGOTTO G, BASSO E. Mitochondrial dysfunctions: a thread sewing together Alzheimer ' s disease, diabetes, and obesity[J]. Oxid Med Cell Longev, 2019, 2019: 7210892. DOI: 10.1155/2019/7210892.
[16]	MOHD S, STAYTON A S, KEHKASHAN P, et al. Intranasal delivery of mitochondria attenuates brain injury by AMPK and SIRT1/ PGC-1α pathways in a murine model of photothrombotic stroke[J]. Mol Neurobiol, 2023. DOI: 10.1007/s12035-023-03739-4.
[17]	GONZALEZ-FRANQUESA A, STOCKS B, CHUBANAVA S, et al. Mass-spectrometry-based proteomics reveals mitochondrial supercomplexome plasticity[J]. Cell Rep, 2021, 35(8): 109180. DOI: 10.1016/j.celrep.2021.109180.
[18]	GRVNEWALD A, KUMAR K R, SUE C M. New insights into the complex role of mitochondria in Parkinson ' s disease[J]. Prog Neurobiol, 2019, 177: 73-93. doi: 10.1016/j.pneurobio.2018.09.003
[19]	MARCUS L, STEFANIE S, PEER K, et al. Ischemia time impacts on respiratory chain functions and Ca²⁺-handling of cardiac subsarcolemmal mitochondria subjected to ischemia reperfusion injury[J]. J Cardiothorac Surg, 2019, 14(1): 92. doi: 10.1186/s13019-019-0911-1
[20]	张伟平, 屈洪党, 许力. 丁苯酞注射液对脑梗死患者血清细胞凋亡因子水平的影响[J]. 中华全科医学, 2019, 17(7): 1087-1089, 1190. doi: 10.16766/j.cnki.issn.1674-4152.000869 ZHANG W P, QU H D, XU L. Effect of butylphthalide injection on serum levels of apoptotic factors in patients with cerebral infarction[J]. Chinese Journal of General Practice, 2019, 17(7): 1087-1089, 1190. doi: 10.16766/j.cnki.issn.1674-4152.000869
[21]	DE VASCONCELOS N M, VAN OPDENBOSCH N, VAN GORP H, et al. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture[J]. Cell Death Differ, 2019, 26(1): 146-161. doi: 10.1038/s41418-018-0106-7
[22]	ROGERS C, ERKES D A, NARDONE A, et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation[J]. Nat Commun, 2019, 10(1): 1689. DOI: 10.1038/s41467-019-09397-2.
[23]	HUANG L S, HONG Z, WU W, et al. mtDNA activates cGAS signaling and suppresses the YAP-Mediated endothelial cell proliferation program to promote inflammatory injury[J]. Immunity, 2020, 52(3): 475-486. doi: 10.1016/j.immuni.2020.02.002
[24]	DE TORRE-MINGUELA C, GOMEZ A I, COUILLIN I, et al. Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis[J]. FASEB J, 2021, 35(8): e21757. DOI: 10.1096/fj.202100085R.
[25]	DE VASCONCELOS N M, LAMKANFI M. Recent insights on inflammasomes, gasdermin pores, and pyroptosis[J]. Cold Spring Harb Perspect Biol, 2020, 12(5): a036392. DOI: 10.1101/cshperspect.a036392.
[26]	CHU C T, JI J, DAGDA R K, et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells[J]. Nat Cell Biol, 2013, 15(10): 1197-1205. doi: 10.1038/ncb2837
[27]	PIZZUTO M, PELEGRIN P. Cardiolipin in immune signaling and cell death[J]. Trends Cell Biol, 2020, 30(11): 892-903. doi: 10.1016/j.tcb.2020.09.004
[28]	MAMUN A A, WU Y Q, NASRIN F, et al. Role of pyroptosis in diabetes and its therapeutic implications[J]. J Inflamm Res, 2021, 14: 2187-2206. doi: 10.2147/JIR.S291453
[29]	JAYARAJ L R, AZIMULLAH S, BEIRAM R, et al. Neuroinflammation: friend and foe for ischemic stroke[J]. J Neuroinflammation, 2019, 16(1): 1-24. doi: 10.1186/s12974-018-1391-2
[30]	LYKKE K L, BENTE F, HJELM B C. Post-stroke inflammation-target or tool for therapy?[J]. Acta Neuropatho, 2019, 137 (5): 693-714. doi: 10.1007/s00401-018-1930-z
[31]	MALHOTRA K, LIEBESKIND D S. Collaterals in ischemic stroke[J]. Brain Hemorrhages, 2020, 1: 6-12. doi: 10.1016/j.hest.2019.12.003
[32]	ANAMARIA J, AUREL S. Neuroinflammation in cerebral ischemia and Ischemia/Reperfusion injuries: from pathophysiology to therapeutic strategies[J]. Int J Mol Sci, 2021, 23(1): 14. DOI: 10.3390/ijms23010014.
[33]	WANG L Y, XIONG X X, ZHANG L Y, et al. Neurovascular Unit: a critical role in ischemic stroke[J]. CNS Neurosci Ther, 2021, 27(1): 7-16. doi: 10.1111/cns.13561
[34]	KARTIK P, RUKMANI P, CHANDAN C, et al. Role of NLRP3 inflammasome in stroke pathobiology: current therapeutic avenues and future perspective[J]. ACS Chem Neurosci, 2023, 15(1): 31-55.
[35]	FIACHRA H, LIRAZ G S, NATALIA C K, et al. Succination inactivates gasdermin D and blocks pyroptosis[J]. Science (New York, N.Y. ), 2020, 369(6511): 1633-1637. doi: 10.1126/science.abb9818
[36]	HU J, LIU X, ZHAO J X, et al. Identification of pyroptosis inhibitors that target a reactive cysteine in Gasdermin D[J]. Cancer Immunol Res, 2019, 7(2): A132. DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A132.
[37]	HAN B J, XU J J, SHI X W, et al. DL-3-n-Butylphthalide attenuates myocardial hypertrophy by targeting Gasdermin D and inhibiting Gasdermin D mediated inflammation[J]. Front Pharmacol, 2021, 12: 688140. DOI: 10.3389/fphar.2021.688140.
[38]	HAN C Y, HU Q H, YU A Q, et al. Mafenide derivatives inhibit neuroinflammation in Alzheimer ' s disease by regulating pyroptosis[J]. J Cell Mol Med, 2021, 25(22): 10534-10542. doi: 10.1111/jcmm.16984
[39]	WANG Q Y, ZHENG J S, HU Q Y, et al. Magnesium protects against sepsis by blocking gasdermin D N-terminal-induced pyroptosis[J]. Cell Death Differ, 2020, 27(2): 466-481. doi: 10.1038/s41418-019-0366-x
[40]	罗兰, 张凤秋. 细胞间线粒体转移的作用及机制研究进展[J]. 口腔生物医学, 2023, 14(3): 202-205. doi: 10.3969/j.issn.1674-8603.2023.03.012 LUO L, ZHANG Q F. Research progress on the role and mechanism of mitochondrial transfer between cells[J]. Oral Biomedicine, 2023, 14(3): 202-205. doi: 10.3969/j.issn.1674-8603.2023.03.012
[41]	DOULAMIS I P, GUARIENTO A, DUIGNAN T, et al. Mitochondrial transplantation for myocardial protection in diabetic hearts[J]. Eur J Cardiothorac Surg, 2020, 57(5): 836-845. doi: 10.1093/ejcts/ezz326
[42]	NAKAMURA Y, PARK J H, HAYAKAWA K. Therapeutic use of extracellular mitochondria in CNS injury and disease[J]. Exp Neurol, 2020, 324: 113114. DOI: 10.1016/j.expneurol.2019.113114.
[43]	SUN L, ZHAO Z Y, GUO J, et al. Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis[J]. Neural Regen Res, 2024, 19(6): 1325-1335. doi: 10.4103/1673-5374.385313
[44]	ZHANG Z, MA Z, YAN C, et al. Muscle-derived autologous mitochondrial transplantation: a novel strategy for treating cerebral ischemic injury[J]. Behav Brain Res, 2019, 356: 322-331. doi: 10.1016/j.bbr.2018.09.005
[45]	ALI POUR P, KENNEY M C, KHERADVAR A. Bioenergetics consequences of mitochondrial transplantation in cardiomyocytes[J]. J Am Heart Assoc, 2020, 9 (7): e014501. DOI: 10.1161/JAHA.119.014501.