线粒体相关内质网膜在缺血性脑卒中的作用
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摘要
线粒体相关内质网膜(mitochondria-associated endoplasmic reticulum membranes,MAM)是内质网(endoplasmic reticulum,ER)膜与线粒体外膜紧密连接的特化部分,构成ER和线粒体之间通讯的物理基础,并在Ca~(2+)稳态、氧化应激、炎症、线粒体形态功能调控、脂质代谢、细胞凋亡、自噬等过程中发挥重要作用。深入研究发现,MAM功能与缺血性脑卒中病理生理机制高度相关。另一方面,多种具有明确抗缺血性脑卒中作用的药物或化合物通过影响MAM相关蛋白发挥作用。该文就MAM在缺血性脑卒中病理进程中的作用,以及其作为抗缺血性脑卒中的潜在药物靶点作一综述。
Mitochondria-associated endoplasmic reticulum membranes( MAM) provide an excellent scaffold for crosstalk between ER and mitochondria,which play an important role in Ca~(2+) homeostasis,oxidative stress,inflammation,mitochondrial morphological and functional regulation,lipid metabolism,apoptosis,autophagy and other processes. With the in-depth research,the function of MAM and the pathophysiological mechanisms of ischemic stroke overlap highly. On the other hand,a variety of drugs or compounds protect against ischemic stroke by affecting MAM-related proteins. In this review,we summarize the critical role of MAM in ischemic stroke and the potential of MAM as one drug target for treating ischemic stroke.
Mitochondria-associated endoplasmic reticulum membranes( MAM) provide an excellent scaffold for crosstalk between ER and mitochondria,which play an important role in Ca~(2+) homeostasis,oxidative stress,inflammation,mitochondrial morphological and functional regulation,lipid metabolism,apoptosis,autophagy and other processes. With the in-depth research,the function of MAM and the pathophysiological mechanisms of ischemic stroke overlap highly. On the other hand,a variety of drugs or compounds protect against ischemic stroke by affecting MAM-related proteins. In this review,we summarize the critical role of MAM in ischemic stroke and the potential of MAM as one drug target for treating ischemic stroke.
引文
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[18]Spescha R D,Klohs J,Semerano A,et al.Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke[J].Eur Heart J,2015,36(25):1590-600.
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[21]张红艳,翟丽,王婷婷,等.胡黄连苷Ⅱ通过抑制cyto C/caspase-9/caspase-3通路发挥神经保护作用[J].中国药理学通报,2017,33(5):668-74.[21]Zhang H Y,Zhai L,Wang T T,et al.PicrosideⅡplays a neuroprotective role by inhibiting cyto C/caspase-9/caspase-3 pathway[J].Chin Pharmacol Bull,2017,33(5):668-74.
[22]Li S,Wang T,Zhai L,et al.PicrosideⅡexerts a neuroprotective effect by inhibiting m PTP permeability and EndoG release after cerebral ischemia/reperfusion injury in rats[J].J Mol Neurosci,2018,64(1):144-55.
[23]Qiu J,Wang M,Zhang J,et al.The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling[J].Int Immunopharmacol,2016,40:492-500.
[24]Zhang W,Liu J,Hu X,et al.Polyunsaturated fatty acids reduce neonatal hypoxic/ischemic brain injury by promoting phosphatidylserine formation and Akt signaling[J].Stroke,2015,46(10):2943-50
[25]Zheng W,Talley W L,Holstein D M,et al.P2Y1R-initiated,IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse[J].J Cereb Blood Flow Metab,2013,33(4):600-11.
[2]Members W G,Mozaffarian D,Benjamin E J.American Heart Association Statistics Committee;Stroke Statistics Subcommittee:Heart Disease and Stroke Statistics-2016 update:a report from the American Heart Association[J].Circulation,2016,133(4):e38-60.
[3]杜冠华,张雯,杜立达,等.抗脑缺血药物研发现状分析与策略研究[J].神经药理学报,2018,8(1):1-8.[3]Du G H,Zhang W,Du L D,et al.Analysis and strategy research on the development of anticerebral ischemia drugs[J].Acta Neuropharmaco,2018,8(1):1-8.
[4]Rowland A A,Voeltz G K.Endoplasmic reticulum-mitochondria contacts:function of the junction[J].Nat Rev Mol Cell Biol,2012,13(10):607-25.
[5]Wang X,Wen Y,Dong J,et al.Systematic in-depth proteomic analysis of mitochondria-associated endoplasmic reticulum membranes(MAM)in mouse and human testes[J].Proteomics,2018,18(14):e1700478.
[6]Janikiewicz J,Szymański J,Malinska D,et al.Mitochondria-associated membranes in aging and senescence:structure,function,and dynamics[J].Cell Death Dis,2018,9(3):332.
[7]Filadi R,Greotti E,Turacchio G,et al.Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling[J].Proc Natl Acad Sci USA,2015,112(17):E2174.
[8]Kerkhofs M,Bittremieux M,Morciano G,et al.Emerging molecular mechanisms in chemotherapy:Ca2+signaling at the mitochondria-associated endoplasmic reticulum membranes[J].Cell Death Dis,2018,9(3):334.
[9]Danese A,Patergnani S,Bonora M,et al.Calcium regulates cell death in cancer:Roles of the mitochondria and mitochondria-associated membranes(MAMs)[J].Biochim Biophys Acta Bioenerg,2017,1858(8):615-27.
[10]Gilady S Y,Bui M,Lynes E M,et al.Ero1alpha requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane(MAM)[J].Cell Stress Chaperones,2010,15(5):619-29.
[11]Pinton P,Giorgi C,Missiroli S,et al.Mitochondria-associated membranes(MAMs):composition,molecular mechanisms and physiopathological implications[J].Antioxid Redox Signal,2015,22(12):995-1019.
[12]Missiroli S,Patergnani S,Caroccia N,et al.Mitochondria-associated membranes(MAMs)and inflammation[J].Cell Death Dis,2018,9(3):329.
[13]Rimessi A,Bezzerri V,Patergnani S,et al.Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis[J].Nat Commun,2015,6:6201.
[14]Vance J E.MAM(mitochondria-associated membranes)in mammalian cells:lipids and beyond[J].Biochim Biophys Acta,2014,1841(4):595-609.
[15]Schfer M K,Pfeiffer A,Jaeckel M,et al.Regulators of mitochondrial Ca2+homeostasis in cerebral ischemia[J].Cell Tissue Res,2014,357(2):395-405.
[16]Garofalo T,Matarrese P,Manganelli V,et al.Evidence for the involvement of lipid rafts localized at the ER-mitochondria associated membranes in autophagosome formation[J].Autophagy,2016,12(6):917-35.
[17]Peng C,Rao W,Zhang L,et al.Mitofusin 2 ameliorates hypoxiainduced apoptosis via mitochondrial function and signaling pathways[J].Int J Biochem Cell Biol,2015,69:29-40.
[18]Spescha R D,Klohs J,Semerano A,et al.Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke[J].Eur Heart J,2015,36(25):1590-600.
[19]Wu W,Lin C,Wu K,et al.FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions[J].Embo J,2016,35(13):1368-84.
[20]Bonora M,Bononi A,De M E,et al.Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition[J].Cell Cycle,2013,12(4):674-83.
[21]张红艳,翟丽,王婷婷,等.胡黄连苷Ⅱ通过抑制cyto C/caspase-9/caspase-3通路发挥神经保护作用[J].中国药理学通报,2017,33(5):668-74.[21]Zhang H Y,Zhai L,Wang T T,et al.PicrosideⅡplays a neuroprotective role by inhibiting cyto C/caspase-9/caspase-3 pathway[J].Chin Pharmacol Bull,2017,33(5):668-74.
[22]Li S,Wang T,Zhai L,et al.PicrosideⅡexerts a neuroprotective effect by inhibiting m PTP permeability and EndoG release after cerebral ischemia/reperfusion injury in rats[J].J Mol Neurosci,2018,64(1):144-55.
[23]Qiu J,Wang M,Zhang J,et al.The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling[J].Int Immunopharmacol,2016,40:492-500.
[24]Zhang W,Liu J,Hu X,et al.Polyunsaturated fatty acids reduce neonatal hypoxic/ischemic brain injury by promoting phosphatidylserine formation and Akt signaling[J].Stroke,2015,46(10):2943-50
[25]Zheng W,Talley W L,Holstein D M,et al.P2Y1R-initiated,IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse[J].J Cereb Blood Flow Metab,2013,33(4):600-11.