A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

被引:248
作者
Halestrap, Andrew P. [1 ,2 ]
机构
[1] Univ Bristol, Sch Med Sci, Dept Biochem, Bristol BS8 1TD, Avon, England
[2] Univ Bristol, Sch Med Sci, Bristol Heart Inst, Bristol BS8 1TD, Avon, England
基金
英国医学研究理事会;
关键词
brain; cardioprotection; heart; mitochondrion; permeability transition pore (PTP); reperfusion injury; PERMEABILITY TRANSITION PORE; ADENINE-NUCLEOTIDE TRANSLOCASE; DEPENDENT ANION CHANNEL; INTERMEMBRANE JUNCTIONAL COMPLEXES; PERIPHERAL BENZODIAZEPINE-RECEPTOR; CYTOCHROME-C RELEASE; PROTEIN-KINASE-C; CA-2&-INDUCED MEMBRANE TRANSITION; GLYCOGEN-SYNTHASE KINASE-3-BETA; RAT-HEART MITOCHONDRIA;
D O I
10.1042/BST0380841
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In addition to their normal physiological role in ATP production and metabolism, mitochondria exhibit a dark side mediated by the opening of a non-specific pore in the inner mitochondrial membrane. This mitochondrial permeability transition pore (MPTP) causes the mitochondria to breakdown rather than synthesize ATP and, if unrestrained, leads to necrotic cell death. The MPTP is opened in response to Ca2+ overload, especially when accompanied by oxidative stress, elevated phosphate concentration and adenine nucleotide depletion. These conditions are experienced by the heart and brain subjected to reperfusion after a period of ischaemia as may occur during treatment of a myocardial infarction or stroke and during heart surgery. In the present article, I review the properties, regulation and molecular composition of the MPTP. The evidence for the roles of CyP-D (cyclophilin D), the adenine nucleotide translocase and the phosphate carrier are summarized and other potential interactions with outer mitochondrial membrane proteins are discussed. I then review the evidence that MPTP opening mediates cardiac reperfusion injury and that MPTP inhibition is cardioprotective. Inhibition may involve direct pharmacological targeting of the MPTP, such as with cyclosporin A that binds to CyP-D, or indirect inhibition of MPTP opening such as with preconditioning protocols. These invoke complex signalling pathways to reduce oxidative stress and Ca2+ load. MPTP inhibition also protects against congestive heart failure in hypertensive animal models. Thus the MPTP is a very promising pharmacological target for clinical practice, especially once more specific drugs are developed.
引用
收藏
页码:841 / 860
页数:20
相关论文
共 271 条
[1]   Modification of myocardial substrate use as a therapy for heart failure [J].
Abozguia, Khalid ;
Clarke, Kieran ;
Lee, Leong ;
Frenneaux, Michael .
NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE, 2006, 3 (09) :490-498
[2]   Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1 - Mapping the site of binding [J].
Abu-Hamad, Salah ;
Zaid, Hilal ;
Israelson, Adrian ;
Nahon, Edna ;
Shoshan-Barmatz, Varda .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (19) :13482-13490
[3]   The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins [J].
Abu-Hamad, Salah ;
Arbel, Nir ;
Calo, Doron ;
Arzoine, Laetitia ;
Israelson, Adrian ;
Keinan, Nurit ;
Ben-Romano, Ronit ;
Friedman, Orr ;
Shoshan-Barmatz, Varda .
JOURNAL OF CELL SCIENCE, 2009, 122 (11) :1906-1916
[4]   Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury [J].
Adlam, VJ ;
Harrison, JC ;
Porteous, CM ;
James, AM ;
Smith, RAJ ;
Murphy, MP ;
Sammut, IA .
FASEB JOURNAL, 2005, 19 (09) :1088-1095
[5]   A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release [J].
Alcala, S. ;
Klee, M. ;
Fernandez, J. ;
Fleischer, A. ;
Pimental-Muinos, Fx .
ONCOGENE, 2008, 27 (01) :44-54
[6]   Role of the cardiac Na+ /H+ exchanger during ischemia and reperfusion [J].
Allen, DG ;
Xiao, XH .
CARDIOVASCULAR RESEARCH, 2003, 57 (04) :934-941
[7]   THE REVERSIBLE CA-2+-INDUCED PERMEABILIZATION OF RAT-LIVER MITOCHONDRIA [J].
ALNASSER, I ;
CROMPTON, M .
BIOCHEMICAL JOURNAL, 1986, 239 (01) :19-29
[8]   Ischemic and anesthetic preconditioning reduces cytosolic [Ca2+] and improves Ca2+ responses in intact hearts [J].
An, JZ ;
Varadarajan, SG ;
Novalija, E ;
Stowe, DF .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2001, 281 (04) :H1508-H1523
[9]  
APPLEYARD RF, 1993, J CARDIAC SURG, V8, P316
[10]   Postconditioning inhibits mitochondrial permeability transition [J].
Argaud, L ;
Gateau-Roesch, O ;
Raisky, O ;
Loufouat, J ;
Robert, D ;
Ovize, M .
CIRCULATION, 2005, 111 (02) :194-197