The role of hexokinase in cardioprotection - mechanism and potential for translation.
The role of hexokinase in cardioprotection - mechanism and potential for translation.
复制标题
DOI：
10.1111/bph.12899
复制
发表时间：
2015-04
影响因子：
7.3
通讯作者：
Pasdois P
中科院分区：
文献类型：
--
作者：
Halestrap AP;Pereira GC;Pasdois P
线粒体通透性转换孔（mPTP）开放在心脏再灌注损伤中起关键作用，其预防具有心脏保护作用。肿瘤细胞线粒体通常具有高水平的己糖激酶同种型2（HK 2），其结合至其线粒体外膜（OMM），并且结合至心脏线粒体的HK 2也涉及对再灌注损伤的抗性。HK 2在缺血期间从心脏线粒体解离，并且这种解离的程度与再灌注时的梗死面积相关。在这里，我们审查的机制和调节HK 2结合线粒体，这是如何抑制mPTP开放和随之而来的再灌注损伤。HK 2解离的主要决定因素是缺血时葡萄糖-6-磷酸浓度升高和pH值降低。由于缺血前糖原含量减少，这些受预处理方案中涉及的无数信号传导途径调节。缺血期间线粒体HK 2的丢失与OMM对细胞色素c的透化相关，这导致再灌注期间更大的活性氧产生和mPTP开放。研究了在这些过程中与线粒体分裂（例如Drp 1）和细胞凋亡（B‐细胞淋巴瘤2家族成员）相关的HK 2和OMM蛋白之间的潜在相互作用。还考虑了HK 2结合在稳定OMM和内膜之间的接触位点中的作用。这些在缺血期间的断裂被提出以促进细胞色素c在缺血期间的损失，同时增加mPTP开放并在再灌注期间损害细胞生物能量学。最后，我们强调了许多悬而未决的问题，并讨论了潜在的调节线粒体HK 2结合作为一个药理学目标。这篇文章是一个主题部分的一部分调节心脏-途径翻译。要查看本节中的其他文章，请访问http：//dx.doi.org/10.1111/bph.2015.172.issue ‐8
Mitochondrial permeability transition pore (mPTP) opening plays a critical role in cardiac reperfusion injury and its prevention is cardioprotective. Tumour cell mitochondria usually have high levels of hexokinase isoform 2 (HK2) bound to their outer mitochondrial membranes (OMM) and HK2 binding to heart mitochondria has also been implicated in resistance to reperfusion injury. HK2 dissociates from heart mitochondria during ischaemia, and the extent of this correlates with the infarct size on reperfusion. Here we review the mechanisms and regulations of HK2 binding to mitochondria and how this inhibits mPTP opening and consequent reperfusion injury. Major determinants of HK2 dissociation are the elevated glucose‐6‐phosphate concentrations and decreased pH in ischaemia. These are modulated by the myriad of signalling pathways implicated in preconditioning protocols as a result of a decrease in pre‐ischaemic glycogen content. Loss of mitochondrial HK2 during ischaemia is associated with permeabilization of the OMM to cytochrome c, which leads to greater reactive oxygen species production and mPTP opening during reperfusion. Potential interactions between HK2 and OMM proteins associated with mitochondrial fission (e.g. Drp1) and apoptosis (B‐cell lymphoma 2 family members) in these processes are examined. Also considered is the role of HK2 binding in stabilizing contact sites between the OMM and the inner membrane. Breakage of these during ischaemia is proposed to facilitate cytochrome c loss during ischaemia while increasing mPTP opening and compromising cellular bioenergetics during reperfusion. We end by highlighting the many unanswered questions and discussing the potential of modulating mitochondrial HK2 binding as a pharmacological target. This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8
登录
查看更多内容
影响因子：
9.5
作者：
Baines CP
通讯作者：
Baines CP
影响因子：
4.8
作者：
Clarke, SJ;McStay, GP;Halestrap, AP
通讯作者：
Halestrap, AP
影响因子：
3.4
作者：
Beutner, G;Rück, A;Brdiczka, D
通讯作者：
Brdiczka, D
影响因子：
20.1
作者：
Clarke, Samantha J.;Khaliulin, Igor;Das, Manika;Parker, Joanne E.;Heesom, Kate J.;Halestrap, Andrew P.
通讯作者：
Halestrap, Andrew P.
影响因子：
7.3
作者：
Alexander SP;Benson HE;Faccenda E;Pawson AJ;Sharman JL;Spedding M;Peters JA;Harmar AJ;CGTP Collaborators
通讯作者：
CGTP Collaborators