Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
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DOI：
10.1038/nature13909
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发表时间：
2014-11-20
期刊：
影响因子：
64.8
通讯作者：
Murphy, Michael P.
中科院分区：
文献类型：
--
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
缺血再灌注（IR）损伤发生在器官的血液供应中断然后恢复时，并且是许多疾病的基础，特别是心脏病发作和中风。虽然缺血组织的再灌注对于存活是必不可少的，但它也通过产生线粒体活性氧（ROS）而引发氧化损伤、细胞死亡和异常免疫应答。虽然IR中线粒体ROS的产生已经确立，但它通常被认为是对再灌注的非特异性反应。在这里，我们开发了一个比较体内代谢组学分析，并意外地确定了广泛保守的代谢途径，负责线粒体ROS的生产过程中IR。我们表明，选择性积累的柠檬酸循环（CAC）中间琥珀酸是一个普遍的代谢签名缺血的范围内的组织和负责线粒体ROS的生产过程中再灌注。缺血性琥珀酸蓄积由琥珀酸脱氢酶（SDH）逆转引起，而琥珀酸脱氢酶逆转又由嘌呤核苷酸分解产生的富马酸溢出和苹果酸/天冬氨酸穿梭的部分逆转驱动。再灌注后，积累的琥珀酸被SDH快速再氧化，通过线粒体复合物I的反向电子传递（RET）驱动大量ROS产生。通过药理学抑制减少缺血性琥珀酸积累足以改善心脏病发作和中风小鼠模型中的体内IR损伤。因此，我们已经确定了一个保守的组织缺血和再灌注的代谢反应，统一了许多迄今为止不相关的方面的IR损伤。此外，这些发现揭示了体内ROS产生的代谢控制的新途径，同时证明抑制缺血性琥珀酸积累及其在随后的再灌注后的氧化是减少一系列病理中的IR损伤的潜在治疗靶点。
Ischaemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion. Here, we developed a comparative in vivo metabolomic analysis and unexpectedly identified widely conserved metabolic pathways responsible for mitochondrial ROS production during IR. We showed that selective accumulation of the citric acid cycle (CAC) intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase (SDH), which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Upon reperfusion, the accumulated succinate is rapidly re-oxidised by SDH, driving extensive ROS generation by reverse electron transport (RET) at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo IR injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of IR injury. Furthermore, these findings reveal a novel pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation upon subsequent reperfusion is a potential therapeutic target to decrease IR injury in a range of pathologies.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
14.8
作者：
Becker, Scott A.;Feist, Adam M.;Herrgard, Markus J.
通讯作者：
Herrgard, Markus J.
影响因子：
4.7
作者：
Hunter, AJ;Hatcher, J;Parsons, AA
通讯作者：
Parsons, AA
DOI：
10.1073/pnas.0510977103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Kussmaul, Lothar;Hirst, Judy
通讯作者：
Hirst, Judy
影响因子：
56.9
作者：
HOCHACHKA, PW;STOREY, KB
通讯作者：
STOREY, KB