The role of succinate and ROS in reperfusion injury - A critical appraisal.
The role of succinate and ROS in reperfusion injury - A critical appraisal.
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DOI：
10.1016/j.yjmcc.2017.06.016
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发表时间：
2017-09
影响因子：
5
通讯作者：
Halestrap AP
中科院分区：
文献类型：
--
作者：
Andrienko TN;Pasdois P;Pereira GC;Ovens MJ;Halestrap AP
我们严格评估了琥珀酸驱动的反向电子流(REF)在再灌流早期驱动线粒体基质超氧化物的产生，从而作为缺血/再灌注(IR)损伤的关键介质的提议。NAD(P)H和黄素蛋白氧化还原状态的实时表面荧光测量表明，在再灌注早期，条件不利于REF。此外，琥珀酸在缺血期间积累的快速损失可以用它的外流而不是氧化来解释。此外，尽管有强大的心脏保护作用，但缺血预适应(IP)并不能减少缺血时琥珀酸的积聚。此外，用表面荧光和线粒体乌头酸酶活性测定再灌注过程中的细胞内活性氧(ROS)发现，只有在首次检测到线粒体通透性转换孔(MPTP)开放后，ROS才会显著增加。我们得出结论，MPTP开放最初可能是由ROS以外的因素触发的，包括线粒体[Ca~(2+)]增加。然而，IP仅抑制再灌流后期[Ca~(2+)]的升高，在MPTP开放后再次如此，这意味着IP通过其他机制调节MPTP开放。其中之一是线粒体结合己糖激酶2(HK2)，它在对照组心脏缺血期间从线粒体中分离出来，但不是IP患者。事实上，在缺血期间线粒体HK2丢失的程度与随后再灌流时的梗塞范围之间有很强的相关性。HK2解离与MPTP增敏有关的机制仍未完全建立，但已涉及几个相关过程，包括VDAC1寡聚、内外膜接触位点的稳定性、眉骨形态、Bcl-2家族成员和线粒体裂变蛋白如Drp1。再灌注早期线粒体ROS的产生发生在MPTP开放后。在RPF早期，条件不利于通过反向电子流产生ROS。缺血预适应(IP)不能减少缺血时琥珀酸的蓄积。RPF期间ROS和Ca~(2+)的IP减少次于MPTP开放的减弱。IP通过不依赖ROS和Ca~(2+)的机制，如HK2，抑制MPTP的开放。
We critically assess the proposal that succinate-fuelled reverse electron flow (REF) drives mitochondrial matrix superoxide production from Complex I early in reperfusion, thus acting as a key mediator of ischemia/reperfusion (IR) injury. Real-time surface fluorescence measurements of NAD(P)H and flavoprotein redox state suggest that conditions are unfavourable for REF during early reperfusion. Furthermore, rapid loss of succinate accumulated during ischemia can be explained by its efflux rather than oxidation. Moreover, succinate accumulation during ischemia is not attenuated by ischemic preconditioning (IP) despite powerful cardioprotection. In addition, measurement of intracellular reactive oxygen species (ROS) during reperfusion using surface fluorescence and mitochondrial aconitase activity detected major increases in ROS only after mitochondrial permeability transition pore (mPTP) opening was first detected. We conclude that mPTP opening is probably triggered initially by factors other than ROS, including increased mitochondrial [Ca2+]. However, IP only attenuates [Ca2+] increases later in reperfusion, again after initial mPTP opening, implying that IP regulates mPTP opening through additional mechanisms. One such is mitochondria-bound hexokinase 2 (HK2) which dissociates from mitochondria during ischemia in control hearts but not those subject to IP. Indeed, there is a strong correlation between the extent of HK2 loss from mitochondria during ischemia and infarct size on subsequent reperfusion. Mechanisms linking HK2 dissociation to mPTP sensitisation remain to be fully established but several related processes have been implicated including VDAC1 oligomerisation, the stability of contact sites between the inner and outer membranes, cristae morphology, Bcl-2 family members and mitochondrial fission proteins such as Drp1. Mitochondrial ROS production during early reperfusion (RPF) occurs after mPTP opening. Conditions do not favour ROS production by reverse electron flow during early RPF. Ischemic preconditioning (IP) does not attenuate succinate accumulation in ischemia. IP reduction of ROS and Ca2+ during RPF is secondary to attenuation of mPTP opening. IP attenuates mPTP opening by mechanisms independent of ROS and Ca2+ such as HK2.
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DOI：
10.1124/jpet.105.091702
发表时间：
2006-01-01
影响因子：
3.5
作者：
Chen, Q;Hoppel, CL;Lesnefsky, EJ
通讯作者：
Lesnefsky, EJ
影响因子：
3.4
作者：
Beutner, G;Rück, A;Brdiczka, D
通讯作者：
Brdiczka, D
影响因子：
4.8
作者：
Ben-Hail, Danya;Begas-Shvartz, Racheli;Shoshan-Barmatz, Varda
通讯作者：
Shoshan-Barmatz, Varda
影响因子：
5
作者：
Calmettes, Guillaume;Ribalet, Bernard;John, Scott;Korge, Paavo;Ping, Peipei;Weiss, James N.
通讯作者：
Weiss, James N.
影响因子：
5
作者：
Bernardi, Paolo;Di Lisa, Fabio
通讯作者：
Di Lisa, Fabio