Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3.
Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3.
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线粒体复合物 I 内 NDUFA13 的电子泄漏通过二聚化 STAT3 减轻缺血再灌注损伤
DOI：
10.1073/pnas.1704723114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Hu H;Nan J;Sun Y;Zhu D;Xiao C;Wang Y;Zhu L;Wu Y;Zhao J;Wu R;Chen J;Yu H;Hu X;Zhu W;Wang J
由于线粒体电子泄漏而产生的活性氧（ROS）可能参与生理或病理过程。NDUFA 13是线粒体复合物I的辅助亚基，具有独特的分子结构，并且靠近具有低电化学电位的FeS簇。在这里，我们产生了心脏特异性条件NDUFA 13杂合敲除小鼠。在基础状态下，适度下调NDUFA 13在复合物I内产生泄漏，导致细胞质局部H2 O2而非超氧化物轻度增加。由此产生的ROS作为第二信使，并负责STAT 3二聚化，因此，激活抗凋亡信号，最终显着抑制超氧化物爆发，并减少缺血再灌注过程中的梗死面积。线粒体特定的分子结构与活性氧（ROS）产生之间的因果关系已引起人们的广泛关注。NDUFA 13是一个新发现的线粒体复合物I的辅助亚基，具有独特的分子结构和位置，非常接近低电化学电位的复合物I的亚基。据报道，下调的NDUFA 13使肿瘤细胞对凋亡更具抗性。因此，这种分子可能为我们提供了一个理想的机会，研究ROS的产生和它的作用，在细胞保护凋亡。在本研究中，我们产生了心脏特异性他莫昔芬诱导的NDUFA 13基因敲除小鼠，并证明心脏特异性杂合基因敲除（cHet）小鼠在基础状态下表现出正常的心脏形态和功能，但在缺血再灌注（I/R）损伤时对细胞凋亡更具抵抗力。cHet小鼠的耗氧速率在配合物I和II的作用下保持不变，与电子供体TMPD+抗坏血酸的耗氧速率相匹配。有趣的是，在基础状态下，cHet小鼠在胞质溶胶中表现出更高的H2 O2水平，但在线粒体中没有。重要的是，增加H2 O2作为第二信使，导致STAT 3二聚化，因此，激活抗凋亡信号，最终显着抑制超氧化物爆发，并减少梗死面积在I/R过程中cHet小鼠。
Significance Reactive oxygen species (ROS) generation due to electron leak from the mitochondria may be involved in physiological or pathological processes. NDUFA13 is an accessory subunit of mitochondria complex I with a unique molecular structure and is located close to FeS clusters with low electrochemical potentials. Here, we generated cardiac-specific conditional NDUFA13 heterozygous knockout mice. At the basal state, a moderate down-regulation of NDUFA13 created a leak within complex I, resulting in a mild increase in cytoplasm localized H2O2, but not superoxide. The resultant ROS served as a second messenger and was responsible for the STAT3 dimerization and, hence, the activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the ischemia-reperfusion process. The causative relationship between specific mitochondrial molecular structure and reactive oxygen species (ROS) generation has attracted much attention. NDUFA13 is a newly identified accessory subunit of mitochondria complex I with a unique molecular structure and a location that is very close to the subunits of complex I of low electrochemical potentials. It has been reported that down-regulated NDUFA13 rendered tumor cells more resistant to apoptosis. Thus, this molecule might provide an ideal opportunity for us to investigate the profile of ROS generation and its role in cell protection against apoptosis. In the present study, we generated cardiac-specific tamoxifen-inducible NDUFA13 knockout mice and demonstrated that cardiac-specific heterozygous knockout (cHet) mice exhibited normal cardiac morphology and function in the basal state but were more resistant to apoptosis when exposed to ischemia-reperfusion (I/R) injury. cHet mice showed a preserved capacity of oxygen consumption rate by complex I and II, which can match the oxygen consumption driven by electron donors of N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD)+ascorbate. Interestingly, at basal state, cHet mice exhibited a higher H2O2 level in the cytosol, but not in the mitochondria. Importantly, increased H2O2 served as a second messenger and led to the STAT3 dimerization and, hence, activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the I/R process in cHet mice.
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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：
64.8
作者：
Vinothkumar, Kutti R.;Zhu, Jiapeng;Hirst, Judy
通讯作者：
Hirst, Judy
影响因子：
14.8
作者：
Peralta, David;Bronowska, Agnieszka K.;Dick, Tobias P.
通讯作者：
Dick, Tobias P.
影响因子：
4.8
作者：
Angell, JE;Lindner, DJ;Kalvakolanu, DV
通讯作者：
Kalvakolanu, DV
影响因子：
4.7
作者：
Liu, YB;Fiskum, G;Schubert, D
通讯作者：
Schubert, D