Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells.
Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells.
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DOI：
10.1016/j.redox.2014.01.014
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发表时间：
2014
期刊：
影响因子：
11.4
通讯作者：
Macmillan-Crow LA
中科院分区：
文献类型：
--
作者：
Marine A;Krager KJ;Aykin-Burns N;Macmillan-Crow LA
超氧化物歧化被广泛认为是引发下游氧化应激的主要活性氧物种(ROS)。氧化应激增加在一定程度上导致了许多疾病，如癌症、动脉粥样硬化、缺血/再灌注、糖尿病、衰老和神经退化。锰超氧化物歧化酶(MnSOD)催化超氧化物歧化为过氧化氢，可被其他抗氧化酶进一步解毒。MnSOD对维持线粒体的正常功能至关重要，因此其失活被认为会导致线粒体受损。此前，我们的实验室观察到一种新的肾脏特异性MnSOD基因敲除小鼠的线粒体生物发生增加。本研究采用瞬时小干扰RNA介导的正常大鼠肾细胞MnSOD超氧化物歧化酶基因敲除的体外模型，证实了线粒体生物发生的功能，包括PGC1DNA表达、线粒体α拷贝数和完整性、电子传输链蛋白核心II、线粒体质量、耗氧率和总三磷酸腺苷产量的增加。进一步使用线粒体靶向抗氧化剂MITOQ和一氧化氮合酶抑制剂L-NAME的机制研究表明，过氧亚硝酸盐(低摩尔水平)诱导线粒体生物发生。这些发现首次证明，低水平的过氧亚硝酸盐可以启动线粒体生物发生的保护性信号级联反应，这可能有助于在短暂的MnSOD失活后恢复线粒体功能。NRK细胞中的MnSOD基因敲除会导致MnSOD活性的一过性丧失、硝基酪氨酸的增加和线粒体超氧化物歧化。NRK细胞中的MnSOD基因敲除导致线粒体生物发生的短暂诱导。一氧化氮合酶抑制和Mitoquone阻断MnSOD基因敲除后线粒体的生物发生。低剂量的过氧亚硝酸盐可诱导NRK细胞的生物发生。
Superoxide is widely regarded as the primary reactive oxygen species (ROS) which initiates downstream oxidative stress. Increased oxidative stress contributes, in part, to many disease conditions such as cancer, atherosclerosis, ischemia/reperfusion, diabetes, aging, and neurodegeneration. Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide into hydrogen peroxide which can then be further detoxified by other antioxidant enzymes. MnSOD is critical in maintaining the normal function of mitochondria, thus its inactivation is thought to lead to compromised mitochondria. Previously, our laboratory observed increased mitochondrial biogenesis in a novel kidney-specific MnSOD knockout mouse. The current study used transient siRNA mediated MnSOD knockdown of normal rat kidney (NRK) cells as the in vitro model, and confirmed functional mitochondrial biogenesis evidenced by increased PGC1α expression, mitochondrial DNA copy numbers and integrity, electron transport chain protein CORE II, mitochondrial mass, oxygen consumption rate, and overall ATP production. Further mechanistic studies using mitoquinone (MitoQ), a mitochondria-targeted antioxidant and L-NAME, a nitric oxide synthase (NOS) inhibitor demonstrated that peroxynitrite (at low micromolar levels) induced mitochondrial biogenesis. These findings provide the first evidence that low levels of peroxynitrite can initiate a protective signaling cascade involving mitochondrial biogenesis which may help to restore mitochondrial function following transient MnSOD inactivation. MnSOD knockdown in NRK cells results in a transient loss of MnSOD activity, increased nitrotyrosine and mitochondrial superoxide. MnSOD knockdown in NRK cells results in a transient induction of mitochondrial biogenesis. Nitric oxide synthase inhibition and Mitoquinone blocks mitochondrial biogenesis after MnSOD knockdown. Low doses of peroxynitrite induce biogenesis in NRK cells.
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影响因子：
3.5
作者：
ISCHIROPOULOS, H;ALMEHDI, AB
通讯作者：
ALMEHDI, AB
影响因子：
5.1
作者：
MIYAKI, M;YATAGAI, K;ONO, T
通讯作者：
ONO, T
影响因子：
5.5
作者：
Lira, Vitor A.;Brown, Dana L.;Criswell, David S.
通讯作者：
Criswell, David S.
DOI：
10.1073/pnas.93.21.11853
发表时间：
1996-10-15
影响因子：
11.1
作者：
MacMillanCrow, LA;Crow, JP;Thompson, JA
通讯作者：
Thompson, JA
影响因子：
7.8
作者：
Davis, AF;Clayton, DA
通讯作者：
Clayton, DA