Impaired spare respiratory capacity in cortical synaptosomes from Sod2 null mice.
Impaired spare respiratory capacity in cortical synaptosomes from Sod2 null mice.
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DOI：
10.1016/j.freeradbiomed.2010.12.030
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发表时间：
2011-04-01
影响因子：
7.4
通讯作者：
Melov, Simon
中科院分区：
文献类型：
--
作者：
Flynn, James M.;Choi, Sung W.;Day, Nicholas U.;Gerencser, Akos A.;Hubbard, Alan;Melov, Simon
关键词：
突触前神经末梢需要高水平的三磷酸腺苷来维持突触功能。突触线粒体不能产生足够的ATP被认为是神经退行性疾病中突触网络丧失之前的致病事件。内源性氧化应激通常被认为是这种病理的病因学基础，但很难在体内进行测试。编码线粒体超氧阴离子自由基主要防御酶的超氧化物歧化酶基因(Sod2)失活会导致新生儿死亡。然而，使用SOD模拟物的干预延长了该模型的寿命，并揭示了一种神经退行性表型，为体内氧化应激的检查提供了一个独特的模型。我们在此介绍了从Sod2缺失小鼠的额叶皮质分离的突触终末的研究，表明由于线粒体氧化应激导致生物能量功能受损。Sod2基因缺失小鼠皮质突触体表现为线粒体呼吸链与FCCP解偶联或4-氨基吡啶引起的质膜去极化导致线粒体的备用呼吸能力严重下降，以满足生理需求。然而，Sod2缺失的动物通过巴斯德效应部分补偿受损的氧化代谢，允许突触释放正常的神经递质，建立了潜在有害的能量范例。这项研究的结果表明，高通量呼吸测量是分析转基因模型中大脑特定区域的一种简便方法，并可以揭示由于内源性氧化应激而导致的亚细胞区域的生物能量缺陷。
Pre-synaptic nerve terminals require high levels of ATP for the maintenance of synaptic function. Failure of synaptic mitochondria to generate adequate ATP has been implicated as a causative event preceding loss of synaptic networks in neurodegenerative disease. Endogenous oxidative stress has often been postulated as an etiological basis for this pathology, but has been difficult to test in vivo. Inactivation of the superoxide dismutase gene (Sod2) encoding the chief defense enzyme against mitochondrial superoxide radicals results in neonatal lethality. However, intervention with an SOD mimetic extends the lifespan of this model, and uncovers a neurodegenerative phenotype providing a unique model for the examination of in vivo oxidative stress. We present here studies on synaptic termini isolated from the frontal cortex of Sod2 null mice demonstrating impaired bioenergetic function as a result of mitochondrial oxidative stress. Cortical synaptosomes from Sod2 null mice demonstrate a severe decline in mitochondrial spare respiratory capacity to physiological demand induced by mitochondrial respiratory chain uncoupling with FCCP or plasma membrane depolarization induced by 4-aminopyridine treatment. However, Sod2 null animals compensate for impaired oxidative metabolism in part by Pasteur effect allowing for normal neurotransmitter release at the synapse, setting up a potentially detrimental energetic paradigm. The results of this study demonstrate that high throughput respirometry is a facile method for analyzing specific regions of the brain in transgenic models, and can uncover bioenergetic deficits in subcellular regions due to endogenous oxidative stress.
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影响因子：
7.4
作者：
Gerencser, Akos A.;Neilson, Andy;Choi, Sung W.;Edman, Ursula;Yadava, Nagendra;Oh, Richard J.;Ferrick, David A.;Nicholls, David G.;Brand, Martin D.
通讯作者：
Brand, Martin D.
影响因子：
7.4
作者：
Lynn, S;Huang, EJ;Huang, TT
通讯作者：
Huang, TT
DOI：
10.1073/pnas.96.3.846
发表时间：
1999-02-02
影响因子：
11.1
作者：
Melov, S;Coskun, P;Wallace, DC
通讯作者：
Wallace, DC
影响因子：
4.7
作者：
Choi SW;Gerencser AA;Nicholls DG
通讯作者：
Nicholls DG
线粒体氧化应激会导致tau的过度磷酸化。
影响因子：
3.7
作者：
Melov, Simon;Adlard, Paul A.;Morten, Karl;Johnson, Felicity;Golden, Tamara R.;Hinerfeld, Doug;Schilling, Birgit;Mavros, Christine;Masters, Colin L.;Volitakis, Irene;Li, Qiao-Xin;Laughton, Katrina;Hubbard, Alan;Cherny, Robert A.;Gibson, Brad;Bush, Ashley I.
通讯作者：
Bush, Ashley I.