Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy.
Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy.
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DOI：
10.18632/aging.100038
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发表时间：
2009-04-09
期刊：
影响因子：
--
通讯作者：
Finkel T
中科院分区：
文献类型：
--
作者：
Wu JJ;Quijano C;Chen E;Liu H;Cao L;Fergusson MM;Rovira II;Gutkind S;Daniels MP;Komatsu M;Finkel T
自噬受损或缺陷被认为会导致或促进衰老以及许多与年龄相关的病理。自噬改变引起这些不同病理的确切机制尚不清楚。 在这里，我们描述了两种体内小鼠模型的创建，这些模型允许表征线粒体功能的改变以及 Atg7 删除后相应氧化应激的贡献。使用这些模型，我们证明从 Atg7-/- 骨骼肌获得的分离线粒体在线粒体呼吸方面表现出显着缺陷。 我们进一步表明，来自 Atg7-/- 小鼠的细胞具有改变的代谢特征，其特征是静息线粒体耗氧量减少和基础糖酵解率代偿性增加。 Atg7-/-细胞还表现出活性氧稳态水平增加的证据。在胰腺 β 细胞内删除 Atg7 的小鼠模型中，观察到的线粒体功能障碍和氧化应激也很明显。在该模型中，简单施用抗氧化剂可以显着改善葡萄糖刺激的胰岛素分泌的生理损伤。 综上所述，这些结果证明了线粒体功能障碍和氧化应激在自噬相关病理学中的潜在作用。
Impaired or deficient autophagy is believed to cause or contribute to aging, as well as a number of age-related pathologies. The exact mechanism through which alterations in autophagy induce these various pathologies is not well understood. Here we describe the creation of two in vivo mouse models that allow for the characterization of the alteration in mitochondrial function and the contribution of the corresponding oxidative stress following deletion of Atg7. Using these models we demonstrate that isolated mitochondria obtained from Atg7-/- skeletal muscle exhibit a significant defect in mitochondrial respiration. We further show that cells derived from Atg7-/- mice have an altered metabolic profile characterized by decreased resting mitochondrial oxygen consumption and a compensatory increase in basal glycolytic rates. Atg7-/-cells also exhibit evidence for increased steady state levels of reactive oxygen species. The observed mitochondrial dysfunction and oxidative stress is also evident in a mouse model where Atg7 is deleted within the pancreatic β cell. In this model, the simple administration of an antioxidant can significantly ameliorate the physiological impairment in glucose-stimulated insulin secretion. Taken together, these results demonstrate the potential role of mitochondrial dysfunction and oxidative stress in autophagy related pathology.
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DOI：
10.1084/jem.20061303
发表时间：
2007-01-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pua HH;Dzhagalov I;Chuck M;Mizushima N;He YW
通讯作者：
He YW
DOI：
10.1073/pnas.0807694106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Tal, Michal Caspi;Sasai, Miwa;Iwasaki, Akiko
通讯作者：
Iwasaki, Akiko
影响因子：
29
作者：
Ebato, Chie;Uchida, Toyoyoshi;Watada, Hirotaka
通讯作者：
Watada, Hirotaka
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
影响因子：
11.4
作者：
Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria