Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes.
Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes.
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DOI：
10.1002/art.39025
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发表时间：
2015-04
影响因子：
13.3
通讯作者：
Carames, Beatriz
中科院分区：
文献类型：
--
作者：
Lopez de Figueroa, Paloma;Lotz, Martin K.;Blanco, Francisco J.;Carames, Beatriz
自噬是细胞稳态的关键途径，用于清除受损的大分子和细胞器（包括线粒体）。最近的研究表明，衰老和骨关节炎 (OA) 中自噬激活存在缺陷，导致细胞死亡和组织损伤。此外，越来越多的证据表明线粒体功能障碍在 OA 发病机制中发挥着重要作用。本研究的目的是确定自噬的激活是否可以保护人类软骨细胞免受线粒体功能障碍的影响。用寡霉素（线粒体呼吸链 (MRC) 复合物 V 的抑制剂）处理人软骨细胞。通过测定 LC3-II（自噬体形成的标记物）来分析自噬激活。为了研究自噬是否可以防止线粒体功能障碍，通过哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 选择性抑制剂雷帕霉素以及 mTORC1 和 mTORC2 双重抑制剂 Torin 1 诱导自噬。使用 SiAtg5 来评估自噬在线粒体功能障碍中的作用。寡霉素治疗可诱导线粒体功能障碍，显着降低线粒体膜电位 (Δψm)。这与 ROS 产生增加和细胞死亡有关。 LC3-II 反映的自噬激活以时间依赖性方式减少。为了评估自噬是否调节线粒体功能，在寡霉素之前用雷帕霉素和 Torin 1 预处理软骨细胞。自噬激活可显着防止线粒体功能障碍。相反，自噬的基因抑制会导致显着的线粒体功能缺陷。我们的数据强调了自噬作为针对线粒体功能障碍的关键保护机制的作用。增强自噬的药物干预可能对骨关节炎等软骨退行性过程具有软骨保护活性。
Autophagy, is a key pathway of cellular homeostasis for removing damaged macromolecules and organelles, including mitochondria. Recent studies indicate that autophagy activation is defective in aging and osteoarthritis (OA), contributing to the cell death and tissue damage. In addition, there is increasing evidence that mitochondrial dysfunction plays an important role in OA pathogenesis. The objective of this study is to determine whether activation of autophagy protects from mitochondrial dysfunction in human chondrocytes. Human chondrocytes were treated with Oligomycin, an inhibitor of mitochondrial respiratory chain (MRC) complex V. Autophagy activation was analyzed by determination of LC3-II, a marker for autophagosome formation. To investigate whether autophagy protects from mitochondrial dysfunction, autophagy was induced by mammalian target of rapamycin complex 1 (mTORC1) selective inhibitor Rapamycin and the dual mTORC1 and mTORC2 inhibitor Torin 1. SiAtg5 was employed to evaluate the role of autophagy in mitochondrial dysfunction. Mitochondrial dysfunction was induced by treatment with Oligomycin, which significantly decreased mitochondrial membrane potential (Δψm). This was associated with increased ROS production and cell death. Autophagy activation, reflected by LC3-II, was decreased in a time dependent manner. To evaluate whether autophagy regulates mitochondrial function, chondrocytes were pre-treated with Rapamycin and Torin 1 before Oligomycin. Autophagy activation significantly protected against mitochondrial dysfunction. Conversely, genetic inhibition of autophagy induced significant mitochondrial function defects. Our data highlight the role of autophagy as a critical protective mechanism against mitochondrial dysfunction. Pharmacological interventions that enhance autophagy may have chondroprotective activity in cartilage degenerative processes such as OA.
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影响因子：
--
作者：
Carames, Beatriz;Taniguchi, Noboru;Seino, Daisuke;Blanco, Francisco J.;D'Lima, Darryl;Lotz, Martin
通讯作者：
Lotz, Martin
影响因子：
2.3
作者：
Cillero-Pastor B;Rego-Pérez I;Oreiro N;Fernandez-Lopez C;Blanco FJ
通讯作者：
Blanco FJ
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：
64.8
作者：
Kuma, A;Hatano, M;Mizushima, N
通讯作者：
Mizushima, N
影响因子：
4.8
作者：
Cuervo, AM;Dice, JF
通讯作者：
Dice, JF