Activation of AMPK-SIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function.
Activation of AMPK-SIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function.
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DOI：
10.1016/j.joca.2018.07.004
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发表时间：
2018-11
影响因子：
7
通讯作者：
Liu-Bryan R
中科院分区：
文献类型：
--
作者：
Chen LY;Wang Y;Terkeltaub R;Liu-Bryan R
在骨关节炎（OA）中，关节软骨细胞表现出线粒体损伤，包括损害线粒体功能的线粒体DNA 4977-bp（mtDNA 4977）缺失。OA软骨细胞AMPK活性降低，AMPK是一种促进线粒体生物合成的能量生物传感器。在这里，我们测试了药理学AMPK激活，通过下游激活的主要定位于卵巢的sirtuin 3（SIRT 3），逆转现有的减少线粒体DNA的完整性和功能在人类OA软骨细胞和限制小鼠膝关节OA的发展。我们评估了线粒体DNA（mtDNA）的完整性和功能，包括常见的mtDNA 4977缺失和mtDNA含量，线粒体活性氧（mtROS）的产生，氧消耗和细胞内ATP水平。检测AMPKα的磷酸化、SIRT 3的表达和活性、线粒体抗氧化酶SOD 2和DNA修复酶8-氧代鸟嘌呤糖基化酶（OGG 1）的乙酰化和表达以及线粒体呼吸复合物亚基的表达。我们评估了AMPK的药理学激活对年龄相关的自发性小鼠膝关节OA的影响。在OA软骨细胞和甲萘醌处理的正常软骨细胞中均检测到mtDNA 4977缺失，与mtROS增加，SIRT 3减少以及SOD 2和OGG 1乙酰化增加相关。AMPKα1缺陷型软骨细胞表现出SIRT 3活性显着降低。AMPK药理学激活通过SIRT 3通过减少乙酰化和增加SOD 2和OGG 1的表达减弱了现有的mtDNA 4977缺失并改善了OA软骨细胞中的线粒体功能，并限制了衰老相关的小鼠膝关节OA的发展和进展。AMPK激活，通过SIRT 3，限制氧化应激和改善线粒体DNA的完整性和OA软骨细胞的功能。这些作用可能有助于AMPK活性的软骨保护作用。
In osteoarthritis (OA), articular chondrocytes manifest mitochondrial damage, including mitochondrial DNA 4977-bp (mtDNA4977) deletion that impairs mitochondrial function. OA chondrocytes have decreased activity of AMPK, an energy biosensor that promotes mitochondrial biogenesis. Here, we tested if pharmacologic AMPK activation, via downstream activation of predominately mitochondrially localized sirtuin 3 (SIRT3), reverses existing decreases in mtDNA integrity and function in human OA chondrocytes and limits mouse knee OA development. We assessed mitochondrial DNA (mtDNA) integrity and function including the common mtDNA4977 deletion and mtDNA content, mitochondrial reactive oxygen species (mtROS) generation, oxygen consumption and intracellular ATP levels. Phosphorylation of AMPKα, expression and activity of SIRT3, acetylation and expression of the mitochondrial antioxidant enzyme SOD2 and DNA repair enzyme 8-oxoguanine glycosylase (OGG1), and expression of subunits of mitochondrial respiratory complexes were examined. We assessed effect of pharmacologic activation of AMPK on age-related spontaneous mouse knee OA. The mtDNA4977 deletion was detected in both OA chondrocytes and menadione-treated normal chondrocytes, associated with increased mtROS, decreased SIRT3, and increased acetylation of SOD2 and OGG1. AMPKα1 deficient chondrocytes exhibited significantly reduced SIRT3 activity. AMPK pharmacologic activation attenuated existing mtDNA4977 deletion and improved mitochondrial functions in OA chondrocytes via SIRT3 by reducing acetylation and increasing expression of SOD2 and OGG1, and limited aging-associated mouse knee OA development and progression. AMPK activation, via SIRT3, limits oxidative stress and improves mitochondrial DNA integrity and function in OA chondrocytes. These effects likely contribute to chondroprotective effects of AMPK activity.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
SIRT3 线粒体脱乙酰酶在细胞生理学、癌症和神经退行性疾病中的功能。
影响因子：
7.8
作者：
Ansari A;Rahman MS;Saha SK;Saikot FK;Deep A;Kim KH
通讯作者：
Kim KH
影响因子：
4.7
作者：
Hollenbach, S;Dhénaut, A;Epe, B
通讯作者：
Epe, B
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
13.8
作者：
Baeza J;Smallegan MJ;Denu JM
通讯作者：
Denu JM