PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products.
PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products.
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PINK1/Parkin 介导的线粒体自噬抑制高级氧化蛋白产物诱导的成骨细胞凋亡。
DOI：
10.1038/s41419-023-05595-5
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发表时间：
2023-02-07
影响因子：
9
通讯作者：
Zhu, Si-Yuan
中科院分区：
文献类型：
--
作者：
Li, Wei;Jiang, Wang-Sheng;Su, Ya-Ru;Tu, Ke-Wu;Zou, Lin;Liao, Cong-Rui;Wu, Qian;Wang, Zi-Han;Zhong, Zhao-Ming;Chen, Jian-Ting;Zhu, Si-Yuan
成骨细胞凋亡在老年性骨质流失和骨质疏松症中起重要作用。我们之前的研究表明，高级氧化蛋白产物（AOPPs）可以诱导烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）衍生的活性氧（ROS）产生，引起线粒体膜电位（ΔΨm）去极化，触发线粒体依赖的内在凋亡途径，导致成骨细胞凋亡，最终导致骨质减少和骨微结构破坏。在本研究中，我们发现AOPPs还诱导成骨细胞MC3T3-E1产生线粒体ROS (mtROS)，这与nox来源的ROS密切相关，并加重氧化应激状况，从而进一步促进细胞凋亡。清除过量的ROS和受损的线粒体是逆转aopp诱导的细胞凋亡的关键因素。这里，我们通过体外研究发现，雷帕霉素进一步激活了aopp刺激的MC3T3-E1细胞中PINK1/ parkinson介导的线粒体自噬，并通过消除ROS和损伤的线粒体显著减轻aopp诱导的细胞凋亡。我们的体内研究发现，PINK1/ parkin介导的线粒体自噬可以降低血浆AOPP浓度，抑制AOPP诱导的成骨细胞凋亡，从而改善AOPP积累相关的骨质流失、骨微结构破坏和骨密度（BMD）损失。总之，我们的研究表明，旨在上调成骨细胞线粒体自噬和保持线粒体功能的治疗策略可能具有治疗年龄相关性骨质疏松症的潜力。
Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.
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DOI：
10.1042/bj20091372
发表时间：
2010-01-27
期刊：
The Biochemical journal
影响因子：
--
作者：
Fogarty S;Hawley SA;Green KA;Saner N;Mustard KJ;Hardie DG
通讯作者：
Hardie DG
影响因子：
44.1
作者：
通讯作者：
--
DOI：
10.1007/s00467-007-0456-8
发表时间：
2007-07
期刊：
Pediatric nephrology (Berlin, Germany)
影响因子：
--
作者：
Alvarez-Garcia O;Carbajo-Pérez E;Garcia E;Gil H;Molinos I;Rodriguez J;Ordoñez FA;Santos F
通讯作者：
Santos F
影响因子：
32.4
作者：
O'Sullivan TE;Johnson LR;Kang HH;Sun JC
通讯作者：
Sun JC
雷帕霉素通过激活骨细胞自噬降低老年骨质疏松症的严重程度
影响因子：
4
作者：
Luo, D.;Ren, H.;Lin, D.
通讯作者：
Lin, D.