MG53缺乏通过损害线粒体分裂介导慢性阻塞性肺疾病中的骨骼肌功能障碍。
MG53 deficiency mediated skeletal muscle dysfunction in chronic obstructive pulmonary disease via impairing mitochondrial fission.
作者信息
Liao Liwei, Zheng Ziwen, Deng Mingming, Xu Weidong, Zhang Qin, Wang Zilin, Li Chang, Li Jiaye, Bian Yiding, Wang Kai, Miao Jinrui, Li Ruixia, Yin Yan, Zhou Xiaoming, Hou Gang
机构信息
National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
出版信息
Redox Biol. 2025 Jun;83:103663. doi: 10.1016/j.redox.2025.103663. Epub 2025 May 3.
BACKGROUND
Myokine dysregulation and mitochondrial dysfunction are implicated in the pathogenesis of sarcopenia in chronic obstructive pulmonary disease. The objective of this study is to explore the role of myokines and mitochondrial dysfunction in sarcopenia in chronic obstructive pulmonary disease.
METHODS
We identified mitsugumin 53 and its clinical correlation through an enzyme-linked immunosorbent assay using the plasma samples of patients with chronic obstructive pulmonary disease. The role of mitsugumin 53 was confirmed in mitsugumin 53-knockout mice. The underlying mechanisms were investigated using multi-omics sequencing, live-cell imaging, and histological and molecular experiments. The effectiveness and safety of recombinant mitsugumin 53 in treating cigarette smoke-induced muscle dysfunction were evaluated in vitro and in vivo.
RESULTS
Plasma mitsugumin 53 levels were decreased in patients with chronic obstructive pulmonary disease and were associated with skeletal muscle dysfunction. Mitsugumin 53 deficiency exacerbated cigarette smoking-induced skeletal muscle atrophy. In muscle cells, mitsugumin 53 co-localized with the mitochondria and regulated mitochondrial fission. As a lipid transporter, mitsugumin 53 directly bound to the mitochondria-specific lipid cardiolipin and participated in maintaining mitochondrial homeostasis and membrane integrity. As an E3-ligase, mitsugumin 53 deletion triggered BCL2L13-mediated mitochondrial fission upon cigarette smoking stimulation. Supplementation with recombinant mitsugumin 53 significantly alleviated cigarette smoking-induced muscle atrophy and rescued mitochondrial dysfunction in vitro and in vivo.
CONCLUSIONS
Mitsugumin 53 is a vital regulator of sarcopenia in patients with chronic obstructive pulmonary disease. Thus, mitsugumin 53 and mitochondrial fission may be promising therapeutic targets for muscle dysfunction in chronic obstructive pulmonary disease.
背景
肌动蛋白失调和线粒体功能障碍与慢性阻塞性肺疾病中肌肉减少症的发病机制有关。本研究的目的是探讨肌动蛋白和线粒体功能障碍在慢性阻塞性肺疾病肌肉减少症中的作用。
方法
我们通过酶联免疫吸附测定法，使用慢性阻塞性肺疾病患者的血浆样本，鉴定了三宅素53及其临床相关性。在三宅素53基因敲除小鼠中证实了三宅素53的作用。使用多组学测序、活细胞成像以及组织学和分子实验研究其潜在机制。在体外和体内评估重组三宅素53治疗香烟烟雾诱导的肌肉功能障碍的有效性和安全性。
结果
慢性阻塞性肺疾病患者血浆三宅素53水平降低，且与骨骼肌功能障碍相关。三宅素53缺乏加剧了吸烟诱导的骨骼肌萎缩。在肌肉细胞中，三宅素53与线粒体共定位并调节线粒体分裂。作为一种脂质转运蛋白，三宅素53直接与线粒体特异性脂质心磷脂结合，参与维持线粒体稳态和膜完整性。作为一种E3连接酶，三宅素53缺失在吸烟刺激下引发BCL2L13介导的线粒体分裂。补充重组三宅素53可显著减轻吸烟诱导的肌肉萎缩，并在体外和体内挽救线粒体功能障碍。
结论
三宅素53是慢性阻塞性肺疾病患者肌肉减少症的重要调节因子。因此，三宅素53和线粒体分裂可能是慢性阻塞性肺疾病肌肉功能障碍有前景的治疗靶点。
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