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The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence
bioRxiv - Cell Biology Pub Date : 2024-09-05 , DOI: 10.1101/2020.08.03.233874
Xianpeng Ge , Lizhi He , Haibo Liu , Cole M. Haynes , Jae-Hyuck Shim

The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

中文翻译:


ESCRT 蛋白 CHMP5 通过控制内溶酶体-线粒体介导的细胞衰老来限制骨形成



细胞内溶酶体途径的功能障碍,例如溶酶体贮积病,可导致严重的肌肉骨骼疾病。然而,内溶酶体功能障碍如何导致肌肉骨骼异常仍然知之甚少,这限制了治疗选择。在这里,我们报告CHMP5是运输所需的内体分选复合物(ESCRT)-III蛋白家族的成员,对于维持内溶酶体途径和调节成骨谱系细胞中的骨形成至关重要。小鼠成骨细胞中 Chmp5 的基因消除可增加体内和体外的骨形成。从机制上讲,Chmp5缺失通过减少VPS4A蛋白导致内溶酶体功能障碍,而CHMP5过表达足以增加VPS4A蛋白。随后,内溶酶体功能障碍扰乱线粒体功能并增加线粒体活性氧,最终导致骨骼细胞衰老。衰老的骨骼细胞通过结合细胞自主和旁分泌作用导致骨形成异常。重要的是,使用衰老药物消除衰老细胞可以减轻 Chmp5 条件敲除小鼠的肌肉骨骼异常。因此,我们的结果表明,细胞衰老代表了异常内溶酶体途径引起的肌肉骨骼疾病的基础机制和治疗靶点。这些结果还揭示了CHMP5通过影响内溶酶体-线粒体途径调节细胞衰老的功能和机制。
更新日期:2024-09-06
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