Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration.
Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration.
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DOI：
10.1038/s41467-022-34694-8
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发表时间：
2022-11-11
影响因子：
16.6
通讯作者：
Shim, Jae-Hyuck
中科院分区：
文献类型：
--
作者：
Lin, Chujiao;Yang, Qiyuan;Guo, Dongsheng;Xie, Jun;Yang, Yeon-Suk;Chaugule, Sachin;DeSouza, Ngoc;Oh, Won-Taek;Li, Rui;Chen, Zhihao;John, Aijaz A.;Qiu, Qiang;Zhu, Lihua Julie;Greenblatt, Matthew B.;Ghosh, Sankar;Li, Shaoguang;Gao, Guangping;Haynes, Cole;Emerson, Charles P.;Shim, Jae-Hyuck
尽管骨骼祖细胞为成骨细胞提供了一个储存库，但其成骨的主要能量来源仍不清楚。在这里，我们证明了在骨骼祖细胞的成骨承诺和分化中线粒体氧化磷酸化的要求。骨祖细胞中进化保守信号通路（ECSIT）的缺失会阻碍骨形成和再生，导致骨骼畸形、骨髓生态位缺陷和自发性骨折，随后出现持续不愈合。在骨骼骨折时，缺乏ecsit的骨骼祖细胞迁移到邻近的骨骼肌，导致肌肉萎缩。这些表型是骨骼祖细胞中ECSIT功能固有的，因为在稳定的骨祖细胞或成熟的成骨细胞中缺乏ECSIT的小鼠中观察到很少的骨骼异常。在机制上，骨骼祖细胞中的Ecsit缺失损害线粒体复合物组装和线粒体氧化磷酸化，并提高糖酵解。ECSIT相关的骨骼表型通过体内重构与野生型ECSIT表达逆转，但没有显示线粒体定位缺陷的突变体。总的来说，这些发现确定了线粒体氧化磷酸化是骨骼祖细胞成骨的主要能量驱动力，控制着肌肉骨骼的完整性。骨骼祖细胞为成骨细胞提供了一个储存库。然而，它们成骨的主要能量来源仍未得到解决。在这里，作者证明escit介导的线粒体代谢调节是成骨所必需的。
Although skeletal progenitors provide a reservoir for bone-forming osteoblasts, the major energy source for their osteogenesis remains unclear. Here, we demonstrate a requirement for mitochondrial oxidative phosphorylation in the osteogenic commitment and differentiation of skeletal progenitors. Deletion of Evolutionarily Conserved Signaling Intermediate in Toll pathways (ECSIT) in skeletal progenitors hinders bone formation and regeneration, resulting in skeletal deformity, defects in the bone marrow niche and spontaneous fractures followed by persistent nonunion. Upon skeletal fracture, Ecsit-deficient skeletal progenitors migrate to adjacent skeletal muscle causing muscle atrophy. These phenotypes are intrinsic to ECSIT function in skeletal progenitors, as little skeletal abnormalities were observed in mice lacking Ecsit in committed osteoprogenitors or mature osteoblasts. Mechanistically, Ecsit deletion in skeletal progenitors impairs mitochondrial complex assembly and mitochondrial oxidative phosphorylation and elevates glycolysis. ECSIT-associated skeletal phenotypes were reversed by in vivo reconstitution with wild-type ECSIT expression, but not a mutant displaying defective mitochondrial localization. Collectively, these findings identify mitochondrial oxidative phosphorylation as the prominent energy-driving force for osteogenesis of skeletal progenitors, governing musculoskeletal integrity. Skeletal progenitors provide a reservoir for bone-forming osteoblasts. However, the major energy source for their osteogenesis remains unresolved. Here, the authors demonstrate that ESCIT-mediated regulation of mitochondrial metabolism is required for osteogenesis.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
1.4
作者：
Cholley, F;Edery, P;Tardieu, M
通讯作者：
Tardieu, M
影响因子：
29
作者：
Guerrero-Castillo, Sergio;Baertling, Fabian;Nijtmans, Leo
通讯作者：
Nijtmans, Leo
DOI：
10.1074/jbc.m116.771899
发表时间：
2017-03-24
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jones AJ;Blaza JN;Varghese F;Hirst J
通讯作者：
Hirst J
DOI：
10.1016/j.cub.2016.06.002
发表时间：
2016-08-08
期刊：
Current biology : CB
影响因子：
--
作者：
Fiorese CJ;Schulz AM;Lin YF;Rosin N;Pellegrino MW;Haynes CM
通讯作者：
Haynes CM