Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration

Chujiao Lin, Qiyuan Yang, Dongsheng Guo, Jun Xie, Yeon-Suk Yang, Sachin Chaugule, Ngoc DeSouza, Won-Taek Oh, Rui Li, Zhihao Chen, Aijaz A. John, Qiang Qiu, Lihua Julie Zhu, Matthew B. Greenblatt, Sankar Ghosh, Shaoguang Li, Guangping Gao, Cole Haynes, Charles P. Emerson and Jae-Hyuck Shim ()
Additional contact information
Chujiao Lin: UMass Chan Medical School
Qiyuan Yang: UMass Chan Medical School
Dongsheng Guo: UMass Chan Medical School
Jun Xie: UMass Chan Medical School
Yeon-Suk Yang: UMass Chan Medical School
Sachin Chaugule: UMass Chan Medical School
Ngoc DeSouza: UMass Chan Medical School
Won-Taek Oh: UMass Chan Medical School
Rui Li: UMass Chan Medical School
Zhihao Chen: UMass Chan Medical School
Aijaz A. John: UMass Chan Medical School
Qiang Qiu: UMass Chan Medical School
Lihua Julie Zhu: UMass Chan Medical School
Matthew B. Greenblatt: Cornell University
Sankar Ghosh: Columbia University Vagelos College of Physicians and Surgeons
Shaoguang Li: UMass Chan Medical School
Guangping Gao: UMass Chan Medical School
Cole Haynes: UMass Chan Medical School
Charles P. Emerson: UMass Chan Medical School
Jae-Hyuck Shim: UMass Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34694-8

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