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Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage

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Item Type:Article
Title:Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage
Creators Name:Bubb, K. and Holzer, T. and Nolte, J.L. and Krüger, M. and Wilson, R. and Schlötzer-Schrehardt, U. and Brinckmann, J. and Altmüller, J. and Aszodi, A. and Fleischhauer, L. and Clausen-Schaumann, H. and Probst, K. and Brachvogel, B.
Abstract:Energy metabolism and extracellular matrix function together orchestrate and maintain tissue organization, but crosstalk between these processes is poorly understood. Here, we used single cell RNA-seq (scRNA-seq) analysis to uncover the importance of the mitochondrial respiratory chain for extracellular matrix homeostasis in mature cartilage. This tissue produces large amounts of a specialized extracellular matrix to promote skeletal growth during development and maintain mobility throughout life. A combined approach of high-resolution scRNA-seq, mass spectrometry/matrisome analysis, and atomic force microscopy was applied to mutant mice with cartilage-specific inactivation of respiratory chain function. This genetic inhibition in cartilage results in the expansion of a central area of 1-month-old mouse femur head cartilage, showing disorganized chondrocytes and increased deposition of extracellular matrix material. scRNA-seq analysis identified a cell cluster-specific decrease in mitochondrial DNA-encoded respiratory chain genes and a unique regulation of extracellular matrix-related genes in nonarticular chondrocytes. These changes were associated with alterations in extracellular matrix composition, a shift in collagen/non-collagen protein content, and an increase of collagen crosslinking and ECM stiffness. These results demonstrate that mitochondrial respiratory chain dysfunction is a key factor that can promote ECM integrity and mechanostability in cartilage and presumably also in many other tissues.
Keywords:Atomic Force Microscopy, Extracellular Matrix, MMP10, Matrisome, Matrix Metalloproteinase, Mitochondria, Mitochondrial Respiratory Chain, Single Cell RNA-Seq, THBS1, Transcriptomics, Animals, Mice
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:101224
Date:October 2021
Official Publication:https://doi.org/10.1016/j.jbc.2021.101224
PubMed:View item in PubMed

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