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Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage


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Bubb, K, Holzer, T, Nolte, JL, Kruger, M, Wilson, R ORCID: 0000-0003-0152-4394, Schlotzer-Schrehardt, U, Brinckmann, J, Altmuller, J, Aszodi, A, Fleischhauer, L, Clausen-Schaumann, H, Probst, K and Brachvogel, B 2021 , 'Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage' , Journal of Biological Chemistry, vol. 297, no. 4 , pp. 1-16 , doi: 10.1016/j.jbc.2021.101224.

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Energy metabolism and extracellular matrix (ECM) 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 ECM homeostasis in mature cartilage. This tissue produces large amounts of a specialized ECM 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 ECM material. scRNA-Seq analysis identified a cell cluster–specific decrease in mitochondrial DNA–encoded respiratory chain genes and a unique regulation of ECM-related genes in nonarticular chondrocytes. These changes were associated with alterations in ECM composition, a shift in collagen/noncollagen 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.

Item Type: Article
Authors/Creators:Bubb, K and Holzer, T and Nolte, JL and Kruger, M and Wilson, R and Schlotzer-Schrehardt, U and Brinckmann, J and Altmuller, J and Aszodi, A and Fleischhauer, L and Clausen-Schaumann, H and Probst, K and Brachvogel, B
Keywords: MMP10, THBS1, atomic force microscopy, extracellular matrix, matrisome, matrix metalloproteinase, mitochondria, mitochondrial respiratory chain, single-cell RNA-Seq, transcriptomics, proteomics
Journal or Publication Title: Journal of Biological Chemistry
Publisher: Elsevier
ISSN: 1083-351X
DOI / ID Number: 10.1016/j.jbc.2021.101224
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Copyright 2021 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

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