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Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage

Authors

  • K. Bubb
  • T. Holzer
  • J.L. Nolte
  • M. Krüger
  • R. Wilson
  • U. Schlötzer-Schrehardt
  • J. Brinckmann
  • J. Altmüller
  • A. Aszodi
  • L. Fleischhauer
  • H. Clausen-Schaumann
  • K. Probst
  • B. Brachvogel

Journal

  • Journal of Biological Chemistry

Citation

  • J Biol Chem 297 (4): 101224

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.


DOI

doi:10.1016/j.jbc.2021.101224