Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage
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, Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage, Journal of Biological Chemistry, 297, (4) Article 101224. ISSN 1083-351X (2021) [Refereed Article]
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.