Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage

Kristina Bubb, Tatjana Holzer, Janica L. Nolte, Marcus Krüger, Richard Wilson, Ursula Schlötzer-Schrehardt, Jürgen Brinckmann, Janine Altmüller, Attila Aszodi, Lutz Fleischhauer, Hauke Clausen-Schaumann, Kristina Probst, Bent Brachvogel

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish
Article number101224
JournalJournal of Biological Chemistry
Issue number4
StatePublished - 1 Oct 2021
Externally publishedYes


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