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

Abstract

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
Volume279
Issue number4
DOIs
StatePublished - 1 Oct 2021
Externally publishedYes

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