Mitochondrial dysfunction in cartilage and its consequences for extracellular matrix and joint homeostasis

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The extracellular matrix (ECM) of the cartilage is mainly composed of the collagen-based fibrillar network and the proteoglycan-enriched extrafibrillar matrix and its stability is conferred by the functional interaction of the two compartments. Changes in the interaction or destabilization of the ECM compartments profoundly impair cartilage and bone homeostasis leading to chondrodysplasias or degenerative skeletal diseases. Very recently, we showed that mitochondrial respiration chain (mtRC) function is a crucial metabolic cue for skeletal growth and ECM formation in cartilage. We have now collected evidence that metabolic signalling pathways are activated in chondrocytes with mtRC dysfunction and are associated with the disturbed vesicle trafficking that impair ECM secretion and subsequent assembly and crosslinking in cartilage. In this project, we aim to understand through which metabolic signalling mechanisms is mtRC dysfunction translated into disturbed vesicle-mediated ECM secretion and assembly processes in cartilage. Our studies will reveal not only how chronic mtRC dysfunction disturbs cell survival and ECM homeostasis in skeletal tissues, but could also open new channels of drug discovery. Thus, we may reveal additional therapeutic options to treat ECM damage in mitochondrial diseases and in progressive cartilage degeneration that are associated with mtRC dysfunction.