Mitochondrial respiratory chain dysfunction and its consequences for metabolite-dependent skeletal differentiation and ageing processes

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Disturbed chondrocyte differentiation and impaired survival is a main cause of reduced skeletal growth and joint diseases and emerging data link mitochondrial respiratory chain (mtRC) dysfunction to these aging-related pathological processes. Intact mitochondria are crucial for healthy postnatal skeletal growth, but how mtRC dysfunction contributes to skeletal growth retardation in patients with mitochondrial and joint diseases is still incompletely understood. We provided direct evidence for a critical role of mtRC function and metabolites in cartilage homeostasis, skeletal growth and aging. This proposal aims at a fundamental understanding of mtRC dysfunction-driven cartilage degeneration to provide a granular knowledge of how metabolism regulates chondrocyte differentiation and survival. Based on this knowledge, we will develop novel strategies to target mtRC dysfunction in chondrocytes to restore cartilage homeostasis, inhibit cartilage degeneration and prevent premature skeletal aging. This will open up new therapeutic opportunities for targeting mtRC dysfunction in mitochondrial diseases, chondrodysplasias or cartilage degenerative diseases, and establish novel molecular concepts of mtRC-dependent cellular aging processes.