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

软骨细胞分化障碍和生存受损是骨骼生长减慢和关节疾病的主要原因，新出现的数据将线粒体呼吸链(MtRC)功能障碍与这些衰老相关的病理过程联系起来。完整的线粒体对出生后骨骼的健康生长至关重要，但mtRC功能障碍如何导致线粒体和关节疾病患者的骨骼生长迟缓仍不完全清楚。我们为mtRC功能和代谢产物在软骨内稳态、骨骼生长和衰老中的关键作用提供了直接证据。这项建议旨在对mtRC功能障碍导致的软骨退变有一个基本的了解，以提供代谢如何调节软骨细胞分化和存活的细粒度知识。基于这一认识，我们将开发针对软骨细胞mtRC功能障碍的新策略，以恢复软骨内稳态，抑制软骨退变，防止骨骼过早老化。这将为针对线粒体疾病、软骨发育不良或软骨退行性疾病的mtRC功能障碍开辟新的治疗机会，并建立依赖mtRC的细胞衰老过程的新分子概念。

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.