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

线粒体呼吸链功能障碍及其对代谢物依赖性骨骼分化和衰老过程的影响

• 批准号: 270922282
• 负责人: Professor Dr. Bent Brachvogel
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/270922282?language=en
• 关键词: Mitochondrial; respiratory; chain; dysfunction; its

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.

软骨细胞分化障碍和存活受损是骨骼生长减少和关节疾病的主要原因，并且新兴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，但线粒体RC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。我们提供了直接的证据证明了mtRC功能和代谢物在软骨稳态、骨骼生长和衰老中的关键作用。该提案旨在从根本上了解mtRC功能障碍驱动的软骨退变，以提供代谢如何调节软骨细胞分化和存活的颗粒知识。基于这些知识，我们将开发新的策略来靶向软骨细胞中的mtRC功能障碍，以恢复软骨稳态，抑制软骨退化和预防骨骼过早老化。这将为靶向线粒体疾病、软骨发育不良或软骨退行性疾病中的mtRC功能障碍开辟新的治疗机会，并建立mtRC依赖性细胞衰老过程的新分子概念。