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.

软骨细胞分化和生存受损是骨骼生长和关节疾病降低的主要原因，以及新兴数据链接线粒体呼吸链（MTRC）功能障碍与这些与衰老相关的病理学过程。完整的线粒体对于健康的产后骨骼生长至关重要，但是MTRC功能障碍如何导致线粒体和关节疾病患者的骨骼生长延迟。我们提供了MTRC功能和代谢产物在软骨稳态，骨骼生长和衰老中的关键作用的直接证据。该提案旨在对MTRC功能障碍驱动的软骨变性进行基本理解，以提供有关代谢如何调节软骨细胞分化和生存的颗粒知识。基于这些知识，我们将制定新的策略来靶向软骨细胞中MTRC功能障碍以恢复软骨稳态，抑制软骨变性并防止过早的骨骼老化。这将为靶向线粒体疾病，软骨发育不全或软骨退化性疾病的MTRC功能障碍的新新治疗机会，并建立了MTRC依赖性细胞衰老过程的新型分子概念。