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

软骨的细胞外基质(ECM)主要由胶原基纤维网络和富含蛋白多糖的纤维外基质组成，其稳定性取决于两个隔室之间的功能相互作用。细胞外基质相互作用或不稳定的变化会严重损害软骨和骨骼的稳态，导致软骨发育不良或退行性骨骼疾病。最近，我们发现线粒体呼吸链(MtRC)功能是骨骼生长和软骨细胞外基质形成的关键代谢信号。我们现在收集的证据表明，代谢信号通路在mtRC功能障碍的软骨细胞中被激活，并与破坏细胞外基质分泌和随后的软骨组装和交联性的囊泡运输障碍有关。在这个项目中，我们的目标是了解mtRC功能障碍通过哪些代谢信号机制转化为囊泡介导的软骨细胞外基质分泌和组装过程。我们的研究不仅将揭示慢性mtrc功能障碍如何扰乱骨骼组织中的细胞生存和细胞外基质稳态，而且还可能开辟新的药物发现渠道。因此，我们可能会发现治疗线粒体疾病和进行性软骨退变中与mtRC功能障碍相关的细胞外基质损伤的其他治疗方案。

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.