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

软骨的细胞外基质（ECM）主要由基于胶原蛋白的纤维网络和富含蛋白聚糖的纤维外基质组成，其稳定性是由这两个部分的功能相互作用赋予的。ECM间室相互作用或不稳定的改变严重损害软骨和骨的内稳态，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ECM形成的关键代谢线索。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，并与干扰的囊泡运输有关，这损害了ECM的分泌和随后的软骨组装和交联。在这个项目中，我们的目标是了解代谢信号机制是通过mtRC功能障碍转化为软骨中囊泡介导的ECM分泌和组装过程的紊乱。我们的研究不仅将揭示慢性mtRC功能障碍如何扰乱骨组织细胞存活和ECM稳态，而且还可以开辟新的药物发现渠道。因此，我们可能会发现额外的治疗选择来治疗线粒体疾病和与mtRC功能障碍相关的进行性软骨退变中的ECM损伤。

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.