Altered mitochondrial dynamics in chondrocytes cause metabolic reprogramming and influence HIF-2 alpha expression in osteoarthritis

Abstract This study investigated the relationship between mitochondrial dynamics, cell metabolism and extracellular matrix metabolism in chondrocytes to evaluate contribution of mitochondrial dynamics to the development of osteoarthritis (OA). Dynamin-related protein (DRP) 1 and optic atrophy (OPA)1 expression were examined in cartilage from surgical specimens and mouse models. Functional analyses were carried out by short interfering RNA-mediated knockdown of DRP1 and OPA1 in cultured spheroids. Seahorse XF96 assay to determine metabolism state of chondrocytes. RNA-seq was performed to find potential mechanism in OPA1-/- chondrocytes. OA progression was assessed by OA score, immunohistochemistry and micro-CT analysis after destabilizing the medial meniscus surgery with intra-articular injection of adeno-associated virus. DRP1 was markedly downregulated while OPA1 was upregulated in OA cartilage compared to healthy cartilage of human and mice knee joint. DRP1 knockdown in chondrocytes resulted in the formation of megamitochondria, and OPA1 knockdown resulted in the increased fragmented mitochondria of. Both knockdown of DRP1 and OPA1 restored the normal mitochondrial morphology. Loss of OPA1 inhibited cartilage degradation and promoted chondrocyte extracellular matrix synthesis while DRP1 knockdown had the opposite effects; cartilage homeostasis was restored in chondrocytes lacking both DRP1 and OPA1. IL-1β causing a shift from oxidative phosphorylation to glycolysis in chondrocytes, which was reversed by OPA1 depletion. OPA1 knockdown downregulated HIF-2α mRNA and protein level and protected mice against OA. Perturbation of mitochondrial dynamics in chondrocytes contributes to cartilage destruction and the progression of OA. These data identify OPA1 as a therapeutic target in OA.