Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China.
National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China.
Cell Commun Signal. 2023 Mar 13;21(1):55. doi: 10.1186/s12964-023-01069-5.
Fibroblast growth factor 19 (FGF19) is recognized to play an essential role in cartilage development and physiology, and has emerged as a potential therapeutic target for skeletal metabolic diseases. However, FGF19-mediated cellular behavior in chondrocytes remains a big challenge. In the current study, we aimed to investigate the role of FGF19 on chondrocytes by characterizing mitochondrial biogenesis and fission-fusion dynamic equilibrium and exploring the underlying mechanism. We first found that FGF19 enhanced mitochondrial biogenesis in chondrocytes with the help of β Klotho (KLB), a vital accessory protein for assisting the binding of FGF19 to its receptor, and the enhanced biogenesis accompanied with a fusion of mitochondria, reflecting in the elongation of individual mitochondria and the up-regulation of mitochondrial fusion proteins. We then revealed that FGF19-mediated mitochondrial biogenesis and fusion required the binding of FGF19 to the membrane receptor, FGFR4, and the activation of AMP-activated protein kinase alpha (AMPKα)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/sirtuin 1 (SIRT1) axis. Finally, we demonstrated that FGF19-mediated mitochondrial biogenesis and fusion was mainly dependent on the activation of p-p38 signaling. Inhibition of p38 signaling largely reduced the high expression of AMPKα/PGC-1α/SIRT1 axis, decreased the up-regulation of mitochondrial fusion proteins and impaired the enhancement of mitochondrial network morphology in chondrocytes induced by FGF19. Taking together, our results indicate that FGF19 could increase mitochondrial biogenesis and fusion via AMPKα-p38/MAPK signaling, which enlarge the understanding of FGF19 on chondrocyte metabolism. Video Abstract.
成纤维细胞生长因子 19（FGF19）被认为在软骨发育和生理学中发挥着重要作用，并且已成为骨骼代谢疾病的潜在治疗靶点。然而，FGF19 在软骨细胞中的细胞行为仍然是一个巨大的挑战。在本研究中，我们旨在通过研究 FGF19 对软骨细胞中线粒体生物发生和分裂-融合动态平衡的影响，来探索其作用机制。我们首先发现，FGF19 通过β Klotho（KLB）增强软骨细胞中的线粒体生物发生，KLB 是一种重要的辅助蛋白，可协助 FGF19 与其受体结合，增强的生物发生伴随着线粒体的融合，反映在单个线粒体的伸长和线粒体融合蛋白的上调。然后，我们揭示了 FGF19 介导的线粒体生物发生和融合需要 FGF19 与膜受体 FGFR4 的结合以及 AMP 激活的蛋白激酶α（AMPKα）/过氧化物酶体增殖物激活受体-γ 共激活因子 1α（PGC-1α）/沉默调节蛋白 1（SIRT1）轴的激活。最后，我们证明了 FGF19 介导的线粒体生物发生和融合主要依赖于 p-p38 信号的激活。p38 信号的抑制在很大程度上降低了 AMPKα/PGC-1α/SIRT1 轴的高表达，减少了线粒体融合蛋白的上调，并损害了 FGF19 诱导的软骨细胞中线粒体网络形态的增强。综上所述，我们的研究结果表明，FGF19 可以通过 AMPKα-p38/MAPK 信号增加线粒体生物发生和融合，从而扩大了对 FGF19 对软骨细胞代谢影响的认识。视频摘要。
