Nuclear receptor subfamily 4 group A member 1 (NR4A1)âinduced chondrocyte death plays a critical role in the development of osteoarthritis through poorly defined mechanisms. The present study aimed to investigate the role of NR4A1 in regulating chondrocyte death in response to tumor necrosis factorâα (TNFâα) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMPâactivated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNFâα and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynaminârelated protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) openingârelated cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of Fâactin homeostasis. Inhibiting NR4A1 attenuated TNFâα and CHXâinduced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP openingârelated cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1âmediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP openingâinduced cell death and Fâactinârelated migratory inhibition.
KEYWORDS: osteoarthritis, nuclear receptor subfamily 4 group A member 1, AMP‑activated protein kinase, mitochondrial fission