NR4A1 promotes TNF‑α‑induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway

Int J Mol Med. 2020 Jan;45(1):151-161. doi: 10.3892/ijmm.2019.4398. Epub 2019 Nov 8.

Abstract

Nuclear receptor subfamily 4 group A member 1 (NR4A1)‑induced 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 factor‑α (TNF‑α) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMP‑activated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNF‑α and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynamin‑related protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) opening‑related cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of F‑actin homeostasis. Inhibiting NR4A1 attenuated TNF‑α and CHX‑induced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP opening‑related cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1‑mediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP opening‑induced cell death and F‑actin‑related migratory inhibition.

Keywords: osteoarthritis; nuclear receptor subfamily 4 group A member 1; AMP‑activated protein kinase; mitochondrial fission.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Movement
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Dynamins / metabolism*
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Male
  • Membrane Potential, Mitochondrial
  • Mitochondrial Dynamics*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Rats
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Tumor Necrosis Factor-alpha
  • Adenosine Triphosphate
  • AMP-Activated Protein Kinases
  • DNM1L protein, human
  • Dynamins