Inhibition of CISD1 alleviates mitochondrial dysfunction and ferroptosis in mice with acute lung injury

Int Immunopharmacol. 2024 Mar 30:130:111685. doi: 10.1016/j.intimp.2024.111685. Epub 2024 Feb 20.

Abstract

The NET family member, CDGSH iron-sulfur domain-containing protein 1 (CISD1), is located in theoutermembrane of mitochondria, where it regulates energy and iron metabolism. CISD1 has vital functions in certain human diseases; however, its function in acute lung injury (ALI) is unknown. ALI pathogenesis critically involves mitochondrial dysfunction and ferroptosis, which might be regulated by CISD1. Therefore, we investigated CISD1's function in mitochondrial dysfunction and ferroptosis regulation in lipopolysaccharide (LPS)-induced ALI. We found that CISD1 was upregulated in LPS-induced ALI,and silencing Cisd1 prevented cell apoptosis and increased cell viability. When CISD1was inhibited by mitoNEET ligand-1 (NL-1) there was a significant mitigation of pathological injury and lung edema, and reduced numbers of total cells, polymorphonuclear leukocytes, and a decreased protein content in the bronchoalveolar lavage fluid (BALF). Moreover, inhibition of CISD1 markedly decreased the interleukin (IL)6, IL-1β, and tumor necrosis factor alpha (TNF-α) levels in the lungs and BALF of ALI-model mice. Silencing of Cisd1 prevented LPS-induced mitochondrial membrane potential depolarization, cellular ATP reduction, and reactive oxygen species (ROS) accumulation, suggesting mitochondrial protection. ALI activated ferroptosis, as evidenced by the increased lipid-ROS, intracellular Fe2+ level, reduced Gpx4 (glutathione peroxidase 4) expression, and the glutathione/glutathione disulfide ratio. Interestingly, inhibition of CISD1 reduced LPS-induced ferroptosis in vivo and in vitro. In conclusion, inhibition of CISD1 alleviated mitochondrial dysfunction and ferroptosis in LPS-induced ALI, identifying CISD1 as possible target for therapy of LPS-induced ALI.

Keywords: Acute lung injury; CISD1; Ferroptosis; Iron-sulfur protein; Mitochondria.

MeSH terms

  • Acute Lung Injury* / drug therapy
  • Acute Lung Injury* / metabolism
  • Animals
  • Ferroptosis*
  • Humans
  • Interleukin-6 / metabolism
  • Iron / metabolism
  • Iron-Binding Proteins* / antagonists & inhibitors
  • Lipopolysaccharides / metabolism
  • Lung / pathology
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Reactive Oxygen Species / metabolism

Substances

  • Interleukin-6
  • Iron
  • Iron-Binding Proteins
  • Lipopolysaccharides
  • Membrane Proteins
  • mitoNEET protein, mouse
  • Reactive Oxygen Species