CISD3 inhibition drives cystine-deprivation induced ferroptosis

Cell Death Dis. 2021 Sep 8;12(9):839. doi: 10.1038/s41419-021-04128-2.

Abstract

Ferroptosis, a new form of programmed cell death, not only promotes the pathological process of various human diseases, but also regulates cancer progression. Current perspectives on the underlying mechanisms remain largely unknown. Herein, we report a member of the NEET protein family, CISD3, exerts a regulatory role in cancer progression and ferroptosis both in vivo and in vitro. Pan-cancer analysis from TCGA reveals that expression of CISD3 is generally elevated in various human cancers which are consequently associated with a higher hazard ratio and poorer overall survival. Moreover, knockdown of CISD3 significantly accelerates lipid peroxidation and accentuates free iron accumulation triggered by Xc- inhibition or cystine-deprivation, thus causing ferroptotic cell death. Conversely, ectopic expression of the shRNA-resistant form of CISD3 (CISD3res) efficiently ameliorates the ferroptotic cell death. Mechanistically, CISD3 depletion presents a metabolic reprogramming toward glutaminolysis, which is required for the fuel of mitochondrial oxidative phosphorylation. Both the inhibitors of glutaminolysis and the ETC process were capable of blocking the lipid peroxidation and ferroptotic cell death in the shCISD3 cells. Besides, genetic and pharmacological activation of mitophagy can rescue the CISD3 knockdown-induced ferroptosis by eliminating the damaged mitochondria. Noteworthily, GPX4 acts downstream of CISD3 mediated ferroptosis, which fails to reverse the homeostasis of mitochondria. Collectively, the present work provides novel insights into the regulatory role of CISD3 in ferroptotic cell death and presents a potential target for advanced antitumor activity through ferroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cystine / deficiency*
  • Disease Progression
  • Ferroptosis* / drug effects
  • Ferroptosis* / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Glutamine / metabolism
  • Homeostasis / drug effects
  • Humans
  • Iron / metabolism
  • Iron-Sulfur Proteins / genetics
  • Iron-Sulfur Proteins / metabolism*
  • Lipid Peroxides / metabolism
  • Mice
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitophagy / drug effects
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Neoplasms / ultrastructure
  • Organophosphorus Compounds / pharmacology
  • Piperazines / pharmacology
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • CISD3 protein, human
  • Iron-Sulfur Proteins
  • Lipid Peroxides
  • Mitochondrial Proteins
  • Organophosphorus Compounds
  • Piperazines
  • erastin
  • Glutamine
  • Ubiquinone
  • mitoquinone
  • Cystine
  • Iron