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Mitoferrin-1 Promotes Proliferation and Abrogates Protein Oxidation via the Glutathione Pathway in Glioblastoma

Md Yousuf Ali1, Corinne E Griguer1,2, Susanne Flor1,2

  • 1Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA.

Antioxidants (Basel, Switzerland)
|February 25, 2023
PubMed

Insights

Mitochondrial iron transporter MFRN1 promotes glioblastoma (GBM) progression by increasing mitochondrial iron and glutathione levels. Targeting MFRN1 may offer a new therapeutic strategy for GBM patients.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Glioblastoma (GBM) exhibits poor patient survival due to therapeutic resistance.
  • Cytosolic labile iron pool reduction is linked to radioresistance.
  • Iron metabolism, particularly mitochondrial iron, influences reactive oxygen species (ROS) production, tumor progression, and therapy response.

Purpose of the Study:

  • Investigate the role of mitochondrial iron transporters mitoferrin-1 (MFRN1) and mitoferrin-2 (MFRN2) in GBM progression.
  • Determine the correlation between MFRN1/MFRN2 expression and patient survival.
  • Elucidate the mechanistic link between MFRN1 and GBM aggressiveness.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) database for MFRN1 and MFRN2 mRNA expression in GBM.
  • Overexpression of MFRN1 in glioma cells.
  • Assessment of mitochondrial iron levels, cell proliferation, and anchorage-independent growth.
  • Evaluation of mouse survival in an orthotopic glioma model.
  • Measurement of glutathione levels and protein damage.

Main Results:

  • GBM tissue shows increased MFRN1 mRNA and decreased MFRN2 mRNA compared to non-GBM tissue.
  • Higher MFRN1 mRNA levels correlate with reduced overall survival in GBM patients.
  • MFRN1 overexpression in glioma cells increases mitochondrial iron, enhances proliferation and anchorage-independent growth, and decreases survival in mice.
  • MFRN1 overexpression upregulates glutathione, conferring protection against protein damage.

Conclusions:

  • Mitochondrial iron transporter MFRN1 plays a crucial role in GBM progression.
  • MFRN1-mediated mitochondrial iron metabolism is mechanistically linked to GBM aggressiveness.
  • Targeting MFRN1 presents a potential therapeutic strategy to improve outcomes for GBM patients.
Keywords:
4-HNEMichael adductsglioblastomaglutathioneironmitoferrin

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