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Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers TXNIP

Ola Karmi1, Yang-Sung Sohn2, Sara I Zandalinas3

  • 1Department of Surgery, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center University of Missouri, 1201 Rollins St, Columbia, MO, 65201, USA; The Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem, 91904, Israel.

Free Radical Biology & Medicine
|September 21, 2021
PubMed

Insights

Disrupting the CISD2 protein immediately impairs mitochondrial labile iron (mLI) and enhances mitochondrial reactive oxygen species (mROS). This cascade affects calcium signaling and promotes TXNIP expression, impacting cancer cells and ferroptosis.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Cancer Research

Background:

  • The CISD2 (NAF-1) protein is crucial for cellular homeostasis, aging, cancer, and neurodegenerative diseases.
  • CISD2 regulates calcium, reactive oxygen species (ROS), and iron signaling pathways.
  • Previous studies using constitutive CISD2 alterations limit understanding of signaling hierarchies.

Purpose of the Study:

  • To elucidate the signaling hierarchy following CISD2 disruption.
  • To investigate the temporal relationship between CISD2, mitochondrial labile iron (mLI), mitochondrial ROS (mROS), calcium, and TXNIP expression.
  • To determine CISD2's role in regulating TXNIP and ferroptosis in cancer cells.

Main Methods:

  • Development of an inducible CISD2 expression system in human breast cancer cells.
  • Utilized a dominant-negative H114C inhibitor of CISD2.
  • Monitored mLI, mROS, cytosolic and ER calcium levels, TXNIP expression, and ferroptosis markers.

Main Results:

  • Inducible CISD2 disruption immediately impaired mLI, leading to increased mROS.
  • Alterations in cytosolic and ER calcium occurred downstream and were independent of mLI/mROS changes.
  • CISD2 disruption enhanced TXNIP expression, dependent on mLI accumulation and linked to ferroptosis.

Conclusions:

  • CISD2 disruption initiates a signaling cascade starting with mLI disruption, followed by mROS elevation.
  • Calcium signaling changes are secondary events, not directly driven by initial mLI/mROS alterations.
  • CISD2 regulates TXNIP expression in cancer cells, mediated by mLI levels and ferroptosis activation.
Keywords:
CISD2CancerFerroptosisIron homeostasisIron-sulfur cluster [Fe–S]MitochondriaNAF-1Oxidative stressReactive oxygen species (ROS)TXNIP

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