Related Experiment Video

Updated: Aug 11, 2025

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts
09:21

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts

Published on: February 23, 2024

993

ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4

Hao Wu1,2,3, Qian Liu1,2,3, Xinyi Shan1,2,3

  • 1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.

Autophagy
|February 8, 2023
PubMed

Insights

The protein kinase ATM is essential for ferroptosis, a cell death pathway involving iron. ATM regulates iron levels by affecting ferritinophagy, offering new therapeutic targets for cancer.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Programmed Cell Death

Background:

  • Ferroptosis is a programmed cell death characterized by lipid peroxide accumulation, driven by intracellular iron.
  • Targeting ferroptosis is a promising strategy for treating therapy-resistant cancers.
  • Post-translational modifications influence ferroptosis sensitivity, but regulatory mechanisms are still being uncovered.

Purpose of the Study:

  • To investigate the role of the DNA damage sensor ATM (ataxia telangiectasia mutated) in ferroptosis execution.
  • To elucidate the molecular mechanisms by which ATM influences ferroptosis.
  • To identify novel regulatory pathways for ferroptosis.

Main Methods:

  • Pharmacological inhibition and genetic ablation of ATM in cellular models.
  • Assessment of ferroptosis sensitivity using cell viability assays and ferroptosis markers.
  • Analysis of downstream signaling pathways, including TRP53 (transformation related protein 53) and NCOA4 (nuclear receptor coactivator 4) interactions.
  • Investigation of ferritinophagy and iron bioavailability.

Main Results:

  • Pharmacological or genetic inhibition of ATM significantly reduces ferroptosis.
  • ATM ablation confers resistance to ferroptosis, largely independent of TRP53.
  • ATM phosphorylates NCOA4, promoting its interaction with ferritin and sustaining ferritinophagy, which regulates iron recycling.

Conclusions:

  • The Ser/Thr protein kinase ATM is indispensable for ferroptosis.
  • A novel regulatory circuit involving ATM, NCOA4, and ferritinophagy controls iron bioavailability and ferroptosis.
  • This finding provides new insights into ferroptosis regulation and potential therapeutic strategies targeting cancer.
Keywords:
ATMNCOA4ferritinophagyferroptosisiron

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