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Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing

Yuki Takakura1,2, Seika Kawamura1, Yui Hashiguchi1,2

  • 1Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.

Scientific Reports
|June 4, 2026
PubMed

Insights

A novel mitochondrial protein, COXFA4L3, was discovered to confer resistance to DNA-damaging chemotherapy. It prevents mitochondrial DNA release, thereby blocking cell death pathways and enhancing cancer cell survival.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Mitochondrial Biology

Background:

  • DNA-damaging anticancer agents are crucial in chemotherapy but face acquired resistance.
  • The role of mitochondria and mitochondrial DNA (mtDNA) in this resistance is poorly understood.

Purpose of the Study:

  • To investigate the involvement of mitochondria in resistance to DNA-damaging anticancer agents.
  • To identify novel molecular mechanisms underlying chemotherapy resistance.

Main Methods:

  • Investigated the function of COXFA4L3 (C15ORF48) in response to DNA-damaging agents.
  • Analyzed mtDNA damage, release, and the mitochondrial permeability transition pore (mPTP) opening.
  • Assessed the cGAS-STING innate immune pathway activation.

Main Results:

  • The mitochondrial protein COXFA4L3 confers resistance to DNA-damaging anticancer agents.
  • COXFA4L3 inhibits mtDNA damage and mPTP opening, preventing mtDNA release into the cytosol.
  • This mechanism blocks cell death triggered by the cGAS-STING pathway.

Conclusions:

  • Mitochondria play a significant role in sensitivity to DNA-damaging chemotherapy via COXFA4L3.
  • COXFA4L3-mediated repression of mtDNA damage responses is a key factor in chemotherapy resistance.
  • Targeting COXFA4L3 may offer new strategies to overcome resistance to DNA-damaging anticancer agents.

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