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DNA-PKcs and ATM modulate mitochondrial ADP-ATP exchange as an oxidative stress checkpoint mechanism

Wei-Min Chen1,2, Jui-Chung Chiang1,2, Zengfu Shang1

  • 1Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.

The EMBO Journal
|February 2, 2023
PubMed

Insights

DNA-PKcs regulates mitochondrial function and cellular response to oxidative stress. A novel complex involving DNA-PKcs, ANT2, and VDAC2 (DAV) controls energy production and dissipates during stress to reduce ROS.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • DNA-PKcs is crucial for DNA repair and involved in oxidative stress response.
  • Its precise role in oxidative stress and mitochondrial function is not fully understood.

Purpose of the Study:

  • To elucidate the role of DNA-PKcs in the cellular response to oxidative stress.
  • To investigate the interaction of DNA-PKcs with mitochondrial proteins and its impact on oxidative phosphorylation.

Main Methods:

  • Studied DNA-PKcs-deficient human cells to assess mitochondrial membrane potential and metabolism.
  • Utilized co-immunoprecipitation to identify protein interactions.
  • Investigated the effect of oxidative stress on the DNA-PKcs/ANT2/VDAC2 complex and its phosphorylation by ATM kinase.

Main Results:

  • DNA-PKcs deficiency leads to depolarized mitochondrial membrane potential and altered metabolism.
  • DNA-PKcs forms a complex (DAV) with ANT2 and VDAC2, essential for ADP/ATP exchange and oxidative phosphorylation (OXPHOS).
  • Oxidative stress induces DAV complex dissociation, mediated by ATM-dependent DNA-PKcs phosphorylation at Thr2609, attenuating OXPHOS.

Conclusions:

  • The DAV complex and ATM kinase act as an oxidative stress checkpoint.
  • This checkpoint regulates mitochondrial oxidative phosphorylation to minimize ROS production and promote cellular recovery from oxidative stress.
Keywords:
ANT2ATMDNA-PKcsVDAC2mitochondrial oxidative stress checkpoint

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