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In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
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Beyond the nucleus: the ATM-CHEK2 axis senses mtROS to orchestrate mitophagy

Qi-Qiang Guo1,2, Xiao-Yu Song1,2, Liu Cao1,2,3

  • 1The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.

Autophagy
|November 19, 2025
PubMed

Insights

Mitochondrial reactive oxygen species (mtROS) are essential signaling molecules, not just harmful byproducts. They activate protective pathways, including DNA damage response and mitophagy, to maintain cellular homeostasis.

Area of Science:

  • Cellular Biology
  • Mitochondrial Biology
  • Stress Response

Background:

  • Mitochondrial reactive oxygen species (mtROS) are traditionally considered detrimental byproducts of cellular stress.
  • Emerging evidence suggests a more complex role for mtROS in cellular signaling.

Purpose of the Study:

  • To elucidate the fundamental role of mtROS as signaling molecules in activating protective adaptive responses.
  • To identify the specific signaling pathways and molecular players involved in mtROS-mediated cellular protection.

Main Methods:

  • Investigated the role of mtROS in activating the ATM-CHEK2 DNA damage response pathway.
  • Examined the coordination of PINK1-PRKN/Parkin-dependent mitophagy by mtROS signaling.
  • Analyzed the phosphorylation events mediated by CHEK2 on key mitophagy-related proteins (ATAD3A, OPTN, BECN1).

Main Results:

  • mtROS were identified as specific triggers for the ATM-CHEK2 DNA damage response pathway.
  • This pathway was shown to coordinate PINK1-PRKN/Parkin-dependent mitophagy.
  • CHEK2 activation by mtROS leads to phosphorylation of ATAD3A, OPTN, and BECN1, regulating mitophagy initiation and progression.

Conclusions:

  • Revealed a novel mtROS-driven signaling cascade where mtROS act as essential signaling molecules.
  • Demonstrated that the ATM-CHEK2 pathway integrates both genomic and mitochondrial stress signals.
  • Expanded the known functions of the ATM-CHEK2 pathway beyond nuclear DNA damage to include mitochondrial quality control via mitophagy.
Keywords:
DNA damage response pathwayOPTNPINK1mitophagymtROS

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