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Mitochondrial DNA: cellular genotoxic stress sentinel

Zheng Wu1, Alva G Sainz2, Gerald S Shadel3

  • 1Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Graduate Program in Genetics, Yale School of Medicine, New Haven, CT 06437, USA.

Trends in Biochemical Sciences
|June 5, 2021
PubMed

Insights

Mitochondrial DNA (mtDNA) acts as a genotoxic stress sentinel, not just for energy production. Escaping mitochondria, it signals nuclear DNA damage, potentially driving cancer chemoresistance, inflammation, and aging.

Area of Science:

  • Mitochondrial biology
  • Genetics
  • Cellular stress response

Background:

  • Mitochondrial DNA (mtDNA) is essential for oxidative phosphorylation but possesses unique features like high copy number and damage proneness.
  • The role of mtDNA beyond energy production remains incompletely understood.

Purpose of the Study:

  • To propose and discuss evidence for mitochondrial DNA (mtDNA) functioning as a genotoxic stress sentinel and second messenger.
  • To explore the implications of mtDNA's role in cellular stress signaling.

Main Methods:

  • Review and synthesis of existing evidence.
  • Discussion of mtDNA's ability to exit the mitochondrial matrix.
  • Analysis of downstream signaling pathways involving interferon-stimulated genes.

Main Results:

  • Mitochondrial DNA (mtDNA) can escape the mitochondrial matrix to activate nuclear DNA damage and repair responses.
  • This signaling involves interferon-stimulated gene products and other downstream effectors.

Conclusions:

  • Mitochondrial DNA (mtDNA) serves a dual role as an energy producer and a genotoxic stress sentinel.
  • This sentinel function may contribute to cancer chemoresistance, inflammation, disease pathology, and aging.
Keywords:
DNA repaircGAS-STINGchemoresistanceinterferon-stimulated gene (ISG)mtDNAretrograde signaling

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