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Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying

Riikka H Hämäläinen1,2, Juan C Landoni3, Kati J Ahlqvist3

  • 1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. riikka.martikainen@uef.fi.

Nature Metabolism
|July 23, 2020
PubMed

Insights

Mitochondrial DNA (mtDNA) mutations indirectly cause aging by depleting nucleotides needed for nuclear DNA repair. This nuclear genome instability, especially in stem cells, drives premature aging, challenging mtDNA

Area of Science:

  • Cellular and Molecular Biology
  • Genetics and Genomics
  • Aging Research

Background:

  • Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are linked to cellular aging mechanisms.
  • Mitochondrial disease patients and mice with mitochondrial dysfunction do not exhibit premature aging, posing a research question.

Purpose of the Study:

  • To investigate the relationship between mitochondrial dysfunction, nuclear genome maintenance, and premature aging.
  • To elucidate the mechanisms by which mitochondrial DNA replication defects impact nuclear genome stability and organismal aging.

Main Methods:

  • Analysis of nuclear genome maintenance in cells from mtDNA mutator mice.
  • Assessment of DNA replication fork progression, cell cycle dynamics, and DNA damage.
  • Investigation of nucleotide pool dynamics and their impact on nuclear DNA replication.

Main Results:

  • Cells from mtDNA mutator mice exhibit impaired nuclear genome maintenance, characterized by slow replication fork progression and DNA double-strand breaks.
  • Increased mtDNA replication sequesters nucleotides, depleting cellular pools and reducing deoxynucleoside 5'-triphosphate (dNTP) availability for nuclear DNA replication.
  • Defects in mtDNA replication compromise nuclear genome stability, particularly in proliferating progenitor and stem cells.

Conclusions:

  • Defects in mitochondrial DNA replication can directly challenge nuclear genome stability.
  • Nuclear genome maintenance defects, especially in stem cells, may represent a unified mechanism for premature aging in mice.
  • Mitochondrial DNA mutations contribute indirectly to organismal aging through their destabilizing effects on the nuclear genome.

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