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Mitochondrial DNA competition: starving out the mutant genome

Antonella Spinazzola1, Diego Perez-Rodriguez1, Jan Ježek1

  • 1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London NW3 2PF, UK.

Trends in Pharmacological Sciences
|February 24, 2024
PubMed

Insights

Targeting nutrient metabolism offers a novel therapeutic strategy to eliminate harmful mitochondrial DNA (mtDNA) variants. Restricting nutrient consumption can purge cells of deleterious mtDNA and restore mitochondrial function.

Area of Science:

  • Mitochondrial Medicine
  • Genetics
  • Metabolic Disorders

Background:

  • Pathogenic mitochondrial DNA (mtDNA) variants cause severe genetic diseases and may contribute to common disorders.
  • Selection against these mutants is a key objective in mitochondrial medicine.
  • While random drift occurs, active forces and metabolic cues influence mtDNA variant selection.

Purpose of the Study:

  • To clarify mechanisms of mtDNA variant selection.
  • To investigate the role of metabolic cues in shaping mtDNA heteroplasmy.
  • To explore therapeutic strategies targeting nutrient metabolism for mtDNA disorders.

Main Methods:

  • Analysis of mtDNA variant selection mechanisms.
  • Investigation of metabolic cues influencing mtDNA heteroplasmy.
  • Exploration of small molecules to restrict nutrient consumption.

Main Results:

  • Metabolic reprogramming supports deleterious mtDNA variants, granting them a replicative advantage.
  • Elevated nutrient requirements of mutant mtDNA present a therapeutic vulnerability.
  • Small molecules restricting nutrient intake can purge cells of pathogenic mtDNA.

Conclusions:

  • Metabolic interventions show promise for treating diseases caused by pathogenic mtDNA.
  • Targeting nutrient metabolism offers a new avenue for small-molecule therapies against mtDNA disorders.
  • Restricting nutrient consumption can restore mitochondrial respiration by eliminating deleterious mtDNA.
Keywords:
2-Deoxy-d-glucoseepigenetic rewiringheteroplasmymitochondrial DNAnutrient metabolismnutrient signaling

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