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Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and

Yun Soo Hong1, Stephanie L Battle1,2, Wen Shi1

  • 1McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Nature Communications
|September 30, 2023
PubMed

Insights

Mitochondrial DNA heteroplasmy is linked to a 1.5-fold higher risk of death. Specific mitochondrial variants also correlate with cancer risk and mortality, particularly leukemia.

Area of Science:

  • Genetics
  • Molecular Biology
  • Gerontology

Background:

  • Mitochondria possess their own genome (mtDNA), distinct from nuclear DNA.
  • mtDNA variants can exist as heteroplasmy, with varying proportions of variant DNA molecules.
  • Disruptions in mitochondrial DNA are implicated in aging and related diseases.

Purpose of the Study:

  • To quantify mitochondrial DNA heteroplasmy in a large cohort.
  • To investigate the association of mtDNA heteroplasmy and variants with all-cause mortality.
  • To explore the role of mtDNA variants in cancer prevalence, incidence, and mortality.

Main Methods:

  • Quantification of mtDNA heteroplasmy in 194,871 UK Biobank participants.
  • Functional characterization of mtDNA single nucleotide variants (SNVs) using the mitochondrial local constraint score sum (MSS).
  • Statistical analysis to determine associations with mortality and cancer outcomes.

Main Results:

  • mtDNA heteroplasmy was associated with a 1.5-fold increased risk of all-cause mortality.
  • The MSS score for mtDNA SNVs showed associations with all-cause mortality.
  • mtDNA variants were linked to the prevalence, incidence, and mortality of cancer, especially leukemia.

Conclusions:

  • Mitochondrial heteroplasmy is a significant risk factor for all-cause mortality.
  • mtDNA variants may play a functional role in the development of certain cancers, notably leukemia.
  • Mitochondrial heteroplasmic SNVs show potential as prognostic markers for cancer, particularly leukemia.

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