mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

EMBO Mol Med. 2018 Jun;10(6):e8262. doi: 10.15252/emmm.201708262.


Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R2 = 0.61-0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G-harbouring individuals; increasing age and heteroplasmy contribute (R2 = 0.27, P < 0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R2 = 0.40, P < 0.001), although activity level and disease severity are likely to affect copy number. Whilst our data indicate that age-corrected blood m.3243A>G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.

Keywords: MELAS; m.3243A>G; mitochondrial disease; mtDNA copy number; mtDNA heteroplasmy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • DNA, Mitochondrial / analysis*
  • DNA, Mitochondrial / blood
  • DNA, Mitochondrial / urine
  • Disease Progression
  • Female
  • Genes, Mitochondrial*
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Mitochondrial Diseases / genetics*
  • Muscle, Skeletal / metabolism
  • Mutation*
  • Regression Analysis
  • Sex Factors


  • DNA, Mitochondrial