Mitochondrial DNA copy number and D-loop region methylation in carriers of amyotrophic lateral sclerosis gene mutations

To investigate mitochondrial DNA (mtDNA) copy number and D-loop region methylation in carriers of SOD1, TARDBP, FUS and C9orf72 mutations.Investigations were performed in blood DNA from 114 individuals, including amyotrophic lateral sclerosis (ALS) patients, presymptomatic carriers and noncarrier family members.Increased mtDNA copy number (p = 0.0001) was observed in ALS patients, and particularly in those with SOD1 or C9orf72 mutations. SOD1 mutation carriers showed also a significant decrease in D-loop methylation levels (p = 0.003). An inverse correlation between D-loop methylation levels and the mtDNA copy number (p = 0.0005) was observed.Demethylation of the D-loop region could represent a compensatory mechanism for mtDNA upregulation in carriers of ALS-linked SOD1 mutations.