Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism

Molecular Autism (Impact Factor: 5.41). 01/2013; 4(1):2. DOI: 10.1186/2040-2392-4-2
Source: PubMed


The mitochondrial genome (mtDNA) is particularly susceptible to damage mediated by reactive oxygen species (ROS). Although elevated ROS production and elevated biomarkers of oxidative stress have been found in tissues from children with autism spectrum disorders, evidence for damage to mtDNA is lacking.

mtDNA deletions were evaluated in peripheral blood monocytic cells (PBMC) isolated from 2–5 year old children with full autism (AU; n = 67), and typically developing children (TD; n = 46) and their parents enrolled in the CHildhood Autism Risk from Genes and Environment study (CHARGE) at University of California Davis. Sequence variants were evaluated in mtDNA segments from AU and TD children (n = 10; each) and their mothers representing 31.2% coverage of the entire human mitochondrial genome. Increased mtDNA damage in AU children was evidenced by (i) higher frequency of mtDNA deletions (2-fold), (ii) higher number of GC→AT transitions (2.4-fold), being GC preferred sites for oxidative damage, and (iii) higher frequency of G,C,T→A transitions (1.6-fold) suggesting a higher incidence of polymerase gamma incorporating mainly A at bypassed apurinic/apyrimidinic sites, probably originated from oxidative stress. The last two outcomes were identical to their mothers suggesting the inheritance of a template consistent with increased oxidative damage, whereas the frequency of mtDNA deletions in AU children was similar to that of their fathers.

These results suggest that a combination of genetic and epigenetic factors, taking place during perinatal periods, results in a mtDNA template in children with autism similar to that expected for older individuals.

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Available from: Eleonora Napoli, Apr 28, 2014
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    • "By 4 weeks, increases in mtDNA copy number in lymphocytes and skeletal muscle [43], increased hepatic oxidative stress, lower CCO activity (by 30%) and increased mitochondrial depolarization [44] were reported. Deficiencies in perinatal folate intake have been reported in mothers of children with autism [45] in which also abnormalities in their mtDNA copy number have been observed [46]. "
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    ABSTRACT: Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency. Recently, mutations in the gene encoding for the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) have been identified as a causative gene for FGD; however, no NNT activities have been reported in FGD patients carrying NNT mutations.Methods Clinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutationResultsIn this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644 T > C; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. The NNT activities of the parents, heterozygous for the mutation, were 61% of controls.Conclusions Our results indicated that (i) mitochondrial biogenesis (citrate synthase activity) and/or mtDNA replication (mtDNA copy number) were affected at ≤ 60% NNT activity because these parameters were affected in individuals carrying either one or both mutated alleles; and (ii) other outcomes (mtDNA deletions, protein tyrosine nitration, OXPHOS capacity) were affected at ≤ 30% NNT activity as also observed in murine cerebellar mitochondria from C57BL/6 J (NNT-/-) vs. C57BL/6JN (NNT+/+) substrains.General significanceBy studying a family affected with a novel point mutation in the NNT gene, a gene-dose response was found for various mitochondrial outcomes providing for novel insights into the role of NNT in the maintenance of mtDNA integrity beyond that described for preventing oxidative stress.KeywordsFamilial glucocorticoid deficiencymitochondrial biogenesismitochondrial replicationnicotinamide nucleotide transhydrogenaseoxidative phosphorylationoxidative stress
    Biochimica et Biophysica Acta - Clinical 06/2015; 3. DOI:10.1016/j.bbacli.2014.12.003
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    • "In vivo studies in rodents have also shown that PM 2.5 activates the stress axis, involves microglial activation, and causes production of pro-inflammatory cytokines in the brain (MohanKumar et al. 2008). In one study, increased mitochondrial DNA damage, possibly caused by reactive oxygen species, was found to be more common in 67 children with ASD than in 46 typically developing children (Napoli et al. 2013). PM 2.5 may alter the development of the neonatal immune system. "
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    Environmental Health Perspectives 12/2014; 123(3). DOI:10.1289/ehp.1408133 · 7.98 Impact Factor
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    • "Otherwise the increases in mass might not be sufficient to rescue the already impaired ATP production in ASD individuals. Moreover, given the presence of mitochondrial DNA (mtDNA) deletions in PBMC from ASD (44, 68, 69), the KGD-driven mitochondrial biogenesis may result in an enrichment of defective mitochondria due to the proliferating advantage of damaged or deleted mtDNA over wild-type (70, 71). Conversely, treatment of cells containing large-scale mtDNA deletions from a patient with Kearns–Sayre syndrome with KB shifted the heteroplasmy between and within cells (72). "
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    Frontiers in Pediatrics 06/2014; 2:69. DOI:10.3389/fped.2014.00069
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