Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

Abstract

Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

“…Indeed, knockdown of either ATM or G6PD in the context of FLT3 inhibition caused further decreases in intracellular glucose and glutamine, major sources for central carbon metabolism. It has previously been shown that a proportion of ATM is localized in the mitochondria and that ATM deficiency is associated with increased mitochondrial ROS (16)(17)(18), consistent with our data from AML cells. Together, these results suggest a model in which ATM acts as a sentinel for mitochondrial ROS, activating G6PD and the PPP when ROS levels become excessive, such as on FLT3 inhibition, to quell oxidative stress through up-regulation of glutathione metabolism and possibly other pathways.…”

725 Lymphocyte Respiration in Children with Trisomy 21

“…It is unknown if our finding of slower lymphocyte respiration in trisomy 21 children is applicable to other organs. Nevertheless, our findings are consistent with the recent reports on mitochondrial disturbances in those with trisomy 21 [19][20][21][22][23]. Decreased basal 3'-5'-cyclic adenosine monophosphate, increased reactive oxygen species and impaired NADH:ubiquinone reductase (complex I of the respiratory chain) were noted in fibroblasts from those with trisomy 21 [20].…”

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

“…We have recently demonstrated that FRAAs during gestation may play a role in thyroid abnormalities present in children with ASD [67]. Furthermore, genetic syndromes associated with ASD future science group www.futuremedicine.com such as Rett syndrome [68][69][70] and Down syndrome [71,72] demonstrate abnormalities in folate metabolism. Thus, a better understanding of how to identify and treat folate pathway abnormalities could have a significant impact in ASD and other neurodevelopmental disorders.…”