Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: An overview of Down syndrome, autism, Fragile X and Rett syndrome

Valenti, Daniela; Bari, Lidia de; Filippis, Bianca De; Henrion‐Caude, Alexandra; Vacca, Rosa Anna

doi:10.1016/j.neubiorev.2014.01.012

Cited by 160 publications

(146 citation statements)

References 255 publications

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“…The cAMP pathway has been found to play also a central role in neurodevelopmental disorders and neurodegenerative diseases such as autism, Alzheimer's, Parkinson's, Huntington's disease and Down syndrome [25,27]. Recently a disturbance of the cAMP homeostasis has been proposed also in MeCP2−/y mice [58], and moreover, it has been shown that β2-Adrenergic receptor agonist ameliorates phenotypes in a mouse model of RTT [59]. As cAMP signaling has been shown to regulate OXPHOS activity and biogenesis [28,60], we investigated cAMP-dependent mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Cervellati

Sticozzi

Romani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A strong correlation between oxidative stress (OS) and Rett syndrome (RTT), a rare neurodevelopmental disorder affecting females in the 95% of the cases, has been well documented although the source of OS and the effect of a redox imbalance in this pathology has not been yet investigated. Using freshly isolated skin fibroblasts from RTT patients and healthy subjects, we have demonstrated in RTT cells high levels of H2O2 and HNE protein adducts. These findings correlated with the constitutive activation of NADPH-oxidase (NOX) and that was prevented by a NOX inhibitor and iron chelator pre-treatment, showing its direct involvement. In parallel, we demonstrated an increase in mitochondrial oxidant production, altered mitochondrial biogenesis and impaired proteasome activity in RTT samples. Further, we found that the key cellular defensive enzymes: glutathione peroxidase, superoxide dismutase and thioredoxin reductases activities were also significantly lower in RTT. Taken all together, our findings suggest that the systemic OS levels in RTT can be a consequence of both: increased endogenous oxidants as well as altered mitochondrial biogenesis with a decreased activity of defensive enzymes that leads to posttranslational oxidant protein modification and a proteasome activity impairment.

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Section: Discussionmentioning

confidence: 99%

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Cervellati

Sticozzi

Romani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…For example, several lines of evidence suggest that individuals with DS have mitochondrial dysfunction (38, 39). Since anthracyclines can be toxic to the mitochondria, it is possible that patients with DS may be more susceptible to cardiotoxicity due to underlying mitochondrial dysfunction (40).…”

Section: Discussionmentioning

confidence: 99%

Anthracycline-Related Cardiotoxicity in Patients with Acute Myeloid Leukemia and Down Syndrome: A Literature Review

Hefti

Blanco

2015

Cardiovasc Toxicol

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Pediatric patients with Down syndrome (DS) are at an increased risk of developing certain cancers. Specifically, patients with DS have a reported 10 – 20 fold increased risk of developing acute myeloid leukemia (AML). Anthracycline-based treatment regimens achieve good results in patients with DS and AML. It has been proposed that DS status constitutes a risk factor for the cardiotoxicity associated with the use of anthracyclines in the pediatric setting. However, published evidence pointing towards an increased risk for cardiotoxicity in patients with DS is relatively scarce and conflictive. This concise review compiles literature relating to the incidence of anthracycline-related cardiotoxicity in pediatric patients with DS. In general, reports from trials using anthracyclines at the maximum recommended dose showed increases in the incidence of anthracycline-related cardiotoxicity in patients with DS in comparison to trials that used anthracyclines at reduced doses. Evidence from the literature suggests that patients with DS can achieve favorable therapeutic outcomes after receiving treatment with reduced doses of anthracyclines to minimize the potential for cardiotoxicity. Further prospective trials, along with the available evidence would assist the design of treatment protocols for patients with pediatric leukemias and DS.

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“…Mitochondrial dysfunction may contribute to the DS phenotype [16]. There is a paucity of reports on the role of specific miRNAs during the regulation of TFAM expression and mitochondrial biogenesis in the DS setting.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial dysfunction has been noted as a possible contributor to the DS phenotype [16]. For example, Coskun et al .…”

Section: Introductionmentioning

confidence: 99%

Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM)

Quiñones-Lombraña

Blanco

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The regulation of mitochondrial biogenesis is under the control of nuclear genes including the master mitochondrial transcription factor A (TFAM). Recent evidence suggests that the expression of TFAM is regulated by microRNAs (miRNAs) in various cellular contexts. Here, we show that hsa-miR-155-5p, a prominent miRNA encoded in chromosome 21, controls the expression of TFAM at the post-transcriptional level. In human fibroblasts derived from a diploid donor, downregulation of TFAM by hsa-miR-155-5p decreased mitochondrial DNA (mtDNA) content. In contrast, downregulation of TFAM by hsa-miR-155-5p did not decrease mtDNA content in fibroblasts derived from a donor with Down syndrome (DS, trisomy 21). In line, downregulation of mitochondrial TFAM levels through hsa-miR-155-5p decreased mitochondrial mass in diploid fibroblasts but not in trisomic cells. Due to the prevalence of mitochondrial dysfunction and cardiac abnormalities in subjects with DS, we examined the presence of potential associations between hsa-miR-155-5p and TFAM expression in heart samples from donors with and without DS. There were significant negative associations between hsa-miR-155-5p and TFAM expression in heart samples from donors with and without DS. These results suggest that regulation of TFAM by hsa-miR-155-5p impacts mitochondrial biogenesis in the diploid setting but not in the DS setting.

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Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: An overview of Down syndrome, autism, Fragile X and Rett syndrome

Cited by 160 publications

References 255 publications

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Anthracycline-Related Cardiotoxicity in Patients with Acute Myeloid Leukemia and Down Syndrome: A Literature Review

Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM)

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