Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

Pecorelli, Alessandra; Ferrara, Francesca; Messano, Nicolò; Cordone, Valeria; Schiavone, Maria Lucia; Cervellati, Franco; Woodby, Brittany; Cervellati, Carlo; Hayek, Joussef; Valacchi, Giuseppe

doi:10.1096/fj.201902677r

Cited by 30 publications

(33 citation statements)

References 41 publications

(76 reference statements)

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“…STOML2 is also well-established as an anti-apoptotic gene in cancer cells, highlighting the importance of fusion to re-establish mitochondrial homeostasis and prevent mitophagy (autophagy of mitochondria) under stress. Our data is consistent with previous work showing that both fission and fusion genes are differentially expressed in ASD (20,42,43). This supports the link between ASD and mitochondrial fusion and fission which highlights the differential methylation of mitochondrial genes on an integrated pathway level.…”

Section: Discussionsupporting

confidence: 93%

“…Our data show genes that regulate mitochondrial biogenesis, fission and fusion are DM in our cohort. While we were unable to measure gene expression because of the low integrity of RNA extracted from the tissue source (buccal swabs) used in our study, previous studies have shown that differential methylation alters the expression of these genes (20,42,43,53). We investigated whether mitochondrial DNA copy number, a marker of mitochondrial function (46), was altered in our cohort.…”

Section: Discussionmentioning

confidence: 99%

“…PGC-1α is reported to play an important role in excitatory neurotransmitter signaling, neuroprotection, neuroinflammation and neurogenesis and has been implicated in bipolar disorder, Parkinson’s disease, Huntington’s disease, schizophrenia and Alzheimer’s disease (41). In addition, recent studies have implicated PGC-1α (29), fusion and fission genes (42,43) in ASD aetiology (29).…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Preprint

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BackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children.ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1α that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1α promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 × 10−6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter. There was a positive correlation between methylation at PGC-1α at CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1α at CpG#4 promoter and mtDNA copy number in controls (Spearman’s r = −0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1α methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1α at CpG#4 (Spearman’s r = −0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1α CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology.ConclusionsThese data show an association between PGC-1α promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Preprint

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“…Since mitochondrial function is very intricately linked to inflammation and oxidative stress, the changes in mitochondrial function measured may have been related to changes in oxidative stress and inflammation, as has been suggested in other studies [ 51 , 52 ]. Notably, Nrf2 expression is decreased in ASD [ 53 ] and is likely to be an important regulator of such “oxinflammation” [ 54 , 55 ], and sulforaphane is an effective inducer of Nrf2 signaling [ 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder

et al. 2021

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Background Sulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD. Methods We conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3–12 years, with ASD over 36 weeks. Twenty-eight were assigned SF and 29 received placebo (PL). Clinical effects, safety and tolerability of SF were measured as were biomarkers to elucidate mechanisms of action of SF in ASD. Results Data from 22 children taking SF and 23 on PL were analyzed. Treatment effects on the primary outcome measure, the Ohio Autism Clinical Impressions Scale (OACIS), in the general level of autism were not significant between SF and PL groups at 7 and 15 weeks. The effect sizes on the OACIS were non-statistically significant but positive, suggesting a possible trend toward greater improvement in those on treatment with SF (Cohen’s d 0.21; 95% CI − 0.46, 0.88 and 0.10; 95% CI − 0.52, 0.72, respectively). Both groups improved in all subscales when on SF during the open-label phase. Caregiver ratings on secondary outcome measures improved significantly on the Aberrant Behavior Checklist (ABC) at 15 weeks (Cohen’s d − 0.96; 95% CI − 1.73, − 0.15), but not on the Social Responsiveness Scale-2 (SRS-2). Ratings on the ABC and SRS-2 improved with a non-randomized analysis of the length of exposure to SF, compared to the pre-treatment baseline (p < 0.001). There were significant changes with SF compared to PL in biomarkers of glutathione redox status, mitochondrial respiration, inflammatory markers and heat shock proteins. Clinical laboratory studies confirmed product safety. SF was very well tolerated and side effects of treatment, none serious, included rare insomnia, irritability and intolerance of the taste and smell. Limitations The sample size was limited to 45 children with ASD and we did not impute missing data. We were unable to document significant changes in clinical assessments during clinical visits in those taking SF compared to PL. The clinical results were confounded by placebo effects during the open-label phase. Conclusions SF led to small yet non-statistically significant changes in the total and all subscale scores of the primary outcome measure, while for secondary outcome measures, caregivers’ assessments of children taking SF showed statistically significant improvements compared to those taking PL on the ABC but not the SRS-2. Clinical effects of SF were less notable in children compared to our previous trial of a SF-rich preparation in young men with ASD. Several of the effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02561481) on September 28, 2015. Funding was provided by the U.S. Department of Defense.

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“…In fact, oxidative damage is present both in the fibroblasts of ASD patients and at the peripheral and central nervous system levels. In this perspective, Pecorelli et al [ 43 ] have recently suggested the use of antioxidants and an appropriate diet as a more effective therapy for reducing the symptoms of the disease.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial Dysfunction Hypothesis in Autism Spectrum Disorders: Current Status and Future Perspectives

Citrigno

Muglia

Qualtieri

et al. 2020

IJMS

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Autism spectrum disorders (ASDs) constitute a set of heterogeneous neurodevelopmental conditions, characterized by a wide genetic variability that has led to hypothesize a polygenic origin. The metabolic profiles of patients with ASD suggest a possible implication of mitochondrial pathways. Although different physiological and biochemical studies reported deficits in mitochondrial oxidative phosphorylation in subjects with ASD, the role of mitochondrial DNA variations has remained relatively unexplored. In this review, we report and discuss very recent evidence to demonstrate the key role of mitochondrial disorders in the development of ASD.

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Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

Cited by 30 publications

References 41 publications

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder

The Mitochondrial Dysfunction Hypothesis in Autism Spectrum Disorders: Current Status and Future Perspectives

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