Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis

Frye, Richard E.; Rincon, Nicole; McCarty, Patrick J.; Brister, Danielle; Scheck, Adrienne C.; Rossignol, Daniel A.

doi:10.1016/j.nbd.2024.106520

Neurobiology of Disease

2024

DOI: 10.1016/j.nbd.2024.106520

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Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis

Richard E. Frye,

Nicole Rincon,

Patrick J. McCarty

et al.

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2024

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Cited by 3 publications

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Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders

Bonzano,

Dallorto,

Bovetti

et al. 2024

Neurobiology of Disease

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Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders

Bonzano,

Dallorto,

Bovetti

et al. 2024

Neurobiology of Disease

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1H-NMR-based metabolomics reveals metabolic alterations in early development of a mouse model of Angelman syndrome

Gupta,

Barak,

Feuermann

et al. 2024

Molecular Autism

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Background Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development. Methods We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis. Results Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways. Limitations Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain. Conclusions Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development.

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Delving into the Complexity of Valproate-Induced Autism Spectrum Disorder: The Use of Zebrafish Models

Camussi,

Naef,

Brogi

et al. 2024

Cells

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Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose–response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.

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Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis

Cited by 3 publications

References 353 publications

Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders

Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders

1H-NMR-based metabolomics reveals metabolic alterations in early development of a mouse model of Angelman syndrome

Delving into the Complexity of Valproate-Induced Autism Spectrum Disorder: The Use of Zebrafish Models

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