Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.

The Ketogenic Diet Metabolite β-Hydroxybutyrate Promotes Mitochondrial Elongation via Deacetylation and Improves Autism-like Behavior in Zebrafish

“…There is growing evidence that mitochondrial dysfunction, which often correlates with mitochondrial fragmentation, is likely to contribute to ASD (Citrigno et al, 2020; Pecorelli et al, 2020; Rossignol & Frye, 2012; Singh et al, 2020; Thorsen, 2020; Weissman et al, 2008). For example, ASD patient cells (Barone et al, 2021; Frye et al, 2021; Gevezova et al, 2021) and brain organoids (Ilieva et al, 2022) exhibit impaired mitochondrial bioenergetics, while postmortem brains of control and ASD patients have increased expression of mitochondrial fission proteins and decreased expression of mitochondrial fusion proteins (Tang et al, 2013). This correlation is also present in animal models of ASD, as neuronal mitochondria in the BTBR mouse model of ASD have reduced mitochondrial function and are more fragmented (Ahn et al, 2020).…”

A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder

“…A wide variety of mitochondrial metabolism biomarkers have been described with many being associated with core and associated ASD symptoms [ 71 ]. For example, alternations in electron transport chain complex activity derived from buccal tissue [ 72 ] and fatty acid oxidation been linked to ASD-specific symptoms on the SRS [ 73 ] and variations in mitochondrial morphology have been linked to both ASD-specific symptoms on the SRS and core ASD symptoms on the ABC [ 74 ]. Abnormalities in transmethylation and transsulfuration spanning the methylation and redox pathways may be diagnostic for ASD [ 70 ] and have been shown to be related to neurodevelopment as indexed by the VABS in several studies [ 75 , 76 ].…”

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

“…Noteworthy, clinical studies have reported altered mtDNA copy numbers and deletions (130,(134)(135)(136)(137), mtDNA mutations (138,139), mitochondrial ETC deficits (134,136,140) and altered plasma levels of lactate, pyruvate, alanine, creatine kinase, glutathione-S-transferase and caspase 7 (138,141). Recent studies in ASC-derived lymphoblastoid cell lines (LCLs) showed significantly increased mitochondrial respiration and mitochondrial membrane potential as well as elevated activities of ETC complexes (142), while disruptions to mitochondrial bioenergetics, dynamics and morphology were observed in ASC-derived fibroblasts (143,144). This is supported by independent transcriptomic studies that have reported reduced expression of mitochondrial respiration genes in ASC brain tissue (145)(146)(147)(148).…”