Mitochondrial Fatty Acid β-Oxidation and Resveratrol Effect in Fibroblasts from Patients with Autism Spectrum Disorder

Abstract

Patients with autism spectrum disorder (ASD) may have an increase in blood acyl-carnitine (AC) concentrations indicating a mitochondrial fatty acid β-oxidation (mtFAO) impairment. However, there are no data on systematic mtFAO analyses in ASD. We analyzed tritiated palmitate oxidation rates in fibroblasts from patients with ASD before and after resveratrol (RSV) treatment, according to methods used for the diagnosis of congenital defects in mtFAO. ASD participants (N = 10, 60%; male; mean age (SD) 7.4 (3.2) years) were divided in two age-equivalent groups based on the presence (N = 5) or absence (N = 5) of elevated blood AC levels. In addition, electron transport chain (ETC) activity in fibroblasts and muscle biopsies and clinical characteristics were compared between the ASD groups. Baseline fibroblast mtFAO was not significantly different in patients in comparison with control values. However, ASD patients with elevated AC exhibited significantly decreased mtFAO rates, muscle ETC complex II activity, and fibroblast ETC Complex II/III activity (p < 0.05), compared with patients without an AC signature. RSV significantly increased the mtFAO activity in all study groups (p = 0.001). The highest mtFAO changes in response to RSV were observed in fibroblasts from patients with more severe symptoms on the Social Responsiveness Scale total (p = 0.001) and Awareness, Cognition, Communication and Motivation subscales (all p < 0.01). These findings suggested recognition of an ASD patient subset characterized by an impaired mtFAO flux associated with abnormal blood AC. The study elucidated that RSV significantly increased fibroblast mtFAO irrespective of plasma AC status, and the highest changes to RSV effects on mtFAO were observed in the more severely affected patients.

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 Personalized Approach to Evaluating and Treating Autism Spectrum Disorder

“…One article describes a potential important subtype of ASD with a unique type of mitochondrial dysfunction, which may be related to environmental exposures [3]. In another article, researchers from Italy and France demonstrate that children with ASD who had elevations in acyl-carnitines in their blood exhibit changes in fatty-acid oxidation and electron transport chain complex activity in their fibroblasts [12]. Another article describes neurotransmitter dysregulation associated with mitochondrial disease in a unique patient [13].…”

“…In another systematic review and meta-analysis, the effectiveness of cobalamin, a treatment that targets dysfunctional methylation and redox pathways, is analyzed, along with an examination of its metabolic effects [18]. Researchers from Italy and France demonstrate that resveratrol may be effective in correcting metabolic defects in fibroblasts from children with ASD and fatty-acid oxidation defects [12]. Lastly, researchers from Arizona State University demonstrate that Microbiota Transfer Therapy appear to normalize abnormal fecal metabolites in a group of people with ASD [14].…”

“…Perhaps most apparent, these articles underline the primacy of mitochondria in ASD, including oxidative stress and redox regulation, which are themselves major functions of mitochondria. Although the connection between ASD and this important cellular organelle is hardly new, this collection of papers serves to demonstrate the ubiquitous nature of the connection, which ranges from mitochondrial aspects in the prenatal and environmental risk factors/exposures [2,3,8] to biomarkers/metabolites [5,8,[12][13][14][15][16], enzymology [12], and the positive response to therapy, at least in part targeting the mitochondria [8,11,12,15,16,18,19].…”