Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Abstract

Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of $7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing $1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children' s mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.

Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome

“…A role for mitochondrial dysfunction has emerged as a common mechanism underlying many neurological disorders [8, 12, 41–43] including ASD [15, 18, 44] with specific detrimental outcomes, such as lower ATP production, increases in mitochondrial ROS, and/or metabolite-inhibition of critical steps within mitochondrial pathways [45]. In this study, we tested for bioenergetics in fibroblasts from carriers of the premutation before a significant clinical involvement was observed.…”

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…The activity of this enzyme is decreased in granulocytes and lymphocytes of autistic children contributing to a spectrum of mitochondrial malfunction in these cases [273,274].…”

Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder

“…Although ASD is traditionally described as a developmental disorder of the central nervous system, emerging evidence suggests that systemic physiological abnormalities, including dysregulated inflammation and immune system [6,7], elevated oxidative stress [8], and mitochondrial dysfunction [9–12], are present in peripheral tissues as well as in brains of autistic patients [13]. Epidemiological studies also identified a staggeringly high comorbidity between ASD and mitochondrial disorder (MD) [14].…”