Mitochondrial dysfunction in autism.
BACKGROUND
Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.


OBJECTIVE
To evaluate mitochondrial defects in children with autism.


METHODS
Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.


METHODS
Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.


RESULTS
The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol × [min × mg protein](-1) vs 2.3 [95% CI, 1.7-2.9] nmol × [min × mg protein](-1), respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol × [min × mg of protein](-1) vs 0.16 [95% CI, 0.12-0.20] nmol × [min × mg protein](-1) by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 [95% CI, 217-239] vs 179 [95% CI, 165-193] in controls; P = 10(-4)). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 [95% CI, 0.68-0.92] vs 0.99 [95% CI, 0.93-1.05] for controls; P = .01).


CONCLUSIONS
In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.
University of California, School of Veterinary Medicine, Department of Molecular Biosciences, One Shields Avenue, 1120 Haring Hall, Davis, CA 95616, USA. cgiulivi@ucdavis.edu
Cecilia
C
Giulivi
Yi-Fan
YF
Zhang
Alicja
A
Omanska-Klusek
Catherine
C
Ross-Inta
Sarah
S
Wong
Irva
I
Hertz-Picciotto
Flora
F
Tassone
Isaac N
IN
Pessah
D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D016022:Case-Control Studies; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood; D008214:Lymphocytes; D008297:Male; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010766:Phosphorylation; D019289:Pyruvic Acid / Q000097:blood
D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes; D019344:Lactic Acid; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases