Mitochondrial Dysfunction in Autism

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Mitochondrial Dysfunction in Autism

Cecilia Giulivi, PhD; Yi-Fan Zhang, BS; Alicja Omanska-Klusek, MS;

Ross-Inta, BS; Wong, BS; Irva Hertz-Picciotto, PhD; Flora Tassone,

PhD; Isaac N. Pessah, PhD

JAMA. 2010;304(21) :2389-2396. doi:10.1001/ jama.2010. 1706

ABSTRACT

Context 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.

Design, Setting, and Patients 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.

Main Outcome Measures 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 x

[min x mg protein]-1 vs 2.3 [95% CI, 1.7-2.9] nmol x [min x 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 x [min x mg of protein]-1 vs 0.16 [95% CI, 0.12-0.20] nmol x

[min x 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).

Conclusion In this exploratory study, children with autism were more likely

to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA

deletions than typically developing children.

A link to the whole article:

<http://xa.yimg.com/kq/groups/1957724/635851927/name/Giulivi+

et+al_JAMA_2010.pdf>

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> UC study finds children with *autism* have mitochondrial

> dysfunction

> < <http://www.eurekale rt.org/pub_ releases/ 2010-11/uoc- -uds112410. php>

http://www.eurekale rt.org/pub_ releases/ 2010-11/uoc- -uds112410. php>

> EurekAlert (press release) -

> <http://www.eurekale rt.org/pub_ releases/ 2010-11/uoc- -uds112410. php>

http://www.eurekale rt.org/pub_ releases/ 2010-11/uoc- -uds112410. php

>

> Evidence of *mitochondrial dysfunction *in autism and ...

> <

<http://hstrial- astephens3. homestead. com/Evidence_ of_Mitochondrial

_Dysfuncti

on_in_Autism_ and_Implications _for_Treatment. pdf>

http://hstrial- astephens3. homestead. com/Evidence_ of_Mitochondrial

_Dysfunctio

n_in_Autism_ and_Implications _for_Treatment. pdf>

>

> Biomarker-guided interventions of clinically relevant conditions

> associated with autism spectrum disorders and attention deficit

> hyperactivity disorder. < <http://www.ncbi. nlm.nih.gov/ pubmed/20359266>

http://www.ncbi. nlm.nih.gov/ pubmed/20359266>

> Bradstreet JJ, S, Baral M, Rossignol DA.

> Altern Med Rev. 2010 Apr;15(1):15- 32. Review.