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Children with Autism have Mitochondrial Dysfunction

December 3, 2010

(Ivanhoe Newswire) ““ Children with autism are much more likely to have deficits in their ability to produce cellular energy than typically developing children.

The researchers found that cumulative damage and oxidative stress in mitochondria, the energy producer of the cell, could influence the onset and severity of autism, suggesting a strong link between autism and mitochondrial defects.

The authors believe that lack of ability to fuel the brain neurons might lead to some of the cognitive deficits associated with autism, since the brain consumes the second most energy in the body. Mitochondria are the primary source of energy production in the cells. They carry their own set of genetic instructions, mtDNA, that carry out aerobic respiration.

Dysfunction in mitochondria already is associated with a number of other neurological conditions, including Parkinson’s disease, Alzheimer’s disease, schizophrenia and bipolar disorder.

“Children with mitochondrial diseases may present exercise intolerance, seizures and cognitive decline, among other conditions. Some will manifest disease symptoms and some will appear as sporadic cases,” Cecilia Giulivi, the study’s lead author and professor in the Department of Molecular Biosciences in the School of Veterinary Medicine at UC Davis, was quoted as saying. “Many of these characteristics are shared by children with autism.”

The researchers stress that these new findings, which may help physicians provide early diagnoses, do not identify the cause or the effects of autism, which affects as many as 1 in every 110 children in the United States, according to the U.S. Centers for Disease Control and Prevention.

“It is remarkable that evidence of mitochondrial dysfunction and changes in mitochondrial DNA were detected in the blood of these young children with autism,” Geraldine Dawson, chief science officer of Autism Speaks, which provided funding for the study was quoted as saying. “One of the challenges has been that it has been difficult to diagnose mitochondrial dysfunction because it usually requires a muscle biopsy. If we could screen for these metabolic problems with a blood test, it would be a big step forward.”

For the study, Giulivi and her colleagues recruited 10 autistic children aged 2 to 5, and 10 typically developing children of the same ages and backgrounds. The children were randomly selected from Northern California subjects who previously had participated in the 1,600-participant Childhood Autism Risk from Genetics and the Environment (CHARGE) Study and who also consented to return for a subsequent study known as CHARGE-BACK, conducted by the UC Davis Center for Children’s Environmental Health and Disease Prevention.

The researchers got blood samples from each child and analyzed the metabolic pathways of mitochondria in immune cells called lymphocytes, which use aerobic respiration via mitochondria.

The researchers found that mitochondria from children with autism consumed far less oxygen than mitochondria from the group of control children, a sign of lowered mitochondrial activity.
 
“A 66 percent decrease is significant,” Giulivi said. “When these levels are lower, you have less capability to produce ATP (adenosine triphosphate) to pay for cellular work. Even if this decrease is considered moderate, deficits in mitochondrial energy output do not have to be dismissed, for they could be exacerbated or evidenced during the prenatal period but appear subclinical in the adult years.”

Reduced mitochondrial enzyme function proved widespread among the autistic children. Eighty percent had lowered activity in NADH oxidase than did controls, while 60 percent, 40 percent and 30 percent had low activity in succinate oxidase, ATPase and cytochrome c oxidase, respectively. The researchers went on to isolate the origins of these defects by assessing the activity of each of the five enzyme complexes involved in mitochondrial respiration. Complex I was the site of the most common deficiency, found in 60 percent of autistic subjects, and occurred five out of six times in combination with Complex V. Other children had problems in Complexes III and IV.

Levels of pyruvate, the raw material mitochondria transform into cellular energy, were also elevated in the blood plasma of autistic children. This suggests the mitochondria of children with autism are unable to process pyruvate fast enough to keep up with the demand for energy, pointing to a novel deficiency at the level of an enzyme named pyruvate dehydrogenase.

Mitochondria also are the main intracellular source of oxygen free radicals. Free radicals are very reactive and can harm cellular structures, including DNA. Cells are able to repair typical levels of such oxidative damage. Giulivi and her colleagues found that hydrogen peroxide levels in autistic children were twice as high as in normal children. As a result, the cells of children with autism were exposed to higher oxidative stress.

“The various dysfunctions we measured are probably even more extreme in brain cells, which rely exclusively on mitochondria for energy,” Isaac Pessah, director of the Center for Children’s Environmental Health and Disease Prevention, a UC Davis MIND Institute researcher and professor of molecular biosciences at the UC Davis School of Veterinary Medicine was quoted as saying.

Giulivi cautions that these findings do not amount to establishing a cause for autism.

“This important exploratory research addresses in a rigorous way an emerging hypothesis about potential mitochondrial dysfunction and autism,” Cindy Lawler, program director at the National Institute of Environmental Health Sciences (NIEHS), which provided funding for the study was quoted as saying. “Additional research in this area could ultimately lead to prevention or intervention efforts for this serious developmental disorder.”

SOURCE: JAMA, published online December 2, 2010




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