Mechanisms of Mitochondrial Dysfunction in Autism
Posted March 31, 2011
John Shoffner, M.D., Georgia State University, Atlanta, Georgia, and Medical Neurogenetics, LLC, Atlanta, Georgia

Image from Dr. John Shoffner

In order to detect adenosine triphosphate (ATP) production within cells,
HEK293 cells were transfected with luciferase that is targeted to the cytoplasm
(pCyto-Luc) or is targeted to the mitochondria (pMito-Luc). Luciferase
targeted to these locations within the cells allows quantitation of ATP production with
the cytoplasm or the mitochondria. This technique is being used to quantitate
ATP production within the cytoplasm and within the mitochondia of cells from
patients with autistic spectrum disorders. These cells can be used to understand
cellular energetics defects in patients with ASD as well as to screen new drugs for their
ability to increase mitochondrial ATP production.
Localization of luciferase was detected using anti-luciferase antibody. Immunofluorescence
detection used confocal microscopy (63x magnification).

Although all individuals with autism spectrum disorders (ASD) share difficulties in social interaction, communication, and behavior, the complex genetic and phenotypic variability that is observed may indicate the existence of multiple subgroups. Defining these subgroups is the first step to understanding the causes of ASD, developing effective treatments, and eventually finding a cure. One subset of individuals with ASD has defects in oxidative phosphorylation genes, resulting in mitochondrial disease. Oxidative phosphorylation is the process that produces energy for cellular function. Mitochondrial disease, which can affect all systems in the body, presents very differently from individual to individual. Organs that have high energy requirements and low energy reserves, such as the brain, are particularly susceptible to oxidative phosphorylation defects.

Although the cause is unknown, neurologic regression occurs in approximately 25% of children with ASD. Patients with mitochondrial disease are at increased risk for neurologic regression during periods of fever. As a recipient of a Fiscal Year 2008 (FY08) Autism Research Program (ARP) Concept Award, Dr. John Shoffner has used this funding to evaluate links to mitochondrial dysfunction and ASD regression. Performing a retrospective chart review of 28 patients who met the diagnostic criteria for both ASD and mitochondrial disease, Dr. Shoffner found that autistic regression occurred in 17 out of 28 patients (60.7%). Of those with autistic regression, 12 out of 17 patients had regressed with fever (70.6%), while 5 out of 17 patients with autistic regression could not be linked to a febrile event (29.4%). While the study was small and could not account for factors such as dehydration and other metabolic effects of fever, Dr. Shoffner demonstrated that a subgroup of individuals with mitochondrial defects may be at increased risk of autistic regression. Screening for oxidative phosphorylation defects in individuals with ASD may be necessary to further characterize this subset of the ASD population and to develop treatments for the dysfunction. Dr. Shoffner is currently working to develop a minimally invasive screening test to identify key indicators of oxidative phosphorylation defects in children with ASD. The test uses luciferase, an oxidative enzyme that converts ATP into light, targeted to the cytoplasm and mitochondria, to detect ATP production within the cells of patients with autism spectrum disorders caused by mitochondrial defects. This personalized medicine approach to ASD could allow rapid discovery of novel treatments for these children. Dr. Shoffner has received an FY09 ARP Idea Award to continue his research into the relationship between oxidative phosphorylation defects and ASD.

Autism Speaks voted Dr. Shoffner's research, published in the Journal of Child Neurology, as one of the top ten accomplishments in autism research for 2009.


Shoffner J, Hyams L, Niedziela-Langley G, Cossette S, Mylacraine L, Dale J, Ollis L, Kuoch S, Bennett K, Aliberti A, and Hyland K. 2010. Fever plus mitochondrial disease could be risk factors for autistic regression. Journal of Child Neurology 25: 429-34.


Public and Technical Abstracts: Mitochondrial Defects in Autism
Public and Technical Abstracts: Mechanisms of Mitochondrial Dysfunction in Autism

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