Mitochondria and Autism: Energizing the Study of Energetics (from Autism Speaks)
Mitochondria are the “powerhouses” of our cells. However, that description doesn't take into account their role in the interaction between the environment and its effects on genes through control of our metabolism. Because of the importance of this area of research, at the end of 2008 Autism Speaks' High Risk High Impact initiative invested in a ground-breaking grant on mitochondria and autism at the Universities of California at Irvine (UCI) and San Diego (UCSD). In just a year's time, this investment has borne fruit in terms of novel research directions and new investments from the federal government.
The primary investigator on the project, Doug Wallace, Ph.D., is a world-class mitochondria researcher and, some would say, an evangelist for this emerging field. Dr. Wallace will tell anyone who will listen about the many roles of mitochondria in aging, in complex diseases like diabetes, and in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Autism Speaks' support of his research has now him to move some of the considerable resources under his direction to autism. Last fall, Dr. Wallace was also appointed to Autism Speaks' Scientific Advisory Committee.
Rare gene variants—a key to a break in typical function
At UCI, the team of senior investigators, including Dr. Wallace, Jay Gargus, M.D., Ph.D., and Moyra Smith, Ph.D., has focused on genetic samples looking for rare gene variants and copy number variations (CNVs) in the DNA of people with autism, focusing on genes that may relate to mitochondrial function. The idea is that by studying rare mutations that are believed to cause autism, we will learn a great deal about the biology that underlies the disorder. Although the frequency of each of these mutations may be rare, the goal of this approach is to reveal other genetic and non-genetic ways of arriving at the same functional outcome and then to look for ways to normalize the function in this pathway as possible therapeutic approaches for autism.
Several lines of evidence suggest that a subset of autism can be considered a disorder of bioenergetics, which is the specialty of mitochondrial function. How do measured energy metabolites like the lactate/pyruvate ratio, carnitine or ammonia levels relate to the genetic variants observed in autism? To answer these questions the UCI-UCSD team had to deepen their appreciation of the metabolic phenotype of each patient. They collected blood, urine, a cheek swab, muscle biopsy samples, breath for metabolite analysis and an MRI-style imaging technique that examines metabolite levels in the brain. Importantly, since energetics is at the heart of this issue, the expired breath and the brain imaging are done both during rest and after controlled exercise.
The analysis of many of these samples is now falling in the hands of internationally recognized clinical mitochondria experts, Richard Haas, M.D., Robert Naviaux, M.D., Ph.D., and Bruce Barshop, M.D., Ph.D. at UCSD. The team at UCSD is also sequencing the full mitochondrial genome in each subject (mitochondria has a small amount of its own DNA) and examining how these genetic variants relate to the deeper phenotype data that has been collected on each patient through the larger team's experiments. Dr. Barshop is correlating the phenotypic and genotypic data with a metabolomic analysis to see if metabolite peaks observed in classic mitochondrial disease are also observed in autism. He and his team are also looking for unique patterns of metabolites in the autism population.
Minimally-invasive testing for mitochondrial dysfunction
Previous research suggests that in some populations perhaps as much as seven percent of autism may have a mitochondrial component. However, depending on how you measure “impacted” mitochondria, mitochondria that are stressed or not functioning optimally, that number could potentially be even higher. Defining the tests for establishing mitochondrial function in autism is a big part of the aim of this research. Unfortunately, the gold standard method of diagnosing mitochondrial disease is with a fresh muscle biopsy, which is usually done with a needle under light sedation. The team assembled by Autism Speaks is using the data from this study to establish new methods of testing through less invasive means. To do this, scientists in the research network are relating more classical measures, like blood and muscle biopsy, to new ways of examining metabolites. This work makes use of incredible new technologies, including micro-organic breath analysis and a laser technology to analyze mitochondria in the skin. An amazing group has been assembled to carry this out, including Nobel prize-winning atmospheric scientist F. Sherwood Rowland, Ph.D., Bruce Tromberg, Ph.D., Professor of Engineering at the Beckman Laser Institute, and Donald Blake, Ph.D., Professor of Chemistry, along with the UCI team.
A final component to the collaboration involves a magnetic resonance spectroscopy (MRS) study with Beatrice Golomb, M.D., Ph.D. of UCSD, which is allowing researchers to look at metabolism directly in the brain using methods that combine with more traditional MRI. This method has allowed Dr. Golomb and her team to relate brain structure directly to metabolic function, both at rest and after exercise designed to tax the leg muscles. The idea is that if someone has an energetics deficit, any extra demand for metabolic resources will pull them away from where they are currently being utilized, such as in the brain.
As this study nears the end of data collection, we are excited to see that some of the early results show promise in the new screening methods. Equally as important, the High Risk High Impact initiative funding of this new area was indeed just a beginning: at the end of 2009 Dr. Wallace was awarded an NIH stimulus grant to continue this work, and earlier this year Dr. Naviaux was awarded a conference grant to support a day-long “Mitochondria and Autism” symposium at the 2010 Mitochondrial Medicine meeting. Several other members of the large team of investigators have used data collected in the past year as part of the study to apply for further funding from both federal and private sources and are awaiting news.
Autism Speaks is proud to have helped kick-start this productive research endeavor and will continue to share the results as they emerge. To this end, last week at UCI, Dr. Gargus delivered an exciting public lecture to a packed room, which prominently summarized his new work and the Mitochondria and Autism Center that Autism Speaks seeded with funding. A DVD of the talk will be made available shortly.
To read a recent post on the Autism Speaks blog about mitochondria written by Dr. Naviaux, click here.
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