What is Autism to a Mitochondrion?
This is a guest blog by Jane Pickett, Ph.D. Dr. Pickett has been a pinnacle and founding member of the Autism Tissue Program (ATP), with an unparalleled experience in the field of autism tissue research and brain banking. Among her duties, Jane stewards the ATP’s vast tissue resources and accumulated data through the ATP Portal, manages the ATP’s large tissue grant portfolio, oversees the TAB and is the direct contact for our supported scientists. Jane has over 10 years experience serving as coordinator of the Developmental Disability services in Oregon where she participated on the Early Intervention Team, developed and monitored state funded programs for all age groups, provided crisis management for families and facilitated parent support groups. Her research background includes published studies in molecular and behavioral genetics, neuropeptide biosynthesis, cellular and developmental processes and the role of stress, gender and hormones at Princeton University. Jane also holds a staff position at the Harvard Brain and Tissue Research Center (HBTRC).
Biologists often try to understand a particular disorder from the perspective of a particular cell, or cell structure. This was an idea behind a recent public talk, “The Autism Spectrum: Recent Scientific Advances”, by UC Irvine (UCI) medical geneticist Dr. John Jay Gargus. The link between autism and mitochondria is also the subject of a number of research projects supported by post-mortem brain tissue donated by families to the Autism Tissue Program (ATP).
A mitochondrion is an energy-producing organelle found in cells in the body. Cells that require a lot of energy (like brain, muscle and liver) have 1000s of mitochondria and others with low energy demand have just a few. Mitochondria float in the cytoplasm of the cell, outside of the nucleus where the cell’s chromosomes reside. Each mitochondrion has its own set of 37 genes in a small circular ring of DNA that encode proteins integral for mitochondrial function. However, the mitochondria cannot act entirely alone, depending in part on the production of proteins from some of the genes in the nucleus for full functionality.
Mitochondria combine the fats and sugars we eat with the oxygen we breathe to produce energy for almost all of our cellular needs. If mitochondria are not functioning properly, cells are affected too. Consider brain cells, highly specialized cells with high energy requirements during their development, migration, maturation and function. Brain cells called neurons develop processes in order to deliver chemical messages over long distances; sometimes these processes, called axons, are several inches long for a neuron in one side (hemisphere) of the brain to communicate with cells on the other side of the brain. Mitochondria must provide the energy to ‘build’ these processes, be transported along the axons and once at the junction with other cells (synapses) their functions are necessary to keep up with the demands of brain circuits performing such roles as sensory processing, attention, learning and memory.
The donor, age 25, had autism and a chromosome duplication called IDIC15q. The pathology observed may be linked to a problem with the system of electron carriers that are needed to make energy rich molecules from metabolism in the mitochonrida. A partial block in the electron-transport chain (respiratory chain) was observed in living persons with autism and IDIC15q by a team working with Dr. Jay Gargus and reported in the journal Mitochrondrion (2).
Muscle hypotonia is common in autism and IDIC15q patients. The energy made by mitochondria provides the main source of power for muscle cell contraction and nerve cell firing so that muscle cells and nerve cells are especially sensitive to mitochondrial defects. The combined effects of energy deprivation contributes to the main symptoms of mitochondrial myopathies and encephalopathies (muscle and brain disorders). The link between autism and mitochondrial disease is the focus of rigorous study and the subject of one of the top ten research achievements in 2009 (3).
Other mitochondrial abnormalities have been described in brain tissue of individuals with autism. A molecular survey of the tissues of the cortex and cerebellum of brains of individuals with autism showed a change in the function of a gene, SLC25A12, a key element in mitochondrial energy production and cell metabolism (4). This gene is important in neurodevelopment and ‘turns on’ early in fetal brain tissue giving rise to a select region associated with early exaggerated postnatal brain growth in children with autism. A second report on brain genetics from the same French-US group explored another susceptibility locus for autism, a gene called MARK1 (5). The MARK1 gene product is an enzyme that regulates mitochondrial trafficking along microtubules in neurons: a process which serves as a sort of “highway” within a cell. Without the right amount of MARK1 produced, mitochondria are likely to be stuck in a “traffic jam” and impair cellular function. In both studies, the authors discovered an over expression of the two genes in the prefrontal cortex but not in the cerebellum.
So, what is autism to a mitochondrion? The significance of these findings is that cellular and molecular changes found in the brains of persons with autism are linked to mitochondrial function and are thought to compromise a host of physical and cognitive problems seen in the disorder. Continued research on the state of mitochondria in autism increases the potential for new diagnostics and therapies. Brain tissue is important to be able to visualize structural changes as well as to document molecular changes within the cell.
Acknowledgement: We wish to gratefully recognize the gifts of hope by the families of brain donors. Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. Anyone can register to be a future brain tissue donor. Information can be found at www.autismtissueprogram.org or call toll-free 877-333-0999 for a packet of information, with questions or to initiate a brain donation. Without this partnership between families and scientists, our progress in understanding the underlying biology of autism so effective treatments can be discovered would be much slower.
1. ATP Informatics Portal, ATP Documents, www.atpportal.org
2. Filipek, Pauline A. et al. (2008) Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication. Mitochondrion 8: 136–145.
3. Shoffner J, et al. (2009) Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression J Child Neurol. Sep 22. [Epub ahead of print]
4. Lepagnol-Bestel AM, et al. (2008) SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal
cortex of autistic subjects. Molecular Psychiatry. 13(4):385-97.
5. Maussion G, et al. (2008) Convergent evidence identifying MAP/microtubule affinity regulating kinase 1 (MARK1) as a susceptibility gene for autism. Human Molecular Genetics 17:1-11