This PPT is a layman's summary of a brain tissue study by Chauhan and Chauhan that found oxidative stress and mitochiondrial dysfunction in autistic brains. This PPT has not been authorized or reviewed by Chauhan and Chauhan.

1. Potential Mechanisms Depicting The
Role Of Oxidative Stress And
Mitochondrial Dysfunction In Autism
NOTE:
This is an excerpt *adapted* a research paper by Fatemi et al -
http://www.ncbi.nlm.nih.gov/pubmed/22370873 and features a summary of the section by Chauhan &
Chauhan. Please note that this is a summary by a layman with no formal training in the subject matter and
has not been reviewed or endorsed by the original authors. Any mistakes are due to the author of this
summary healingsiggy@gmail.com , not the original authors. The highlighting in the figure – i.e. the
emphasis on certain of the boxes in red color – is also by the author of this summary, . Please send
comments and corrections to the author of the summary at the e-mail address above.

2. Note from healingsiggy@gmail.com
• As ASD parents, many of us are aware that oxidative
stress, mitochondrial dysfunction, inflammation etc. are part of the
dysfunctional processes in autism.
• However, many of these conclusions are based on studies done in the
body, rather than on the brain.
• The Chauhan and Chauhan study summarized here is remarkable in
that it presents results from studies done on post-mortem brains of
autistic individuals.

3. FIRST, LET’S LOOK AT SOME
DEFINITIONS
 Oxidative stress
 Glutathione

4. Oxidative Stress and Why it Matters
 Let’s start with defining reactive oxygen species (ROS).
 ROS are chemically reactive molecules containing oxygen which
form as a natural byproduct of the normal metabolism of oxygen.
 ROS have important roles in cell signaling and homeostasis.
 However, during times of environmental stress ROS levels can
increase dramatically and may exceed the anti-oxidant capacity of a
cell.
 Obviously, this is more likely to happen if an individual’s anti-oxidant
capacity is low to begin with.
 When the levels of reactive oxygen species (ROS) exceed the
antioxidant capacity of a cell, significant cell damage results. This is
called oxidative stress.
 Oxidative stress can lead to inflammation, damaged cell
membranes, autoimmunity, and cell death.

5. Glutathione and Why it Matters
• Glutathione (GSH) is an anti-oxidant which prevents
damage to cells caused by reactive oxygen species
(ROS) such as free radicals.
• Glutathione is the major free radical scavenger in the
brain.
• Diminished GSH levels elevate cellular vulnerability
towards oxidative stress

6. SUMMARY OF FINDINGS

7. Summary of Findings
 There is elevated oxidative stress in the cerebellum and frontal and
temporal lobes of individuals with autism.
 There is reduced glutathione in brains of individuals with autism.
 There is mitochondrial dysfunction in brains of individuals with autism.
What the Study Proposes
 The oxidative stress can be induced or triggered in autism by exposure to
certain environmental factors, which include toxins, maternal drugs, viral
and bacterial infections.
 The timing of this exposure to environmental factors may be pre-natal, per-
natal or post-natal.
 Genetic factors can also influence vulnerability to oxidative stress in autism.
 Therefore, autism may result from genetic, environmental and immune
factors, with oxidative stress as the mechanism linking these factors.
 See the next slide for the potential mechanisms of the role of oxidative
stress and mitochondrial dysfunction in the development of autism.

8. Autism may result from genetic, environmental and immune factors, with
oxidative stress as the mechanism linking these factors.
Defect in mitochondrial Environmental risk factors – Genetic
electron transport chain pre-natal, peri-natal, post-natal susceptibility factors
complexes
Impaired oxidative Reduced anti-oxidant defense
phosphorylation, impaired Increased generation of free  Glutathione redox imbalance
energy (ATP) production radicals  Anti-oxidant enzymes
 Iron/copper transport proteins
Mitochondrial
Dysfunction
OXIDATIVE STRESS DNA methylation
Lipid peroxidation, protein Epigenetic
Inflammation Altered immune
oxidation, DNA oxidation dysregulation
response
Pathogenesis and clinical development of autism

9. MORE DETAILS ON FINDINGS

10. Evidence of oxidative stress has been
found in ASD brain tissues
 Several studies have suggested immunological abnormalities and
inflammation in autism.
 There is also ample evidence of the presence of oxidative stress in
the bodies of children with autism.
 We now know from studies of postmortem brain tissues that
compared to age-matched control subjects, ASD individuals have
elevated levels of markers of oxidative damage in the brain.

11. Glutathione - the body’s own powerful
anti-oxidant – is reduced in autistic brains
 The brain is highly vulnerable to oxidative stress because of its
limited antioxidant capacity, higher energy requirement, high
amounts of unsaturated lipids and iron.
 ASD individuals have reduced antioxidant status in brain tissues
compared to age-matched controls.
 Glutathione (GSH) is the major endogenous antioxidant produced
by cells, which neutralizes ROS, and participates in detoxification
and elimination of environmental toxins.
 A decrease in GSH, an increase in its oxidized disulfide form
(GSSG), and a decrease in the redox ratio of GSH/GSSG were
observed in the cerebellum and temporal cortex of individuals with
autism, suggesting a glutathione redox imbalance in autism.

12. Evidence of mitochondrial dysfunction
has been found in autistic brains
 Mitochondria produce ATP (energy) with the help of five electron
transport chain (ETC) complexes.
 Emerging evidence suggests increased prevalence of mitochondrial
dysfunction in autism.
 Chauhan and Chauhan report a deficit specific to brain regions in the
levels of ETC complexes in children with autism.
Healingsiggy’s note:
Note that the mitochondrial dysfunction mentioned by the authors is specific to
certain brain regions. Would these individuals have shown generalized
mitochondrial dysfunction on biochemistry screens? Per clinical criteria? We do
not know whether they did or not – but to my mind, this speaks to the fact that we
may not be able to easily rule out mitochondrial dysfunction in autism just though
biochemistry screens.

13. The level of mitochondrial dysfunction
varies even within brain regions!
 Reduced levels of complexes III and V in the cerebellum, of
complex I in the frontal cortex, and of complexes II, III, and V in the
temporal cortex were observed in children with autism as compared
to age-matched control subjects.
 Chauhan and Chauhan’s studies of different brain regions showed
that oxidative stress differentially affects selective brain
regions, such as cerebellum, temporal, and frontal cortices, in
autism.
 Increased oxidative stress and mitochondrial abnormalities were
not observed in the parietal and occipital cortices in autism.
 In other words, the level of oxidative stress and mitochondrial
abnormalities varies even within brain regions.

14. Conclusion – there is elevated
oxidative stress in autistic brains
 In conclusion, there is elevated oxidative stress in the cerebellum and
frontal and temporal lobes of individuals with autism
 The oxidative stress can be induced or triggered in autism by exposure to
certain environmental factors, which include toxins and toxicants, maternal
drugs, viral and bacterial infections.
 The timing of this exposure to environmental factors may be pre-natal, per-
natal or post-natal.
 Genetic factors can also influence vulnerability to oxidative stress in autism.
 Therefore, autism may result from genetic, environmental and immune
factors, with oxidative stress as the mechanism linking these factors.
 See the next slide for the potential mechanisms of the role of oxidative
stress and mitochondrial dysfunction in the development of autism.