Is Mitochondrial Dysfunction the Root Cause of
Autism Spectrum Disorder?
UCLA HEALTH
UCLA BrainSPORT Podcast clip featuring Harvard Psychiatrist and
best-selling author, Dr. Chris Palmer. The pair discuss whether mitochondrial dysfunction is the cause of
Autism Spectrum Disorder.
The gut
microbiome of Autistic Children is controlled by
Mitochondria
Research suggests a
strong link where the gut microbiome in autistic
children produces metabolites, like short-chain fatty acids
(SCFAs) such as butyrate and propionic
acid, that can
directly impact mitochondrial function, causing
dysfunction or alteration,
and this disruption in energy production
(mitochondria) is central to many gastrointestinal
issues and core ASD symptoms, forming a critical
part of the microbiota-gut-brain axis.
This interplay means gut bacteria influence
mitochondria, and mitochondrial issues can worsen GI
problems, creating a cycle seen in many with ASD.
.
How the Connection Works
Microbial Metabolites as Messengers: Bacteria in the
gut produce substances (metabolites) as they break
down food.
Impact on Mitochondria: Specific metabolites,
especially SCFAs like propionic acid (PPA) and
butyrate, can enter cells and directly affect
mitochondrial processes, influencing energy
production (ATP), calcium balance, and oxidative
stress.
Mitochondrial Dysfunction in ASD: Many children with
autism have underlying mitochondrial issues,
impacting high-energy organs like the brain and gut.
The Vicious Cycle: In ASD, certain bacteria
overproduce these metabolites, which can then
overstimulate or disrupt mitochondria, leading
to:
A Mitochondrial
Supplement Improves Function and
Mitochondrial Activity in Autism: A
Double-Blind Placebo-Controlled Cross-Over
Trial
March 2025
Abstract
Autism spectrum disorder
(ASD) is associated with mitochondrial
dysfunction, but studies demonstrating the
efficacy of treatments are scarce. We sought
to determine whether a
mitochondrial-targeted dietary supplement
designed for children with ASD improved
mitochondrial function and ASD
symptomatology using a double-blind
placebo-controlled cross-over design.
Sixteen children
[mean age 9 years 4 months; 88% male] with
non-syndromic ASD and mitochondrial enzyme
abnormalities, as measured by MitoSwab
(Religen, Plymouth Meeting, PA, USA),
received weight-adjusted SpectrumNeeds®
(NeuroNeeds, Old Lyme, CT, USA) and QNeeds®
(NeuroNeeds, Old Lyme, CT, USA) and placebos
matched on taste, texture and appearance
during two separate 12-week blocks. Which
product was received first was randomized.
The treatment
significantly normalized citrate synthase
and complex IV activity as measured by the
MitoSwab. Mitochondrial respiration of
peripheral blood mononuclear cell
respiration, as measured by the Seahorse
XFe96 (Agilent, Santa Clara, CA, USA) with
the mitochondrial oxidative stress test,
became more resilient to oxidative stress
after the treatment, particularly in
children with poor neurodevelopment.
The
mitochondrial supplement demonstrated
significant improvement in standardized
parent-rated scales in neurodevelopment,
social withdrawal, and hyperactivity with
large effect sizes (Cohen's d' = 0.77-1.25),
while changes measured by the clinical and
psychometric instruments were not
significantly different. Adverse effects
were minimal.
This small study
on children with ASD and mitochondrial
abnormalities demonstrates that a simple,
well-tolerated mitochondrial-targeted
dietary supplement can improve mitochondrial
physiology and ASD symptoms. Further larger
controlled studies need to verify and extend
these findings. These findings are
significant as children with ASD have few
other effective treatments.
Biomarkers of mitochondrial dysfunction in
autism spectrum disorder: A systematic review
and meta-analysis
July 2024
Abstract
Autism spectrum disorder
(ASD) is a neurodevelopmental disorder
affecting 1 in 36 children and is associated
with physiological abnormalities, most
notably mitochondrial dysfunction, at
least in a subset of
individuals. This systematic review and
meta-analysis discovered 204 relevant
articles which evaluated biomarkers
of mitochondrial dysfunction in ASD
individuals. Significant elevations (all p <
0.01) in the prevalence of lactate (17%),
pyruvate (41%), alanine (15%) and creatine
kinase (9%) were found in ASD. Individuals
with ASD had significant differences (all p
< 0.01) with moderate to large effect sizes
(Cohen's d' ≥ 0.6) compared to controls in
mean pyruvate, lactate-to-pyruvate ratio,
ATP, and creatine kinase. Some studies found
abnormal TCA cycle metabolites associated
with ASD.
Thirteen controlled
studies reported mitochondrial DNA (mtDNA)
deletions or variations in the ASD group in
blood, peripheral blood mononuclear cells,
lymphocytes, leucocytes, granulocytes, and
brain. Meta-analyses discovered significant
differences (p < 0.01) in copy number of
mtDNA overall and in ND1, ND4 and CytB
genes.... Variability was found across
biomarker studies primarily due to
differences in collection and processing
techniques as well as the intrinsic
heterogeneity of the ASD population. Several
studies reported alterations in
mitochondrial metabolism in mothers of
children with ASD and in neonates who
develop ASD.
Treatments targeting
mitochondria, particularly carnitine and
ubiquinol, appear beneficial in ASD. The
link between mitochondrial dysfunction in
ASD and common physiological abnormalities
in individuals with ASD including
gastrointestinal disorders, oxidative
stress, and immune dysfunction is outlined.
Several subtypes of mitochondrial
dysfunction in ASD are discussed, including
one related to neurodevelopmental
regression, another related to alterations
in microbiome metabolites, and another
related to elevations in acyl-carnitines.
Mechanisms linking abnormal mitochondrial
function with alterations in prenatal brain
development and postnatal brain function are
outlined.
Given the
multisystem complexity of some individuals
with ASD, this review presents evidence for
the mitochondria being central to ASD by
contributing to abnormalities in brain
development, cognition, and comorbidities
such as immune and gastrointestinal
dysfunction as well as neurodevelopmental
regression. A diagnostic approach to
identify mitochondrial dysfunction in ASD is
outlined.
From this
evidence, it is clear that many individuals
with ASD have alterations in mitochondrial
function which may need to be addressed in
order to achieve optimal clinical outcomes.
Mitochondrial
Dysfunction in Autism Spectrum Disorder
October 2018
Abstract
Autism spectrum disorder
(ASD) affects ~ 2% of children in the United
States. The etiology of ASD likely involves
environmental factors triggering
physiological abnormalities in genetically
sensitive individuals. One of these major
physiological abnormalities is mitochondrial
dysfunction, which may affect a significant
subset of children with ASD. Here we
systematically review the literature on
human studies of mitochondrial dysfunction
related to ASD.
Clinical aspects of
mitochondrial dysfunction in ASD include
unusual neurodevelopmental regression,
especially if triggered by an inflammatory
event, gastrointestinal symptoms, seizures,
motor delays, fatigue and lethargy.
Traditional biomarkers of mitochondrial
disease are widely reported to be abnormal
in ASD, but appear non-specific. Newer
biomarkers include buccal cell enzymology,
biomarkers of fatty acid metabolism,
non-mitochondrial enzyme function, apoptosis
markers and mitochondrial antibodies. Many
genetic abnormalities are associated with
mitochondrial dysfunction in ASD, including
chromosomal abnormalities, mitochondrial DNA
mutations and large-scale deletions, and
mutations in both mitochondrial and
non-mitochondrial nuclear genes.
Mitochondrial
dysfunction has been described in immune and
buccal cells, fibroblasts, muscle and
gastrointestinal tissue and the brains of
individuals with ASD. Several environmental
factors, including toxicants, microbiome
metabolites and an oxidized microenvironment
are shown to modulate mitochondrial function
in ASD tissues.
Investigations of
treatments for mitochondrial dysfunction in
ASD are promising but preliminary. The
etiology of mitochondrial dysfunction and
how to define it in ASD is currently
unclear. However, preliminary evidence
suggests that the mitochondria may be a
fruitful target for treatment and prevention
of ASD. Further research is needed to better
understand the role of mitochondrial
dysfunction in the pathophysiology of ASD.
Evidence of
Mitochondrial Dysfunction in Autism: Biochemical
Links,
Genetic-Based
Associations, and Non-Energy-Related Mechanisms
May 2017
Abstract
Autism spectrum disorder
(ASD), the fastest growing developmental
disability in the United States, represents
a group of neurodevelopmental disorders
characterized by impaired social interaction
and communication as well as restricted and
repetitive behavior. The underlying cause of
autism is unknown and therapy is currently
limited to targeting behavioral
abnormalities. Emerging studies
suggest a link between mitochondrial
dysfunction and ASD.
Here, we review the
evidence demonstrating this potential
connection. We focus specifically on
biochemical links, genetic-based
associations, non-energy related mechanisms,
and novel
therapeutic strategies.
Mitochondrial abnormalities in
temporal lobe of autistic brain
Abstract
Autism spectrum disorder (ASD) consists of a group of
complex developmental disabilities characterized by impaired
social interactions, deficits in communication and
repetitive behavior. Multiple lines of evidence
implicate mitochondrial dysfunction in ASD. In
postmortem BA21 temporal cortex, a region that exhibits
synaptic pathology in ASD, we found that compared to
controls, ASD patients exhibited altered protein
levels of mitochondria respiratory chain protein complexes,
decreased Complex I and IV activities, decreased
mitochondrial antioxidant enzyme SOD2, and greater oxidative
DNA damage.
Mitochondrial membrane mass was higher in ASD brain, as
indicated by higher protein levels of mitochondrial membrane
proteins Tom20, Tim23 and porin. No differences were
observed in either mitochondrial DNA or levels of the
mitochondrial gene transcription factor TFAM or cofactor
PGC1α, indicating that a mechanism other than alterations in
mitochondrial genome or mitochondrial biogenesis underlies
these mitochondrial abnormalities.
We further identified higher levels of the
mitochondrial fission proteins (Fis1 and Drp1) and decreased
levels of the fusion proteins (Mfn1, Mfn2 and Opa1) in ASD
patients, indicating altered mitochondrial dynamics
in ASD brain. Many of these changes were evident in cortical
pyramidal neurons, and were observed in ASD children but
were less pronounced or absent in adult patients. Together,
these findings provide evidence that mitochondrial
function and intracellular redox status are compromised in
pyramidal neurons in ASD brain and that
mitochondrial dysfunction occurs during early childhood when
ASD symptoms appear.
Unique acyl-carnitine profiles are
potential biomarkers for
acquired mitochondrial disease in
autism spectrum disorder
Abstract
Autism spectrum disorder (ASD) has been
associated with mitochondrial disease (MD).
Interestingly, most individuals with ASD and MD do not have
a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired,
at least in a subgroup of children with ASD.
Acquired mitochondrial disease (MD) has
been demonstrated in a rodent ASD model in which
propionic acid (PPA), an enteric bacterial fermentation
product of ASD-associated gut bacteria, is infused
intracerebroventricularly. This animal model shows validity
as it demonstrates many behavioral, metabolic,
neuropathologic and neurophysiologic abnormalities
associated with ASD. This animal model also demonstrates a
unique pattern of elevations in short-chain and long-chain
acyl-carnitines suggesting abnormalities in fatty-acid
metabolism .....
Future studies need to identify additional parallels between
the PPA rodent model of ASD and this subset of ASD
individuals with this unique pattern of acyl-carnitine
abnormalities. A better understanding of this animal model
and subset of children with ASD should lead to better
insight in mechanisms behind environmentally induced ASD
pathophysiology and should provide guidance for developing
preventive and symptomatic treatments.
Investigation of the Mitochondrial
ATPase 6/8 and tRNA(Lys) Genes Mutations in Autism
Abstract
OBJECTIVE: Autism results from
developmental factors that affect many or all functional
brain systems. Brain is one of tissues which are crucially
in need of adenosine triphosphate (ATP). Autism is
noticeably affected by mitochondrial dysfunction which
impairs energy metabolism. Considering mutations
within ATPase 6, ATPase 8 and tRNA(Lys) genes, associated
with different neural diseases, and the main role of ATPase
6/8 in energy generation, we decided to investigate
mutations on these mtDNA-encoded genes to reveal their roles
in autism pathogenesis.
MATERIALS AND METHODS: In this experimental
study, mutation analysis for the mentioned genes were
performed in a cohort of 24 unrelated patients with
idiopathic autism by employing amplicon sequencing of mtDNA
fragments.
RESULTS: In this study, 12 patients (50%)
showed point mutations that represent a significant
correlation between autism and mtDNA variations. Most of the
identified substitutions (55.55%) were observed on MT-ATP6,
altering some conserved amino acids to other ones which
could potentially affect ATPase 6 function. Mutations
causing amino acid replacement denote involvement of mtDNA
genes, especially ATPase 6 in autism pathogenesis.
CONCLUSION: MtDNA mutations in relation
with autism could be remarkable to realize an understandable
mechanism of pathogenesis in order to achieve therapeutic
solutions.
Downregulation of the Expression of
Mitochondrial
Electron Transport Complex Genes in Autism
Brains
Abstract
Mitochondrial dysfunction (MtD) and abnormal brain
bioenergetics have been implicated in autism,
suggesting possible candidate genes in the electron
transport chain (ETC). We compared the expression
of 84 ETC genes in the post-mortem brains of autism patients
and controls. Brain tissues from the anterior cingulate
gyrus, motor cortex, and thalamus of autism patients (n = 8)
and controls (n = 10) were obtained from Autism Tissue
Program, USA. Quantitative real-time PCR arrays were used to
quantify gene expression.
We observed reduced expression of several ETC genes in
autism brains compared to controls. Eleven genes of
Complex I, five genes each of Complex III and Complex IV,
and seven genes of Complex V showed brain region-specific
reduced expression in autism. ATP5A1 (Complex V),
ATP5G3 (Complex V) and NDUFA5 (Complex I) showed
consistently reduced expression in all the brain regions of
autism patients. Upon silencing ATP5A1, the expression of
mitogen-activated protein kinase 13 (MAPK13), a p38 MAPK
responsive to stress stimuli, was upregulated in HEK 293
cells.
This could have been induced by oxidative
stress due to impaired ATP synthesis. We report new
candidate genes involved in abnormal brain bioenergetics in
autism, supporting the hypothesis that mitochondria, critical for neurodevelopment, may play a role in
autism.
Mitochondrial dysfunction in autism
spectrum disorders: a systematic review and meta-analysis
Abstract
A comprehensive literature search was performed to collate
evidence of mitochondrial dysfunction in autism spectrum
disorders (ASDs) with two primary objectives. First,
features of mitochondrial dysfunction in the general
population of children with ASD were identified. Second,
characteristics of mitochondrial dysfunction in children
with ASD and concomitant mitochondrial disease (MD) were
compared with published literature of two general
populations:
ASD children without MD, and non-ASD children
with MD. The prevalence of MD in the general population of
ASD was 5.0% (95% confidence interval 3.2, 6.9%), much
higher than found in the general population (≈ 0.01%). The
prevalence of abnormal biomarker values of mitochondrial
dysfunction was high in ASD, much higher than the prevalence
of MD. Variances and mean values of many mitochondrial
biomarkers (lactate, pyruvate, carnitine and ubiquinone)
were significantly different between ASD and controls. Some
markers correlated with ASD severity. Neuroimaging, in vitro
and post-mortem brain studies were consistent with an
elevated prevalence of mitochondrial dysfunction in ASD.
Taken together, these findings
suggest children with ASD
have a spectrum of mitochondrial dysfunction of differing
severity ....Most ASD/MD cases
(79%) were not associated with genetic abnormalities,
raising the possibility of secondary mitochondrial
dysfunction. Treatment studies for ASD/MD were limited,
although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies
suffered from limitations, including small sample sizes,
referral or publication biases, and variability in protocols
for selecting children for MD workup, collecting
mitochondrial biomarkers and defining MD. Overall, this
evidence supports the notion that mitochondrial dysfunction
is associated with ASD. Additional studies are needed to
further define the role of mitochondrial dysfunction in ASD.
January 31, 2011 — Mitochondrial dysfunction (MD) is more
common in children with autism and autism spectrum disorder
(ASD) than the general population, a comprehensive
systematic review and meta-analysis of relevant research
confirms.
Mitochondrial dysfunction "may play a significant role in
contributing to the symptoms of autism and is generally
underrecognized in these children," Daniel A. Rossignol, MD,
of the International Child Development Resource Center,
Melbourne, Florida, told Medscape Medical News.
Dr. Daniel A. Rossignol
"Testing for mitochondrial dysfunction is available, and
early treatment might lead to better long-term developmental
outcomes," said Dr. Rossignol, who coauthored the review
with Richard E. Frye, MD, PhD, of the University of Texas in
Houston.
The report was published online January 25 in Molecular
Psychiatry.
Commenting on the study Cecilia Giulivi, PhD, professor of
biochemistry and metabolic regulation, at the University of
California, Davis, who was not involved in the analysis,
said, "At this point, it looks like there is a higher
incidence of mitochondrial disease in autism, much higher
than we suspected."
She noted, however, that testing for MD "is not a trivial
task [and] we need more research to come up with a consensus
of diagnostic tests to run. In addition, maybe other
metabolic syndromes should be looked into," Dr. Giulivi
said.
Genetics Not the Culprit
The results showed the prevalence of MD in the general
population of children with ASD is approximately 5% (95%
confidence interval [CI], 3.2% – 6.9%), which is 500% higher
than the general population prevalence of 0.01%. For a
variety of reasons, "this 5% value is most likely an
underestimation," Dr. Rossignol said.
It also appears that one-third or more of children with
autism may have some type of dysfunction in their
mitochondria. On the basis of laboratory testing, the
prevalence of abnormal biomarker values of MD, including
lactate, pyruvate, carnitine, and ubiquinone, was high in
children with ASD, much higher than the prevalence of MD.
Some of these markers correlated with the severity of ASD.
Most of the 112 children with ASD and MD (79%) had no
identifiable genetic abnormality that could account for the
MD.
"The mitochondrial dysfunction and disease reported in
autism are related to a genetic abnormality in only 1 out of
5 children; meaning that a majority of these children have
something else contributing to this dysfunction, which might
include multiple environmental factors, such as toxins,
oxidative stress, inflammation, and decreased levels of
antioxidants," said Dr. Rossignol.
"Clearly, mitochondrial function is a ripe area of research
when investigating the biological mechanism(s) of action of
environmental toxicant exposures and indigenous
abnormalities associated with ASD," the study authors write ....
Children With Autism Have
Mitochondrial Dysfunction, Study Finds
Nov. 30, 2010 — Children with autism are far more likely to
have deficits in their ability to produce cellular energy
than are typically developing children, a new study by
researchers at UC Davis has found. The study, published in
the Journal of the American Medical Association (JAMA),
found that cumulative damage and oxidative stress in
mitochondria, the cell's energy producer, could influence
both the onset and severity of autism, suggesting a strong
link between autism and mitochondrial defects.
After the heart, the brain is the most voracious consumer of
energy in the body. The authors propose that deficiencies in
the ability to fuel brain neurons might lead to some of the
cognitive impairments associated with autism. Mitochondria
are the primary source of energy production in cells and
carry their own set of genetic instructions, mitochondrial
DNA (mtDNA), to 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," said Cecilia Giulivi, the
study's lead author and professor in the Department of
Molecular Biosciences in the School of Veterinary Medicine
at UC Davis. "Many of these characteristics are shared by
children with autism."
"It is remarkable that evidence of mitochondrial dysfunction
and changes in mitochondrial DNA were detected in the blood
of these young children with autism," said Geraldine Dawson,
chief science officer of Autism Speaks, which provided
funding for the study. "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."
Context: Impaired mitochondrial function may influence
processes highly dependent on energy, such as
neurodevelopment, and contribute to autism. No studies have
evaluated mitochondrial dysfunction and mitochondrial DNA
(mtDNA) abnormalities in a well-defined population of
children with autism.
Objective: To evaluate mitochondrial defects in children
with autism.
Design, Setting, and Patients: Observational study using
data collected from patients aged 2 to 5 years who were a
subset of children participating in the Childhood Autism
Risk From Genes and Environment study in California, which
is a population-based, case-control investigation with
confirmed autism cases and age-matched, genetically
unrelated, typically developing controls, that was launched
in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10
children with autism and 10 controls.
Main Outcome Measures: Oxidative phosphorylation capacity,
mtDNA copy number and deletions, mitochondrial rate of
hydrogen peroxide production, and plasma lactate and
pyruvate.
Results: The reduced nicotinamide adenine dinucleotide
(NADH) oxidase activity (normalized to citrate synthase
activity) in lymphocytic mitochondria from children with
autism was significantly lower compared with controls (mean,
4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI,
8-16], respectively; P = .001). The majority of children
with autism (6 of 10) had complex I activity below control
range values. (PdLA Complex can specifically increase
Complex1 Activity)
Higher plasma pyruvate levels were found in children with
autism compared with controls (0.23 mM [95% CI, 0.15-0.31
mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P =
.02).
Eight of 10 cases had higher pyruvate levels but only 2
cases had higher lactate levels compared with controls.
These results were consistent with the lower pyruvate
dehydrogenase activity observed in children with autism
compared with controls (1.0 [95% CI, 0.6-1.4] nmol × [min ×
mg protein]−1 vs 2.3 [95% CI, 1.7-2.9] nmol × [min × mg
protein]−1, respectively; P = .01). (Same reason as above)
Children with autism had higher mitochondrial rates of
hydrogen peroxide production compared with controls (0.34
[95% CI, 0.26-0.42] nmol × [min × mg of protein]−1 vs 0.16
[95% CI, 0.12-0.20] nmol × [min × mg protein]−1 by complex
III; P = .02). (PdLA complex reverses hydrogen peroxide
production)
