Mitochondrial dysfunction in autism spectrum disorders: Cause or effect?
Luigi Palmieria,b,⁎, Antonio M. Persicoc,d,⁎
aLaboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Via Orabona 4, 70125, Bari, Italy
bConsiglio Nazionale delle Ricerche, Institute of Biomembranes and Bioenergetics, Bari, Italy
cLaboratory of Molecular Psychiatry and Neurogenetics, University “Campus Bio-Medico”, Rome, Italy
dDepartment of Experimental Neurosciences, I.R.C.C.S. “Fondazione Santa Lucia”, Rome, Italy
a b s t r a c ta r t i c l ei n f o
Received 25 February 2010
Received in revised form 15 April 2010
Accepted 26 April 2010
Available online 9 May 2010
Autism Spectrum Disorders encompass severe developmental disorders characterized by variable degrees of
impairment in language, communication and social skills, as well as by repetitive and stereotypic patterns of
behaviour. Substantial percentages of autistic patients display peripheral markers of mitochondrial energy
metabolism dysfunction, such as (a) elevated lactate, pyruvate, and alanine levels in blood, urine and/or
cerebrospinal fluid, (b) serum carnitine deficiency, and/or (c) enhanced oxidative stress. These biochemical
abnormalities are accompanied by highly heterogeneous clinical presentations, which generally (but by no
means always) encompass neurological and systemic symptoms relatively unusual in idiopathic autistic
disorder. In some patients, these abnormalities have been successfully explained by the presence of specific
mutations or rearrangements in their mitochondrial or nuclear DNA. However, in the majority of cases,
abnormal energy metabolism cannot be immediately linked to specific genetic or genomic defects. Recent
evidence from post-mortem studies of autistic brains points toward abnormalities in mitochondrial function
as possible downstream consequences of dysreactive immunity and altered calcium (Ca2+) signalling.
© 2010 Elsevier B.V. All rights reserved.
Autism Spectrum Disorders (ASDs), encompassing Autistic Disor-
der, Asperger's Disorder, and Pervasive Developmental Disorder Not
Otherwise Specified (PDDNOS), represent a group of severe neuro-
developmental disorders characterized by variable degrees of impair-
ment in language, verbal and non-verbal communication, and social
skills, as well as by repetitive behaviors and an excessive insistence on
sameness, with onset prior to three years of age . Collectively, the
incidence of ASDs has dramatically risen during the last two decades
from 2-5/10,000 to approximately 1-2/1000 children: broader
diagnostic criteria and increased awareness in the medical commu-
nity have certainly contributed to determine this trend, but a real
increase in incidence possibly due to environmental factors cannot be
excluded [2,3]. These disorders are often addressed as discrete clinical
entities, but they should instead be viewed as a continuum, ranging
from minimal autistic traits to severe autism .
No neuropsychiatric disorder displays genetic underpinnings as
prominent as those documented by family and twin studies for autism,
as 3–6% for strictly defined autism . However, only in approximately
10% of cases the disease is “syndromic”, i.e. secondary to a known
of “non-syndromic”, “primary” or “idiopathic” autism remains un-
known. Genome-scans unveiled the existence of approximately 15–20
loci contributing to non-syndromic autism, albeit in complex fashion
due to genetic heterogeneity, incomplete penetrance, phenocopies,
gene–gene and gene–environment interactions .
The cytoarchitectonic abnormalities present in autistic brains are
cell proliferation, abnormal cell migration, and altered cell differentia-
tion with reduced neuronal size, all pointing toward the first/second
trimester of pregnancy as the critical time for deranged neurodevelop-
ment in autism [6,7]. The detection of fine motor symptoms already on
converges with neuropathological findings in dating prenatally the
origin of the disease, although behavioral symptoms typically appear at
6–24 months [8–10]. Finally, large subgroups of ASD patients also
display systemic signs and symptoms, including macrosomy , non-
specific enterocolitis , immune dysreactivity [12,13] and renal
the central nervous system (CNS) and should be viewed as a multi-
Biochimica et Biophysica Acta 1797 (2010) 1130–1137
Abbreviations: AGC, aspartate/glutamate carrier; ASD, autism spectrum disorders;
CK, creatine kinase; CNS, central nervous system; CNV, copy number variant; GSH,
reduced glutathione; GSSG, oxidized glutathione; MDA, malonyldialdehyde; OXPHOS,
oxidative phosphorylation; ROS, reactive oxigen species; SAH, H-adenosylhomocys-
teine; SAM, S-adenosylmethionine
⁎ Corresponding authors. Palmieri is to be contacted at Laboratory of Biochemistry and
Molecular Biology, Department of Pharmaco-Biology, University of Bari, Bari, Italy. Tel.:
Neurogenetics, University “Campus Bio-Medico”, Rome, Italy. Tel.: +39 06 225419155;
fax: +39 06 501703333.
E-mail addresses: email@example.com (L. Palmieri), firstname.lastname@example.org
0005-2728/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
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L. Palmieri, A.M. Persico / Biochimica et Biophysica Acta 1797 (2010) 1130–1137