Mitochondria, containing two plasma membranes, an inner and an outer membrane, are very important cellular organelles. They generate adenosine triphosphate (ATP) — the energy carrier in most mammalian cells — by oxidizing glucose and fatty acids.

Structure and function:

As a key intermediate generated from the oxidation of glucose and fatty acids, acetyl-CoA enters the tricarboxylic acid (TCA) cycle. The TCA cycle produces reduced flavin adenine dinucleotide (FADH2) and reduced nicotinamide adenine dinucleotide (NADH), which donate electrons to the mitochondrial electron transport chain (ETC). The inter-membrane space, between the inner and outer membranes, is the region for converting adenosine diphosphate (ADP) into ATP, utilizing the proton gradient generated from the ETC.

The ETC is located in the inner mitochondrial membrane, and consists of five multi-subunit enzyme complexes, i.e. complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome bc1 complex), complex IV (cytochrome c oxidase) and ATP synthase, also known as complex V) and two electron carriers (ubiquinone, also known as co-enzyme Q10, and cytochrome c). ETC also produces the free radicals, i.e., reactive oxygen species (ROS), which cause oxidative stress and trigger apoptosis1,2,3,4.

Mitochondria have their own genome and multiple copy numbers. Mitochondrial proteins are coded by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). For example, 13 subunits of the ETC complexes I, III, IV and V are coded by 37 mtDNA, and the other subunits are coded by more than 850 nuclear DNA genes5. Therefore, mtDNA or nDNA genome mutations may lead to ETC complex deficiencies, and also mitochondrial dysfunctions.

According to the cell demand for energy, the number of mitochondria may vary from one to several thousand. The brain has a high demand for energy, and neurons contain a large number of mitochondria, especially in synapses. The number and morphology of mitochondria can be affected according to the demand of synaptic transmission.

In addition to supplying cellular energy, mitochondria are involved in several other processes, such as programmed cell death or apoptosis, calcium homeostasis, synaptic plasticity, neurotransmitter release, as well as the control of the cell cycle and cell growth6. Mitochondria have been implicated in several human diseases, including mitochondrial disorders, neurodevelopmental disorders, neurodegenerative diseases and cardiac dysfunction, and may play a role in the aging process. Metabolic and mitochondrial defects affect the function and plasticity of neurons, cause neuronal loss and alter modulation of neurotransmission systems.

Relevance to autism:

In 1998, Lombard presented a hypothesis that mitochondrial dysfunction may be involved in the pathology of autism7. Since then, several biochemical, anatomical and neuro-radiographical reports have shown high lactate, increased lactate-to-pyruvate ratio and low carnitine levels in individuals with autism, suggesting that mitochondrial energy metabolism is perturbed in autism8,9,10,11,12,13,14. However, only a few individuals with autism (5 percent) show classical features of mitochondrial disease. Some individuals with autism have mitochondrial dysfunction accompanied by genetic abnormalities and defects in the respiratory chain15,16.

In autism, both the activities and the expression levels of the ETC have been found to be altered in many cohort research and case reports17,18,19. Oliveira et al. conducted a population-based survey of 11-14 years old children with autism spectrum disorders. They reported that 7.2 percent (5 of 69) met the criteria for definite mitochondrial disease. Weissman undertook a cohort study with 25 individuals with autism/mitochondrial disease. Of these, 20 individuals have deficient activity of ETC complexes on tissue ETC or polarographic analysis, 64 percent of whom have complex I deficiency and 20 percent have complex III deficiency in the blood. Meta analysis results showed that complex I deficiency is the most common (53 percent), and deficiencies of complex III, V, IV and II are in 30 percent, 23 percent, 20 percent and 9 percent respectively, in children with autism/mitochondrial disease.

A study with postmortem frozen brain samples from children with autism and age-matched controls shows significantly lower expression 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 in autism20.

An in vitro study using lymphocytes from individuals with autism showed that six of ten children with autism have complex I activity below control range values, four have a lower complex V activity, and three have a lower complex IV activity. Only one child with autism fulfilled the diagnostic criteria for a definite mitochondrial disease. In another report, activities of complex I and complex IV were found to be changed, and mitochondrial maximal respiratory rate increased 40 to 50 percent in the autism group population compared with controls, which may be a compensatory response to the partial inhibition of ATP synthesis 21. All these studies point to widespread mitochondrial ETC abnormalities in autism spectrum disorders.

ROS is involved in autism. Neurons are very vulnerable to oxidative stress due to the high rate of oxygen delivery and consumption in the brain. Environmental factors such as air pollution, organophosphates, heavy metals and alcohol use during pregnancy may act as a trigger to increase ROS production, induce oxidative stress and cause mitochondrial dysfunction in autism22,23,24.

Several oxidative biomarkers — for example, transmethylation, transsulfuration and lipid peroxidation — are found significantly changed in the blood25,26, urine 27 and brains 28,29,30 of individuals with autism as compared with controls. At the same time, anti-oxidant defense is decreased. Levels of major antioxidant serum proteins, namely transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein), are lower in children with autism compared with controls. Low levels of reduced glutathione and increased oxidized glutathione were reported in plasma31, 32, in lymphoblastoid cell lines 33, and in the cerebellum, temporal and cortex of individuals with autism 34.

Mitochondrial aspartate/glutamate carrier (AGC), which is physiologically activated by calcium, plays an important role in energy metabolism by transporting glutamate into mitochondria. AGC transport rates and AGC1 protein expression levels were significantly higher in the brain of individuals of autism compared with controls35. Another study indicated excessive calcium levels, and an activation of mitochondrial metabolism 36. AGC1-encoding SLC25A12 gene was also found to be associated with autism 37,38. Abnormal calcium signaling has also been found in other studies on autism39,40.

Abnormal gene expression is one of the important etiologies of autism, which may be caused by chromosome depletion, mtDNA mutation and depletion41,42, and decreased levels of mRNA 43. These can affect the mitochondrial protein activities and physical function. Deletion in the 5q14.3 region induces a severe decrease in complex IV activity and mild reduction in complex I activity44.

Individuals with autism who have A3243G mtDNA mutations showed reduction in activities of complexes I, III, and IV to 34 percent, 23 percent and 25 percent of control values. Duplications of the proximal long arm of chromosome 15 are associated with autism, which is related to the defect in complex III of the ETC. This abnormality occurs in up to five percent of individuals with autism45,46. In a large case-control study, Marui et al. reported significant association between the NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene and autism. The product of the NDUFA5 gene is included in the mitochondrial ETC complex I.

Above reports suggest the presence of mitochondrial dysfunction in the pathology of autism spectrum disorders. More studies are needed to further define the role of mitochondrial dysfunction in autism, and to understand whether mitochondrial dysfunction in children with autism is a primary etiology or secondary pathology to other causes.

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