Mitochondrial dysfunction in autistic behaviors

Autism Spectrum Disorders (ASD) refers to a group of neurodevelopmental abnormalities characterized by impairment in communication, social skills and eye contacts with restrictive interests and repetitive behaviors. Individuals with autism show variable reactions in sensitive situations. Some children have normal intelligence and some have intellectual disability, macrocephaly, microcephaly, developmental delay and/or epilepsy. The symptoms appear in infancy and early childhood and affect daily functioning. Recent studies suggest that approximately 1 in 54 children are affected by an autism spectrum disorder. Autism spectrum disorder is notably four times more common in boys than in girls. Many types of research have revealed that genetic and environmental factors are linked to ASD. Major susceptibility factors can play a critical role in the development of autistic behaviors. It is well accepted that ASD have a strong genetic predisposition; however, genes that cause neuropsychiatric disorders are unknown and more than 100 genes are involved in ASD patients. Several genetic factors, such as mitochondrial DNA (mtDNA) variations, have been linked to autistic behaviors. We searched the PubMed, Science Direct, Elsevier, SID, HGMD, SFARI and AUTDB databases for mitochondrial dysfunction associated with the development of autistic behaviors published between 2010 and 2020. The purpose of the search strategy was to obtain relevant studies that provided appropriate information. In 1985, Coleman and Blass made the first hypothesis associating ASD with high levels of lactate in the plasma of individuals with autistic behaviors. Studies showed that various biomarkers of mitochondrial disruption (alanine-to-lysine ratio, acylcarnitine) are altered in some cases with ASD. So far, a great deal of research has been carried out in the field of genetics, perinatal factors, immune and environmental factors affecting autistic behaviors, so that in the latest update of genes involved in human and animal models of autism (on AutDB and SFARI.GENE databases), about 2000 genes involved in the etiology of autism and autistic behaviors have been classified. This list contains many genes including mTOR, MECP2 and genes involved in mitochondrial function or responsible for mtDNA maintenance. Several pathogenic variations that cause defects in mitochondrial metabolic pathways can lead to alterations in neuronal circuits and neurotransmitter systems. Protein coding genes of the mitochondria are components of the respiratory oxidative phosphorylation chain. Oxidative phosphorylation is vital to the growing nerve cells. Studies show that the capacity of oxidative phosphorylation in granulocytes is significantly lower in autistic children, in comparison with normal children. There is evidence of modified immune function in neural systems. The antigen-antibody complexes can induce immune cell migration and stimulate neuro-inflammation. Several investigations revealed that an immune abnormality during pregnancy or postnatal environment results in psychiatric disorders. Immune system irregularities, including defects in T cell responses or Th1/Th2 cytokines, have been reported in individuals with psychiatric disorders, proposing that unusual immune functions in the brain may play an important role in a significant subset of children with autism. Furthermore, Interferons can also induce the expression of more than 300 genes, some of which are mitochondrial genes and some are nuclear genes involved in regulating mitochondrial function. Glucocorticoids can inhibit the production of certain cytokines, such as TNF-α, IL-2, IL-6, IL1β and IL-8, and also can alter the production of anti-inflammatory cytokines, such as IL-10, IL-4, and growth factor-β. Besides, nuclear- or mitochondrial-encoded oxidative phosphorylation subunits (OXPHOS) are regulated by glucocorticoids that their receptors have been identified in the mitochondria. In summary, immune system disorders can impair prenatal brain development or postnatal brain function, so that they can create causality with the ASD phenotype. Also, some maternal allergies during pregnancy, such as exposure to infections, can cause persistent and long-term changes in mitochondrial functions that can lead to autism-like behaviors. This study focused on some clinical aspects of mitochondrial dysfunction in ASD. Most children with autistic behaviors indicate mitochondrial dysfunction and enhanced oxidative stress. Published findings have revealed broad alterations in the immune and nervous systems of children with autistic behaviors. Detection of dependent factors related to ASD can help in the early intervention of these children to address psychological requirements. This article tries to give a useful summary of critical pathways involved in mitochondrial dysfunction in autistic behaviors. Data of this review will give a wide perspective to genetic factors in autism.