An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes

Abstract

Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.

Novel mtDNA Imparts the Connective Tissue Disorder of a Tourette Pedigree

“…While the mother herself does not harbor the HDC variant, we found lower cytosolic ROS levels in her lymphoblastoid cells compared to those of her children, suggesting the presence of additional nuclear antioxidant modifiers. Consistent with previous reports for mitochondrial dysfunction in cells (16) or mice (6) lowering the ROS levels in the ND5 m.13708G>A-H7 cybrids rescued the mitochondrial phenotype.…”

“…Rather, the mtDNA defects must also contribute to the diverse neurological symptoms of the offspring as well as the connective tissue and metabolic manifestations of the mother and her children. It has already been shown that a mtDNA mutation is sufficient to cause ASD-like symptoms in mice (6) and mitochondrial dysfunction is thought to be a key feature in neurodegenerative disorders (23). RNASeq analysis of the patient transmitochondrial cybrids identified the dysregulation of genes associated with neurodevelopment and axon guidance.…”

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

“…Clinical studies have found mitochondrial and metabolic dysfunction or changes in metabolites in primary lymphocytes or brain tissue in individuals with ASD 55, 56, 91–96 , but whether this is direct or indirect is not known. A mouse model expressing an mtDNA variant was shown to display autism associated behavioral deficits 97 , but the variant is weakly associated with ASD. Some ASD associated syndromic disorders, co-morbid disorders and genetic ASD models have shown deficits in mitochondrial and metabolic processes, however the specific proteins involved were unknown 52–54, 98–104, 105 .…”

Energy metabolism in childhood neurodevelopmental disorders

“…These reports are complemented by studies in animal models, leading to the same conclusions. It has been proposed that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations that result in autistic endophenotypes, as was demonstrated in a mouse strain bearing an mtDNA gene missense mutation [69]. Metabolic dysfunction can be either the primary cause (ie, IEM with features of ASD), or secondary contributions to precise ASD pathophysiology [70].…”