An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes
Tal Yardeni, Ana G. Cristancho, Almedia J. McCoy, Patrick M. Schaefer, Meagan J. McManus, Eric D. Marsh, Douglas C. Wallace
Abstract
Significance Autism spectrum disorders (ASDs) have increasingly been associated with mitochondrial dysfunction, corroborated by mitochondrial DNA (mtDNA) germline and somatic variants being found in ASD patients. If mitochondrial defects can generate ASD, then specific mtDNA mutations should induce ASD endophenotypes in mice. We tested this prediction by introduction of an mtDNA ND6 gene missense mutation ( ND6 P25L ) into the mouse germline and found ASD endophenotypes. The ND6 P25L mice exhibit impaired social interaction, compulsive behavior, and increased anxiety. They have reduced electroencephalographic delta and theta wave power, increased predilection to seizures, but without diminution of hippocampal interneurons. These endophenotypes correlate with impaired cortical and hippocampal mitochondrial respiration and increased reactive oxygen species production. Thus, mitochondrial defects can be sufficient to produce ASD phenotypes.