Yardeni 2021 Proc Natl Acad Sci U S A

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Yardeni T, Cristancho AG, McCoy AJ, Schaefer PM, McManus MJ, Marsh ED, Wallace DC (2021) An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes. Proc Natl Acad Sci U S A 118:e2021429118.

» PMID: 33536343 Open Access »O2k-brief

Yardeni Tal, Cristancho Ana G, McCoy Almedia J, Schaefer Patrick M, McManus Meagan J, Marsh Eric D, Wallace Douglas C (2021) Proc Natl Acad Sci U S A

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.

Keywords: ROS, Autism, Mitochondrial dysfunction Bioblast editor: Plangger M O2k-Network Lab: DE Ulm Radermacher P, US PA Philadelphia Wallace DC


Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Autism 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Homogenate 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2021-02, AmR, O2k-brief