# A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $605,969

## Abstract

A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM Abstract: Autism is a neurobehavioral
disorder of unknown etiology that affects one in 68 children. We hypothesize that a major contributor to autism
spectrum disorder (ASD) risk is partial mitochondrial dysfunction causing interneuron inhibition and
developmental migration defects. This results in cortical neuronal excitation-inhibition imbalance. Partial
mitochondrial dysfunction has been repeatedly observed in ASD. ASD patients exhibit EEG abnormalities of
likely GABAergic inhibitory interneuron origin. Interneurons are highly energetic and acutely sensitive to
mitochondrial inhibition and cortical excitation-inhibition imbalance is associated with ASD behavioral
abnormalities. Extensive nuclear DNA (nDNA) genetic studies have identified multiple ASD-associated
haploinsufficient loci, each accounting for a few cases, implying that there are over a thousand ASD loci. The
mitochondrial genome consists of between one and two thousand nDNA genes plus thousands of copies of the
mitochondrial DNA (mtDNA), so partial mitochondrial dysfunction can result from nDNA haploinsufficiency or
deleterious mtDNA variants. We have shown that many ASD-associated nDNA haploinsufficiency variants
affect mitochondrial functions, that certain mtDNA lineages (haplogroups) correlate with ASD-risk, that the
ASD-associated mtDNALeu(UUR) nt 3243A>G mutation results in mitochondrial dysfunction and perturbation of
expression of multiple ASD nDNA genes, that chemical and genetic inhibition of OXPHOS impacts interneuron
cortical developmental migration, and that mice harboring mild mtDNA mutants exhibit ASD-associated
endophenotypes including EEG abnormalities. To further test the mitochondrial defect-interneuron imbalance
hypothesis we propose three specific aims. First, we will determine the mtDNA sequences of ASD patients
and controls using off-target exome sequence data or direct mtDNA sequencing and correlate the mtDNA
haplogroups and recent deleterious mutations with ASD risk. ASD-associated mtDNAs will then be analyzed
for mitochondrial dysfunction within transmitochondrial cybrids. Second, we will analyze 16p11.2 CNV ASD
cell lines for mitochondrial dysfunction and altered transcription profiles and compare the results to ASD
mtDNALeu(UUR) nt 3243A>G cybrids. We will then determine how mtDNA variation affects the clinical variability
associated with 16p11.2 CNVs. Finally, we will determine the effect of interneuron-specific nDNA
mitochondrial gene and systemic mtDNA gene defects on cortical interneuron developmental migration and
associated manifestation of ASD endophenotypes and social-behavioral aberrations. Mice with
endophenotypes but non-overt ASD-like behavior will be exposed to poly (I:C)-induced in utero inflammation to
determine if they are more prone to induction of ASD-like behavior. If validated by these experiments our
mitochondrial defect-interneuron imbalance hypothesis can encompass virtually all of ...

## Key facts

- **NIH application ID:** 9927676
- **Project number:** 5R01MH108592-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Douglas C Wallace
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $605,969
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927676

## Citation

> US National Institutes of Health, RePORTER application 9927676, A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM (5R01MH108592-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927676. Licensed CC0.

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