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Dysfunction in Mitochondrial Electron Transport Chain Complex I, Pyruvate Dehydrogenase Activity, and Mutations in ND1 and ND4 Gene in Autism Spectrum Disorder Subjects from Tamil Nadu Population, India

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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by impaired social interaction and behavioural abnormalities. Growing evidence proved that impairment in mitochondrial functions could inhibit energy production and may contribute to the onset of ASD. Genetic variants in the genes of mitochondrial DNA (mtDNA) could interrupt the normal energy metabolism and production in the brain which lead to a wide range of structural and functional changes in the brain resulting in ASD. The present study aims to compare the activities of mitochondrial electron transport chain (ETC) complex I, pyruvate dehydrogenase (PDH) and specific mitochondrial DNA gene (MT-ND1 and MT-ND4) variants associated with ASD subjects in the Tamil Nadu population. Mutational analysis revealed that most mutations in ASD subjects showed synonymous type followed by missense in both the ND1 and ND4 genes. Interestingly, we found that the complex I and PDH dysfunctions may have a role in ASD compared to the controls (p ≤ 0.0001). Hence, the results of the present study suggest that mitochondrial dysfunction, specifically the complex I genes, may play a major role in the onset of ASD, concluding that further research on mitochondrial genes are mandatory to unravel the mechanism behind ASD pathogenesis.

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Abbreviations

ALT:

Aminotransferase

ASD:

Autism spectrum disorder

AST:

Aspartate aminotransferase

CARS:

Childhood Autism Rating Scale

DSM-V:

Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition)

EDTA:

Ethylenediaminetetraacetic acid

ETC:

Electron transport chain

HCl:

Hydrogen chloride

IHEC:

Institutional Human Ethics Committee

KCl:

Potassium chloride

L:P:

Lactate to pyruvate

MgCL2:

Magnesium dichloride

mtDNA:

Mitochondrial DNA

NaCl:

Sodium chloride

NADH:

Nicotinamide adenine dinucleotide

ND1:

NADH dehydrogenase 1

ND4:

NADH dehydrogenase 4

OXPHOS:

Oxidative phosphorylation

PDH:

Pyruvate dehydrogenase

SDS:

Sodium dodecyl sulfate

CI:

Confidence interval

X 2 :

Chi square

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Acknowledgements

The author Dr. VB would like to thank the Bharathiar University for providing the necessary infrastructure facility and the Science and Engineering Research Board (SERB) (ECR/2016/001688), Government of India, New Delhi, for providing necessary help in carrying out the manuscript. We acknowledge the Department of Human Genetics and Molecular Biology, Bharathiar University, for providing necessary infrastructure facilities, ethical approval, and technical assistance to conduct this article.

Funding

This study was funded by Science and Engineering Research Board (SERB) Early Career Research (ECR) Award funded by the Government of India, New Delhi (Grant No. ECR/2016/ 001688).

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Authors and Affiliations

  1. Livestock Farming and Bioresource Technology, Tamil Nadu, India

    Iyer Mahalaxmi

  2. SN ONGC, Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, 600-006, India

    Mohana Devi Subramaniam

  3. Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India

    Abilash Valsala Gopalakrishnan

  4. Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641-046, Tamil Nadu, India

    Balachandar Vellingiri

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  1. Iyer Mahalaxmi
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Contributions

Concept and design, VB; literature search, IM and MDS; experimental studies, VB, IM and MDS; data analysis and statistical analysis, VB, IM and MDS; manuscript preparation, IM and MDS; manuscript editing and manuscript review, VB and AVG.

Corresponding author

Correspondence to Balachandar Vellingiri.

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Mahalaxmi, I., Subramaniam, M.D., Gopalakrishnan, A.V. et al. Dysfunction in Mitochondrial Electron Transport Chain Complex I, Pyruvate Dehydrogenase Activity, and Mutations in ND1 and ND4 Gene in Autism Spectrum Disorder Subjects from Tamil Nadu Population, India. Mol Neurobiol 58, 5303–5311 (2021). https://doi.org/10.1007/s12035-021-02492-w

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