Universidad Autónoma de Chile

Facultad de Ciencias de la Salud

Santiago, Chile

2013 - A la fecha

Universidad Andrés Bello

Facultad de Ciencias Biológicas

Santiago, Chile

2010 - 2013

Corporación par Investigaciones Biológicas (CIB)

Medellín, Colombia

2000 - 2004

Universidad Autónoma de Chile

Santiago, Chile

2013 - A la fecha

UNIVERSIDAD AUTONOMA DE CHILE

Chile, 2019

High Mitochondrial DNA Levels in Autism Spectrum Disorder is Suggestive of Alterations in the Mitochondrial DNA Replisome: Analysis of The Mitochondrial Transcription Factor A INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic basis. Despite this, only a small fraction of the genes that can be the cause of it are known and supported by strong genetic evidence. Recently, our group started the study of the influence of mitochondrial physiology on the development of ASD. In children with ASD, we found a significant increase in mitochondrial DNA (mtDNA) levels. Likewise, in these children, an increase in the protein oxidation and high expression of the MFN2 gene was observed. The increase in mtDNA levels is suggestive of alterations in the mitochondrial DNA replisome where different proteins are involved than those used for the replication of nuclear DNA, such as the mitochondrial Transcription Factor A (TFAM), the TWINKLE helicase, and the DNA polymerase ?, among others. TFAM is an activator of mitochondrial transcription, it also functions as a histone-like in the packaging of mtDNA, and as mtDNA levels follow TFAM levels. OBJECTIVE: Elucidating the role of TFAM in ASD. METHODS: In the present study was used the computational tool from the Lewis–Sigler Institute for Integrative Genomics at the University of Princeton for the prediction of TFAM gene association with the genetic bases of ASD. Moreover, we analyze the datasets of TFAM expression in ASD by profiling arrays with the Gene Expression Omnibus (GEO) repository. Datasets GSE49105 and GSE111176 were analyzed with GEO2R. Finally, we performed a review of TFAM and ASD in literature. RESULTS: The brain-specific functional relationships involving the TFAM gene show the integration with genes that are more likely to be associated with the development of autism is evident. Also, the enrichment of genes shows the involvement in biological processes such as nuclear transport, nucleocytoplasmic transport, and RNA export from the nucleus. Moreover, the enrichment of genes shows some spatiotemporal signatures such as the orbital prefrontal cortex, striatum, and ventrolateral prefrontal cortex in early-mid fetal development; and inferior temporal cortex, amygdala, hippocampus and ventrolateral prefrontal cortex in early fetal development. The analyses of GSE49105 and GSE111176 datasets show that TFAM gene expression in blood is not altered in ASD. In literature, we found the report that there is no significant difference in the levels of TFAM between ASD and control postmortem brain samples. However, the expression of TFAM in the ASD Lymphoblastoid cell lines was reduced at both RNA and protein levels. CONCLUSION: High mtDNA levels in children with ASD may occur at the TFAM transcriptional level in some specific regions of the brain during fetal development. Further analyses are required to understand the role of TFAM in ASD. Our group continues studying the potential alterations in the mitochondrial DNA replisome in ASD.