Downregulation of the Expression of Mitochondrial Electron Transport Complex Genes in Autism Brains

<jats:title>Abstract</jats:title><jats:p>Mitochondrial dysfunction (<jats:styled-content style="fixed-case">MtD</jats:styled-content>) and abnormal brain bioenergetics have been implicated in autism, suggesting possible candidate genes in the electron transport chain (<jats:styled-content style="fixed-case">ETC</jats:styled-content>). We compared the expression of 84 <jats:styled-content style="fixed-case">ETC</jats:styled-content> genes in the post‐mortem brains of autism patients and controls. Brain tissues from the anterior cingulate gyrus, motor cortex, and thalamus of autism patients (n = 8) and controls (n = 10) were obtained from <jats:styled-content style="fixed-case">A</jats:styled-content>utism <jats:styled-content style="fixed-case">T</jats:styled-content>issue <jats:styled-content style="fixed-case">P</jats:styled-content>rogram, <jats:styled-content style="fixed-case">USA</jats:styled-content>. <jats:styled-content style="fixed-case">Q</jats:styled-content>uantitative real‐time <jats:styled-content style="fixed-case">PCR</jats:styled-content> arrays were used to quantify gene expression. We observed reduced expression of several <jats:styled-content style="fixed-case">ETC</jats:styled-content> genes in autism brains compared to controls. Eleven genes of Complex <jats:styled-content style="fixed-case">I</jats:styled-content>, five genes each of <jats:styled-content style="fixed-case">C</jats:styled-content>omplex <jats:styled-content style="fixed-case">III</jats:styled-content> and <jats:styled-content style="fixed-case">C</jats:styled-content>omplex <jats:styled-content style="fixed-case">IV</jats:styled-content>, and seven genes of <jats:styled-content style="fixed-case">C</jats:styled-content>omplex <jats:styled-content style="fixed-case">V</jats:styled-content> showed brain region‐specific reduced expression in autism. <jats:italic><jats:styled-content style="fixed-case">ATP5A1</jats:styled-content></jats:italic> (<jats:styled-content style="fixed-case">C</jats:styled-content>omplex <jats:styled-content style="fixed-case">V</jats:styled-content>), <jats:italic><jats:styled-content style="fixed-case">ATP5G3</jats:styled-content></jats:italic> (<jats:styled-content style="fixed-case">C</jats:styled-content>omplex <jats:styled-content style="fixed-case">V</jats:styled-content>) and <jats:italic><jats:styled-content style="fixed-case">NDUFA5</jats:styled-content></jats:italic> (<jats:styled-content style="fixed-case">C</jats:styled-content>omplex <jats:styled-content style="fixed-case">I</jats:styled-content>) showed consistently reduced expression in all the brain regions of autism patients. Upon silencing <jats:italic><jats:styled-content style="fixed-case">ATP5A1</jats:styled-content></jats:italic>, the expression of mitogen‐activated protein kinase 13 (<jats:italic><jats:styled-content style="fixed-case">MAPK13</jats:styled-content></jats:italic>), a p38 <jats:styled-content style="fixed-case">MAPK</jats:styled-content> responsive to stress stimuli, was upregulated in <jats:styled-content style="fixed-case">HEK</jats:styled-content> 293 cells. This could have been induced by oxidative stress due to impaired <jats:styled-content style="fixed-case">ATP</jats:styled-content> synthesis. We report new candidate genes involved in abnormal brain bioenergetics in autism, supporting the hypothesis that mitochondria, critical for neurodevelopment, may play a role in autism.</jats:p>