Mitochondria and Autism PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015

Autism Neurodevelopmental disorder1 Symptoms emerge at age 2 or 3 impairments in social interactions communication difficulties repetitive behaviour Symptoms emerge at age 2 or 3 Causes? 1American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders American Psychiatric Association. Washington, DC, 471-475.

Mitochondria “Powerhouse of the cell”2 responsible for generating energy adenosine triphosphate (ATP) Oxidative phosphorylation occurs in inner membrane via Electron Transport Chain (ETC) Has its own genome (mitochondrial DNA) 2Rossignol, D. A., & Frye, R. E. (2012). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Molecular psychiatry, 17(3), 290-314.

Importance of Mitochondria in Brain Development Cells of brain require energy2 high density of mitochondria to support energy needs dysfunction? reduced neurotransmitter release and low firing rates (developmental delays) increased oxidative stress and damage from reactive oxygen species 2Rossignol, D. A., & Frye, R. E. (2012). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Molecular psychiatry, 17(3), 290-314.

Mitochondria Dysfunction and Autism Autistic patients with classical mitochondrial disease make up a total of 5% of autistic patients2 Co-occurrence suggests a pathogenic relationship Pathophysiology of mitochondrial disease stems from either genetic anomalies or environmental factors resulting in reduced mitochondrial function Patients exhibit symptoms common to mitochondrial disease including limb weakness, stroke-like episodes and cardiomyopathy in addition to further cognitive impairments and reduced brain development. 2Rossignol, D. A., & Frye, R. E. (2012). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Molecular psychiatry, 17(3), 290-314.

Mechanisms Relating Autism and Mitochondrial Disease Mitochondrial activation of immune system3 Loss of the mitochondria’s regulatory role will lead to immune-mediated mechanisms damaging brain development Abnormal mitochondrial calcium handling Upsetting Ca2+ homeostasis can further increase the ratio of excitatory to inhibitory neurotransmitters observed in the autistic population Oxidative Stress Inability to prevent damage caused from ROS produced 3Haas, R. H. (2010). Autism and mitochondrial disease. Developmental Disabilities Research Reviews, 16(2), 144–153.

Glutathione (GSH & GSSG) Adapted from lecture slides (2)

Biomarkers of Oxidative Stress Decrease in Reduced Glutathione (GSH)4 Increase in Oxidized Disulfide form (GSSG) GSH used up to deal with ROS Exceed GSH reductase capacity to restore GSH levels Export GSSG to maintain intracellular redox homeostasis 4Palmieri, L., Persico, A.M. (2010). Mitochondrial dysfunction in autism spectrum disorders: Cause or effect? Biochimica et Biophysica Acta 1797: 1130-1137 Inside cell Outside cell Adapted from lecture slides (2)

Biomarkers of Oxidative Stress Decrease in cysteine levels4 Oxidized glutathione exported out of cell -> net loss of glutathione Cysteine depleted to restore GSH levels Reaction gets pushed forward Adapted from lecture slides (2)

Biomarkers of Oxidative Stress Decrease in Superoxide Dismutase, Catalase & Glutathione Peroxidase4 Lipid peroxidation Excessive oxidative stress overload antioxidants Adapted from lecture slides (2)

Suramin Suramin. Digital image. Http://www.scmb.uq.edu.au/academicstaff/mcgeary/medicinal_chemistry.htm. N.p., n.d. Web.

Suramin First created to treat African sleeping sickness Indirectly blocks a cell’s mitochondrial signals Mice who received a shot of Suramin showed:5 Restoration of motor coordination Normal socializing Less brain abnormalities associated with autism compared to mice who received saltwater injection Still in research phase as it has potentially serious side effects in humans1 5Hughes, V. (2013, April 15). Drug linked to mitochondria treats mouse model of autism | Spectrum News – Autism Research News. Retrieved October 12, 2015, from https://spectrumnews.org/news/drug-linked-to-mitochondria-treats-mouse-model-of-autism/

Summary Autism: neurodevelopmental disorder (impairments in social interactions, communication difficulties and repetitive behaviour) Mitochondrion: generates energy in the form of adenosine triphosphate (ATP) and its dysfunction is associated with symptoms of autism due to high mitochondrial density in brain Possible Pathogenic relationship between autism and mitochondrial disease Possible interacting mechanisms include: increased immune activation, abnormal calcium handling and oxidative stress Decreased GSH levels (reduced form) Increased GSSG levels (oxidized form) Decreased cysteine levels Net loss of glutathione Decreased SOD, glutathione peroxidase, catalase levels Lipid peroxidation Suramin is currently being researched as a drug to treat autism Suramin blocks purine receptors on the cell surface that are indirectly controlled by mitochondria causing the cell danger response to end

References American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders American Psychiatric Association. Washington, DC, 471-475. Drug Treatment Corrects Autism Symptoms in Mouse Model. (2013, March 13). Retrieved October 12, 2015 from http://health.ucsd.edu/news/releases/Pages/2013-03-13-drug-treatment-corrects-autism-in-mouse-model.aspx Haas, R. H. (2010). Autism and mitochondrial disease. Developmental Disabilities Research Reviews, 16(2), 144–153. Hughes, V. (2013, April 15). Drug linked to mitochondria treats mouse model of autism | Spectrum News – Autism Research News. Retrieved October 12, 2015, from https://spectrumnews.org/news/drug-linked-to-mitochondria-treats- mouse-model-of-autism/ 100-Year-Old Drug Suramin Under Investigation as Autism Treatment. (2015, June 15). Retrieved October 12, 2015, from http://www.psychiatryadvisor.com/autism-spectrum-disorders/century-old-drug-suramin-autism- treatment/article/420072 Palmieri, L., Persico, A.M. (2010). Mitochondrial dysfunction in autism spectrum disorders: Cause or effect? Biochimica et Biophysica Acta 1797: 1130-1137 Rossignol, D. A., & Frye, R. E. (2012). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Molecular psychiatry, 17(3), 290-314.