mitochondria and autism by: luo fei liu, earl pacson, jennifer tse and eun hye lee october 13, 2015...

Mitochondria and Autism

By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee

October 13, 2015

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

Autism• Neurodevelopmental disorder1

◦ 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)

Inside cell

Outside cell

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

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

Adapted from lecture slides (2)Reaction gets pushed forward

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

ReferencesAmerican 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.