Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015...
-
Upload
martina-quinn -
Category
Documents
-
view
215 -
download
2
Transcript of Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015...
![Page 1: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/1.jpg)
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
![Page 2: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/2.jpg)
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.
![Page 3: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/3.jpg)
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.
![Page 4: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/4.jpg)
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.
![Page 5: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/5.jpg)
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.
![Page 6: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/6.jpg)
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.
![Page 7: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/7.jpg)
Glutathione (GSH & GSSG)
Adapted from lecture slides (2)
![Page 8: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/8.jpg)
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)
![Page 9: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/9.jpg)
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
![Page 10: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/10.jpg)
Biomarkers of Oxidative Stress
Decrease in Superoxide Dismutase, Catalase & Glutathione Peroxidase4
◦ Lipid peroxidation◦ Excessive oxidative stress overload antioxidants
Adapted from lecture slides (2)
![Page 11: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/11.jpg)
Suramin
Suramin. Digital image. Http://www.scmb.uq.edu.au/academicstaff/mcgeary/medicinal_chemistry.htm. N.p., n.d. Web.
![Page 12: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/12.jpg)
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/
![Page 13: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/13.jpg)
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
![Page 14: Mitochondria and Autism By: Luo Fei Liu, Earl Pacson, Jennifer Tse and Eun Hye Lee October 13, 2015 PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfab1a28abf838c9b397/html5/thumbnails/14.jpg)
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.