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Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction
- 1. Richard E. Frye,M.D., Ph.D. Chief, Section on Neurodevelopmental Disorders Director of Autism Program Barrow Neurological Institute at Phoenix Children's Hospital Professor of Child Health University of Arizona College of Medicine Secondary Mitochondrial Dysfunction in Neurodevelopmental Disorders: Origins, Significance and Treatment
- 2. Every attempted hasbeen made to make this presentation as accurate as possible. The information is provided without any expressed or implied warranty. This presentation should not be substituted for medical advice. Treatments in this lecture are considered off- label and are not FDA-approved. Disclaimer Mitochondrial Dysfunction
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- 4. • Relatively newfield • First diseases described in 1988 • Wallace, Leber’s hereditary optic neuropathy, published in Science • Holt, Mitochondrial Myopathy, published in Nature • Usually defined by extremely clinical symptoms with a progressive course • High energy dependent tissues • Neurological Disease • Gastrointestinal Disease • Immune Dysfunction • Not just powerhouse, involved in • programmed (apoptotic) cell death • Oxygen Radical Regulation Mitochondrial Disease Mitochondrial Dysfunction
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- 9. Mitochondrial Dysfunction Now believedto that Mitochondrial Dysfunction is Important in Many Diseases
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- 12. Mol Psych 2012,17:290-314 Discrepancy between prevalence of diagnosed mitochondrial disease and prevalence of biomarkers of mitochondrial disease likely be due to criteria used to define mitochondrial disease Mitochondrial Dysfunction
- 13. • Lymphocytes from10 children with autism and 10 age and gender matched controls • 80% demonstrated abnormal function in at least one electron transport chain complex • 60% complex I abnormality • 40% complex V abnormality • 50% multiple complexes • 20% demonstrated abnormalities in cytB, a mitochondrial DNA gene Mitochondrial Dysfunction
- 14. Mol Psych 2012,17:290-314 ASD children with mitochondrial disease have more medical abnormalities than idiopathic ASD children Only 23% of ASD children with mitochondrial disease have mitochondrial DNA abnormalities Mitochondrial Dysfunction
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- 21. Seahorse Bioscience ExtracellularFlux Analyzer • Poly D lysine coated plates • 110k cells/well • Plated 1hr prior to assay • Seahorse DMEM • 11mM glucose • 2mM glutamax • 1mM pyruvate • DMNQ added directly to cells in plate • Each plate with an AD/ Control LCL pair Mitochondrial Dysfunction
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- 24. Cluster analysis reveals 2 significantly differentsubgroups. • AD-N (n=17) • AD-A (n=8) Mitochondrial Dysfunction
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- 28. Mitochondrial Dysfunction Mitochondrial Dysfunctionin Autism Mechanisms of Molecular Dysregulation
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- 32. Mitochondrial Dysfunction Mitochondrial Dysfunctionin Autism Effects of the Environment
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- 34. Mitochondrial Dysfunction inAutism -40 -20 0 20 40 60 80 0 5 10 15 OCR(pmol/min) DMNQ (uM) Reserve for Controls No ROS Prolonged ROS (D) -40 -20 0 20 40 60 80 0 5 10 15 OCR(pmol/min) DMNQ (uM) Reserve for AD-A No ROS Prolonged ROS (L) 96 hrs 1 hr Prolonged 1uM DMNQ Exposure Acute DMNQ Exposure 0 , 5 , 10, 15uM Seahorse Assay
- 35. Mitochondrial Dysfunction inAutism 1 hr TCAH Exposure 0mM, 0.1mM, 0.5mM, 1.0mM DMNQ Exposure 0uM, 5uM, 10uM Seahorse Assay 96 hrs
- 36. Mitochondrial Dysfunction 25% ofChildren with Autism also show abnormal Reserve Capacity This pattern of abnormal Reserve Capacity is distinct from children with classic mitochondrial disease
- 37. Mitochondrial Dysfunction Changes inMitochondrial Function in Childhood is Associated with Exposure to Air Pollution (PM2.5) during Gestation
- 38. Mitochondrial Dysfunction Mitochondrial Dysfunctionin Autism Effects of the Gut Microbiome
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- 40. Mitochondrial Dysfunction The microbiotainfluences physiology by Short chain fatty acids
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- 43. Autistic Children Rodents MitochondrialDysfunction
- 44. • 213 ASDpatients screened with acyl-carnitine biomarkers • 74 (35%) with >=3 fasting acyl-carnitine elevations • Acyl-carnitine abnormalities were confirmed in 48% • Corrected prevalence of 17% of ASD children screened. Mitochondrial Dysfunction
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- 57. 0.5 1.5 2.5 3.5 0 mM 0.1mM1.0 mM FoldChange Butyrate Concentration UCP2 (Oxidative Stress) p<0.001 0.5 1.0 1.5 2.0 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration mTOR (Metabolic Reg) p<0.001 0.5 1.0 1.5 2.0 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration HIF1a (Cellular Stress) p<0.001 0 10 20 30 40 50 60 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration PGC1α (Cellular Stress) p<0.001 0.5 1.0 1.5 2.0 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration CREB1 (Behavior) p<0.001 0 5 10 15 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration CamKinase II (Behavior) p<0.001 0.5 1.0 1.5 2.0 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration SOD2 (Oxidative Stress) p<0.001 0.5 1.0 1.5 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration NRF2 (Oxidative Stress) p<0.001 0.5 1.0 1.5 2.0 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration ANT2 (Oxidative Stress) 0.5 1.0 1.5 2.0 0 mM 0.1 mM1.0 mM FoldChange Butyrate Concentration AMPK (Metabolic Reg) p<0.001 0.5 1.0 1.5 2.0 0 mM 0.1 mM 1.0 mM FoldChange Butyrate Concentration SIRT1 (Metabolic Reg) 0.5 1.5 2.5 0 mM 0.1 mM 1.0 mM FoldChange Butyrate Concentration SIRT3 (Metabolic Reg) p<0.001 Mitochondrial Dysfunction
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- 63. Mitochondrial Dysfunction Examples ofGenetic Disorder
- 64. Mitochondrial Dysfunction Examples ofGenetic Disorder Down Syndrome
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- 70. Mitochondrial Dysfunction Examples ofGenetic Disorder Phelan-McDermid Syndrome
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- 74. Mitochondrial Dysfunction Examples ofGenetic Disorder WDR45
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- 82. Effect of aCombination of Carnitine, Coenzyme Q10 and Alpha-Lipoic Acid (MitoCocktail) on Mitochondrial Function and Neurobehavioral Performance in Children with Autism Spectrum Disorder Legido A, Goldenthal MJ, Garvin B, Damle S, Corrigan K, Connell J, Thao D, Valencia I, Melvin J, Khurana D, Grant M, Newschaffer CJ Objective: To determine if patients with ASD and mt dysfunction would improve clinically and/or biochemically on a combination of carnitine, coenzyme Q10 and alpha-lipoic acid (MitoCocktail) in an open-label pilot trial with a baseline-treatment-baseline design. Results: Mean buccal complex I/IV activity ratio was significantly (p<0.02) reduced during MitoCocktail treatment compared to baseline. All subjects showed at least one specific sign of metabolic improvement, which waned 3 months post-treatment in 7 of the 11 participants. Of the 11 total or subscale scores considered, all showed change in means from Time 1 to Time 2. Statistically significant changes were observed for the Unusual Behavior subscale from the ASRS (p<0.006), the Lethargy subscale from the ABC (p <0.01), and the Inappropriate Speech subscale from the ABC (p<0.02). From Time 2 to Time 3, scores worsened on each of these three subscales with statistically significant changes on Lethargy (p<0.01) and Inappropriate Speech subscales (p<0.007). Mitochondrial Dysfunction in Autism
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- 89. (Frye and Rossignol,2014) Mitochondrial Dysfunction in Autism
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