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Dr. Wallace - Mitochondrial Genetics and Disease
- 1. A MITOCHONDRIAL ETIOLOGY OF COMPLEX DISEASES Why can’t we understand and cure the common diseases? Neuropsychiatric Disorders: Autism, ADHD, Schizophrenia, Bipolar Disease, Stress Response, Alzheimer Disease, Parkinson Disease, ALS, Multiple Sclerosis, Blindness, Deafness… Heart-Muscle: Cardiomyopathy, Myopathy, Chronic Fatigue… Visceral: Renal, Hepatic, Immunological… Metabolic: Diabetes, Obesity, Cardiovascular Disease… Cancer & Aging Western medicine has approached the common diseases primarily from an anatomical and Mendelian perspective, but Life = Anatomy + Energetics + Information Consequently, the role of bioenergetics and non-Mendelian bioenergetic inheritance has been largely ignored. Our hypothesis is that bioenergetic dysfunction lies at the nexus of the genetic and environmental “causes” of the “common-complex” diseases.
- 3. Information Flow in The Cell DNA Stored Genetic Information PROTEINS Yield Structure (skin, hair) Replication Transcription Translation Nucleus Cytoplasm mRNA + Ribosomes (interpreting structures) RNA Working Copy of Gene (message)
- 5. THE EUKARYOTIC CELL IS COMPOSED OF TWO ORGANISMS THE MITOCHONDRIA SPECIALZED IN ENERGY 1000s of mtDNAs + ~1500 nDNA genes
- 6. ENERGY: Fats + Sugars + Oxygen = Energy (heat + work) + CO2 + H2O REDOX BALANCE: Thiol-Disulfide Regulation of Pathways and Transcription Factors. REACTIVE OXYGEN SPECIES (ROS): Oxygen Radicals + Signal Transduction. Ca++ REGULATION: Regulates Cytosol Ca++, Metabolism, & mtPTP. APOPTOSIS: Energy ↓ + ROS ↑ = mtPTP Activated → Cell Death (Apoptosis). EPIGENOMIC REGULATION: Mito. (ATP, acetyl CoA, SAM, α-ketoglutarate) modify epigenome. MITOCHONDRIAL FUNCTION IS CENTRAL TO HEALTH ANT1 = heart, muscle, brain. ANT2 = systemic . NNT
- 7. THE MITOCHONDRIAL GENOME IS DISTRIBUTED ACROSS THE nDNA & mtDNA THE MITOCHONDRIAL GENOME: ~ 1500 nDNA Genes Dispersed Across the Chromosomes + 37 mtDNA Genes High Mutation Rate: ROS
- 8. THE BODY’S ANALTOMY IS DEFINED BY ENERGY Origin of Tissue-Specific Disease • Energy Utilizing Tissues: – Brain: High demand-Low reserve. ~2% body weight but uses ~20% of the O2. – Heart, Muscle, Renal, etc.: Constant demand-High reserve. • Energy Storage Tissues: – WAT: Energy storage for activities. – BAT: Energy storage for thermal regulation. • Energy Homeostasis Tissues: – Liver: Glucose homeostasis. • Energy Sensing Tissues: – Purpose: Monitor & adapt to seasonal plant carbohydrates – Pancreatic β Cells: Glucose abundant-Insulin signaling. – Pancreatic α Cells: Glucose limitation-Glucagon signaling.
- 9. A MITOCHONDRIAL ETIOLOGY OF COMPLEX DISEASES mtDNA Damage & Somatic Mutations ↓ENERGY,↑ ROS, Δ REBOX, Δ Ca++ PROGRESSIVE BIOENERGETIC DECLINE Apoptosis mtDNA Variants Ancient Adaptive Polymorphisms Recent Deleterious Mutations nDNA Variation Mutations Deleterious Mutations, Mito Gene Polymorphisms Epigenomics Histone Modifications, Signal Transduction, Redox Controls Neuropsychiatric Disorders ASD, Psychiatric Disorders AD, PD, Blindness, Deafness Cardiomyopathy Hypertrophic & Dilated Muscle Myalgia, Fatigability Renal Failure OXPHOS DYSFUNCTION Environmental Factors Energy Sources Carbohydrates, Fats, Amino Acids Energy Uses Growth, Maintenance, Reproduction Toxins Metabolic Type II Diabetes, Obesity Hypertension, CVD Stress Thermal, Trauma Aging Penetrance & Expressivity Delayed-Onset & Progression, Trauma & Sepsis, Inflammation & Immunity MS, Type I Diabetes (Tregs, DAMPs, NLRP3, TLRs, HMGB1) Infection Predisposition MAVS (mt αViral Siganls) Cancer Energy Production, ROS & Redox
- 10. mtDNA GENE MUTATIONS GIVE VARIABLE PHENOTYPES THE SAME mtDNA tRNALeu(UUR) np A3243G MUTATION CAUSES DIFFERENT DISEASES 10-30% Autism & Type I & II diabetes; > 70% mutation myopathy, cardiomyopathy & MELAS; ~100% Leigh Syndrome & perinatal lethality Lactic Acidosis Growth Retardation Dementia Stroke-Like Episodes Hypertrophic Cardiomyopathy Conduction Abnormalities + + + + + + + + + + + + + + + + + + + + + + + + + + - + + + + + + + + + + + + + ? ? + + - - ? ? ? ? Delta wave Wolf-Parkinson-White Conduction
- 11. MULTIPHASIC NUCLER RESPONSES TO CHANGING mtDNA 3243A>G HETEROPLASMY EXPLAINS PHENOTYPIC VARIAITON DIABETES & AUTISM 20-30% NEUODEGENERATION 50-90% NORMAL 0% LEIGH SYNDROME & PERINATAL LETHALITY 100% ρo
- 12. LEBER HEREDITARY OPTIC NEUROPATHY MATERNAL INHERITANCE, MALE BIAS, & BACKGROUND REGULATION OF EXPRESSIVITY Mutation 3460A 11778A 14484C Gene ND1 ND4 ND6 ~ % Patients Complex I Defect AA Cons % Hplgr J ND1 3394C 15 Severe Moderate ~10 - 50 Moderate Moderate 29 + 15 Mild Low 79 + Penetrance of Milder Mutations exacerbated by Haplogroup J or ND1 T3394C (Y30H) MATERNALLY INHERITED OPTIC NEUROPATHY, VARIABLE PENETRANCE, & 4:1 MALE BIAS mtDNA ND4 np 11778 G>A arginine 340 to histidine
- 13. ANCIENT mtDNA VARIANTS PREDISPOSE TO COMMON DISEASES mtDNA VARIATION CORRELATES WITH THE GEOGRAPHIC LOCATIONS OF INDIGENOUS PEOPLES. Groups of Related mtDNA Haplotypes (Haplogroups) were Founded by Adaptive Variants that Permitted Migration into New Environments. M Mutation rate = 2.2 – 2.9% / MYR Time estimates are YBP.
- 14. 769(12) 1018(12) 3594(ND1) 4104(ND1) 7256(COI) 7521(D) 13650(ND5) 10400(ND3) 14783(cytb) 15043(cytb) 8701(A59TATP6) 9540(COII) 10398(A114TND3) 10873(ND4) 15301(cytb) 825T(12) 2758(16) 2885(16) 7146(A415TCOI) 8468(ATP8) 8655(ATP6) 10688(ND4L) 10810(ND4) 13105(V257IND5) 13506(ND5) 15301(cytb) 12705(ND5) L0 L1 L2 L3 M N RM* G D C N*A X I W HVJTUR* rCRS B Nodal Founder mtDNA Mutations for Macro-haplogroup N ND3 G10398A A114T ATP6 G8701A A59T TRANSITIONAL HAPLOGROUPS FOUNDED BY FUNCTIONAL MUTATIONS Membrane Potential, Altered Ca++ Kazuno A et al., 2006, PloS Genet. 2:1167
- 15. NODAL SUBSTITUTIONS ALTERING CONSERVED AMINO ACIDS INITIATE EACH mtDNA HAPLOGROUP EUROPEAN HAPLOGROUPS T & J Hplgr Gene npΔ CI % Funct T ND2 4917A 90 ? J1 Cytb 14798C 79 Qi J2 Cytb 15257A 95 Qo
- 16. AD = 3.3%, PD = 5.3%, AD+PD = 6.8%, CNTL = 0.4% Haplogroup H5a One event = ancient polymorphism AD + PD ND1 A3397G Met 31Val Two independent events = recent deleterious mutation EUROPEAN ASSOCIATION OF tRNAGln A4336G & ND1 (M31V) WITH ALZHEIMER & PARKINSON DISEASE
- 17. ADAPTATIVE SELECTION 0 5 10 15 20 25 30 35 40 1000 2000 3000 4000 5000 M9relativefrequency 0 5 10 15 20 25 30 35 40 1000 2000 3000 4000 5000 T3394Crelativefrequency Lianhshan Gannan Qinghai Diqing Shigatse LhasaChamdo Nyingchi Shannan Nagchu Lianhshan Gannan Qinghai Diqing Shigatse Nagchu Lhasa Chamdo Nyingchi Shannan 0 5 10 15 20 25 30 35 40 1000 2000 3000 4000 5000 M9relativefrequency 0 5 10 15 20 25 30 35 40 1000 2000 3000 4000 5000 T3394Crelativefrequency Lianhshan Gannan Qinghai Diqing Shigatse LhasaChamdo Nyingchi Shannan Nagchu Lianhshan Gannan Qinghai Diqing Shigatse Nagchu Lhasa Chamdo Nyingchi Shannan M9 3394C L3 M8 M14 M11 D D5 M15 T3394C D4 M9 G M2 G2 T3394C T3394C G3b M13 A B F U1 B5 B4a C10400T M T10873C N L3 M8 M14 M11 D D5 M15 T3394C D4 M9 G M2 G2 T3394C T3394C G3b M13 A B F U1 B5 B4a C10400T M T10873C N mtDNA AMINO ACID SUBSTITUTIONS CAN BE POSITIVE OR NEGATIVE DEPENDING ON CONTEXT M [ND3 10398G (114A)] IS ENRICHED IN TIBET & [ND1 3394C (30H)] IS PATHOGENIC ON N BUT ADAPTIVE ON M IN TIBETANS
- 18. NADH:coenzymeQ1 oxidoreductase activity(nmolmin-1 mg-1 ) B4c 3394T 3515C B4c 3394CB4c 3394T F1 3394CF1 3394T M 9 3394C 0 50 100 150 200 250 THE ND1 3394C (30H) MUTATION CAUSES A COMPLEX I DEFICIENCY ON N HAPLOGROUPS B4 & F1, BUT IS DOES NOT IMPAIR COMPLEX I ON M HAPLOTYPE M9 B4c F1 M9 COMPLEX I SPECIFIC ACTIVITY P = 0.0006 P = 0.05 Blood Platelets X 143B (TK-) ρo + BrdU, - uridine Cybrids N M
- 19. ASSOCIATION BETWEEN mtDNA HAPLOGROUPS AND AUTISM SPECTRUM DISORDER RELATIVE TO HAPLOGROUP RO Illumina 550 GWAS data set. Generalized Linear Modeling Analysis Results with GEE Solution for the AGRE Family mtDNA SNPs Relative to R0 (H-HV-V) Continent Co-Variant Haplogro up Odds Ratio 95% Confidence Interval P-Value Benjamini- Hochberg Correction Europeans I 2.12 1.26-3.55 0.004 0.04 J 2.18 1.59-3.00 <0.001 <0.001 K 1.76 1.31-2.36 <0.001 0.002 T 1.79 1.30-2.46 0.003 0.004 U 1.98 1.45-2.71 <0.001 <0.001 W 1.41 0.81-2.45 0.22 0.89 X-O 2.00 1.23-3.25 0.005 0.04 Asians-N Amer A 1.83 1.32-2.53 <0.001 0.004 M 1.55 1.16-2.06 0.003 0.03 N+ 2.02 1.19-3.42 0.009 0.06 Africans L 1.01 0.63-1.61 0.98 0.98 Gender (Male) 3.93 3.3-4.67 <0.001 <0.001 (NALL=4041, NASD=1624, 933 families with 1-12 members) (reference haplogroup = HHV+, NALL=1792, NASD=712) Covariates: haplogroups, sex.
- 20. ASSOCIATIONS BETWEEN mtDNA HAPLOGROUPS & COMMON DISEASES • NEURODEGENERATIVE DISEASES – Autism – Alzheimer Disease – Parkinson Disease – Macular Degeneration – Familial Amyloidosis with Polyneuropathy – Migraine – Psychiatric Disorders • NEUROLOGICAL DISEASES – Stoke • METABOLIC DISEASES – Diabetes – Cardiovascular Disease – Metabolic Syndrome • INFLAMMATORY & INFECTIOUS DISEASES – Sepsis – IgE Levels – Asthma – AIDS progression – Anti-AIDS HAAT* Lipodystrophy – Osteoarthritis • AGING • CANCERS • ATHLETIC PERFORMANCE (L0>L3>N>H>J-U-T) * HAAT- highly active anti-retroviral therapy H > J = T > U (U* > U4 = U5a1 > Uk)
- 21. Leigh Syndrome Lactic Acidosis SN Deafness Epileptic Seizures Metabolic Failure Muscle Myopathy Cerebral atrophy Death Optic Atrophy Cerebellar Atrophy HETEROPLASMIC mtDNA MUTATIONS SEGREGATE RAPIDLY A HUMAN HETEROPLASMIC mtDNA ND6 G14600A P25L MUTATION SEGREGATES TO GIVE VARIOUS PHENOTYPES Malfatti –Zevani
- 22. MOUSE MODELS OF mtDNA DISEASE: ND6 = NEURODEGERATION COI = CARDIOMYOPATHY & METABOLIC SYNDROME 129 + NZB = NEUROPSYCHIATRIC DISEASE Mouse ND6 nt G13997A (P25L) = Human ND6 G14600A (P25L), COI nt 6589 T>C (V421A), & 129+NZB Heteroplasmy Disaggregate Female ES Cells: ND6 13997G>A (P25L) or COI nt 6589 T>C (V421A) mtDNA 129 +NZB Heteroplasmic mtDNAs ES Cell cybrids Pseudopregnant mother Female Chimera ND6 13997G>A (P25L), COI nt 6589 T>C (V421A), 129 + NZB Heteroplasmic mtDNA Mice Mouse Cell Line Mutants ND6 13997G>A (P25L) mtDNA, COI nt 6589 T>C (V421A) mtDNA, 129 + NZB mtDNA R6G 129 Mice
- 23. THE mtDNA ND6 P25L MUTATION RESULTS IN ELEVATED REACTIVE SPECIED (ROS) PRODUCITON AND NEUROLOGICAL DISEASE INCREASED ROS PRODUCTION, NORMAL ATP ALTERED EEGs NEURONAL DEGENERATION 7
- 24. Mitochondrial Myopathy Mitochondrial Cardiomyopathy THE COI V421A mtDNA MOUSE EXHIBITS MYOPATHY, CARDIOMYOPATHY & METABOLIC SYNDROME COI (6589T>C, V421A) MISSENSE MUTATION Glucose Level Time (min) BloodGlucose(mg/dL) 0 50 100 150 0 100 200 300 B6ME ND6 COI ** ** ** Insulin Level Time (min) PlasmaInsulin(ng/mL) 0 50 100 150 0.0 0.5 1.0 1.5 2.0 B6ME ND6 COI ** * * Glucose Intolerance & Insulin Resistance
- 25. 91 “129” vs “NZB” mtDNAs differences: 15 aaΔ +5 tRNA +7 rRNA + 11 CR MATERNAL TRANSMISSION OF NORMAL mtDNA HETERPLASMY M NW BamH A4276G 0 2000 4000 6000 8000 10000 12000 14000 16000 I I II I II I III II I II III I I I II III I I I II I I II III I I II I II IIIII I IIII II I III I II I I I I IIIIII I II I IIII II I I III Backcrossed 20 generations onto C57BL/6L nDNA. Permitted nZB-129 mtDNAs to segregate. Correlated mtDNA NZB-129 genotypes with behavior. CREATION OF NZB-129 HETEROPLASMIC MICE
- 26. 129-NZB mtDNA HETEROPLASMIC MICE ARE DEPRESSED & HAVE LONG TERM MEMORY DEFICITS NZB129 129 + NZB
- 27. MITOCHONDRIAL ALTERATIONS MODULATE NEUROENDOCRINE RESPONSES TO ACUTE STRESS Modulation Catecholamines: of the Sympathetic- Medullary Axis Modulation of Corticosterone: the Hypothalamic- Pituitary-Adrenal (HPA) axis
- 28. ANT1 MITOCHONDRIAL DYFUNCTION IMPAIRS INTERNEURON MIGRATION Excitation-Inhibition Imbalance May Cause Epilepsy, ADHD, Autism, Manic-Depressive Disorder, etc. Excitatory Glutamateric Neurons Migrate Radially while the Inhibitory GABAergic Interneurons Migrate Tangentially from the Medial Ganglionic Eminence (MGE). Cortical Function Requires Excitatory Glutamateric- Inhibitory GABAergic Neuronal Balance Interneurons Pyramidal Neurons Interneurons Pyramidal Neurons Partial Mitochondrial Defects Inhibit Tangential Inhibitory Interneuron Migration but not Radial Excitatory Neuron Migration
- 29. ANT1-/- IMPAIRS INTERNEURONAL MIGRATION = EXCITATION-INHIBITION IMBALANCE ANT1-ND6-NNT DEFICIENCY YIELDS AUTISM ENDOPHENOTYPES ANT1 Inhibitor Bongkrekic Acic (BA) Disorients Interneuron Migration ANT1-/- Inactivation Disorients Interneuron Migration Social Interactions
- 31. Thank You ENERGY IS LIFE Masha Lvova Grant MacGregor Meagan McManus Debbie Murdock Dan Mishmar Xilma Ortiz-Gonzalez Marin Picard Julia Platt Parsanth Potluri Eduardo Ruiz-Pesini Mark Sharpley Larry Singh Jesus Tintos Katrina Waymire Tal Yardeni CMEM, CHOP MAMMAG, UCI MEM, Emory Alessia Angelin Dimitra Chalkia Olga Derbeneva Weiwei Fan Sage Hancock Taosheng Huang Kierstin Keller Ryan Lin NIH, Autism Speaks, Simons Foundation UCI EE Peter Burke CHOP Stewart Anderson Jeff Golden Wayne Hancock Eric Marsh Ulf H. Beier Mount Sinai Cardiology Jagat Narula Taiwan Natl University Leeming Chuang Yi-Cheng Chang Third Military Med Schl, Chongqing Fuyun Ji Guisheng Qian Yaoli Wang Wake Forest University Lorna Moore Epigenomics, UCI Kristin Eckel-Mahan Satoru Masubuchi Paolo Sassone-Corsi DNA BioTech, S Africa Antonlle Olckers Novosibirsk, Russia Rem Sukernik