mitochondria, aging, & aids...
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Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
MITOCHONDRIA, AGING, & AIDSEnergyomics-Energenomics
LIFE = STRUCTURE + ENERGY + INFORMATION
SYMBIOSIS: EUKARYOTIC CELL = TWO ORGANISMS
Nucleus-Cytosol: Controls StructureMitochondrion:
Controls Energy
Mitochondria are bacterial symbionts, ~ 2 X 109
YBP.Each cell has 100s of mitochondria and 1000s mtDNA.
Sun Energy
2 H2
O to 4H
+ O2
Glucose
ATP + Heat
+ H2
O + CO2
CO2
O2 COLLABORATORSMAMMAG, UCI
Leo Alves
Michael BrownDimitra ChalkiaPinar CoskunOlga DerbenevaWeiwei FanMrie LottMarie LvovaDan Mishmar
Ufa Science Center, RussiaElza KhusnutdinovaU WashingtonGeoge Martin Peter RabinovitchUniversity Pochefstroom, S AfricaAntonlle
OlckersNovosibirsk, RussiaRem
SukernikBen Gurion, IsaelDan MishmarYaleGerald Shadel
UCI OphthalmologyCris
KeaneyTony NesburnNCISher hendricksonTom O’Brien
Prasanth PotluruVincent ProcaccioEduardo Ruiz-PesiniMark SharpleySam SchrinerKatrina Waymire
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
ENERGY: Fats + Sugars + Oxygen = Energy (heat + work) + CO2
+ H2
OREDOX BALANCE:
Thiol-Disulfide Regulation of Pathways and Transcription Factors.REACTIVE OXYGEN SPECIES (ROS): Mitochondrial Combustion → Oxygen RadicalCa++
REGULATION: Regulates Cytosol
Ca++, Metabolism, & mtPTPAPOPTOSIS: Energy ↓
+ ROS
↑
= mtPTP
Activated → Cell Death
(Apoptosis)
FIVE CENTRAL FACTORS IN MITOCHONDRIAL BIOLOGY
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
THE MITOCHONDRIAL GENOME & ITS GENETICS
THE MITOCHONDRIAL GENOME:~ 1500 nDNA Genes
Dispersed Across the Chromosomes 37 mtDNA
Genes
High Mutation Rate: ROS
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
ENERGY METABOLISM FLUCTUATES WITH SEASONAL AVAILABILITY OF SUGAR & FATS
Summer Winter
[Glucose] β α
W
GlycolysisGlycolysis
INSULINPI3, Akt, FOXO
GLUCAGON cAMP, CREB
Store Fat
Mobilize Fat Burn Fat
ATP
ATP
[Glucose}αβ
A T WAT
GLUCAGON
↑Mitochondria ↑Antioxidants
INSULIN
↓Mitochondria ↓Antioxidants
PGC1α
SIRT1
PPARγ
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
ANIMAL ENERGY ANATOMY: Origin of Tissue-Specific Disease
•
Energy Utilizing Tissues:–
Brain: Glucose or ketone
bodies–
Heart, Muscle, Renal, etc.: Glucose or fatty acids•
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 abundance-Insulin Signaling–
Pancreatic α
Cells: Glucose limitation-Glucagon Signaling
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
Tiss
ue c
ellu
larit
y
Young Middle Age Old Senescence
FunctionalThreshold
Model for Mitochondrial Role in Aging and Degenerative Diseases
Mitochondrial ROS
damage
mtDNApoint mutations-rearrangements
mtDNA mutant
amplification
mtPTPactivation
CellDeath
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
MITOCHONDRIAL ORIGIN AND PROGRESSION OF DISEASE
somatic mtDNA mutations (control region mutations)
OXPHOS INHIBITION
↑
ROS
mtDNA
VariantsAncient Adaptive Polymorphisms
Recent Deleterious Mutations
nDNA
Variants & EpigenomicsANT1POLG
TwinkleSUV3PPARγ
PGC-1α, βnDNA
Mito Polymorphisms
NeuropsychologicalBlindness, Deafness Stroke-Like Episodes
Dementias, Movement DisordersDepression, Schizophrenia
Autism Muscle
Myalgia, FatigabilityCardiovascular Vascular
RenalMitochondrial dysfunction
Environmental FactorsInhibitorsSmokingCyanide
Toxins, PesticidesStreptozotocin
ActivatorsBenzofibrateResveratrol
Roziglitazone
MetabolicDiabetes, Obesity
Lipids & CholesterolStress
Thermal, Radiation
AgingAging, Delayed-Onset & Progression,
Penetrance
& Expressivity
Inflammation, Immunity Asthma
Autoimmunity DiseaseInfection Predisposition
AIDS, Herpes, etcCancer
Breast, Prostate, Colon, ect.
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
LDYS pedigree
mtDNA
DISEASE WITH DELAYED
ONSET AND VARIABLE
EXPRESSIVITYGeneralized
Dystonia
& Leber’s
Hereditary Optic
Neuropathy (LHON)
due to a missense
mutation in ND6 at
np
14459
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
INFLUENCE OF mtDNA
BACKROUND ON EXPRESSION OF mtDNA
PATHOGENIC MUTATIONS: Milder Leber’s
Hereditary Optic Neuropathy (LHON) Mutations are Associated with Haplogroup
J
Mutation
14459A
3460A
11778A
14484C
10663C
Gene
ND6
ND1
ND4
ND6
ND4L
~ % Patients
Complex I Defect
AA Cons
% Hplgr
J
5 Very Severe
High
ND
15 Severe
Moderate
~10
50 Moderate
Moderate
29
15 Mild
Low
79
<1 Very Mild
Low
100
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
HUMAN MIGRATIONS & NON-RANDOM DISTRIBUTION OF mtDNA
VARIATION
Striking Discontinuities: Tropical Africa to Temperate Eurasia to Arctic Siberia
+/-, +/+, or -/-
= Dde I 10394 / Alu I 10397
* = Rsa I 16239Mutation rate = 2.2 –
2.9% / MYR
Time estimates are YBP.
M
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
NODAL AMINO ACID SUBSTITUTIONS IN EUROPEAN HAPLOGROUPS T & J
Hplgr
Gene npΔ
CI % Funct
T ND2 4917A 90 ?
J1 Cytb
14798C 79 Qi
J2 Cytb
15257A 95 QoPresented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
HAPLOGROUP J CONTROL REGION C295T VARIANT
REGULATES L-STRAND TRANSCRIPTION & mtDNA
COPY NUMBER
J1b J H
C242T+C295T C295T wt
233 nt
160 nt
Transcription templates
J1b J H
C242T+C295T C295T wt
233 nt
160 nt
Transcription templates
C242T C295T
233 - 260 276 - 303 418 - 445 523 - 551
C242T C295T
233 - 260 276 - 303 418 - 445 523 - 551
C242T C295T
233 - 260 276 - 303 418 - 445 523 - 551
Rel
ativ
e bi
ndin
g ef
ficie
ncy
wt-242 C242T wt-295 C295T
Rel
ativ
e bi
ndin
g ef
ficie
ncy
wt-242 C242T wt-295 C295T
0.00
2.00
4.00
6.00
8.00
10.00
12.00
1 2
Haplogroup
mtD
NA
/nD
NA
Rat
io
Protein–DNA complex
Free–DNA
wt-242 C295TC242T wt-295H-TFAM - + - + - + - +
Protein–DNA complex
Free–DNA
wt-242 C295TC242T wt-295H-TFAM - + - + - + - +
J H
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
ASSOCIATIONS BETWEEN mtDNA
HAPLOGROUPS & COMMON DISEASES
•
NEURODEGENERATIVE DISEASES–
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–
AIDS neuroretinopathy–
Anti-AIDS HAART*
Lipodystrophy–
Osteoarthritis•
AGING•
CANCERS•
ATHLETIC PERFORMANCE
(L0>L3>N>H>J-U-T)
H > J = T > U (Uother > U4 = U5a1 > Uk).
HAART-
highly active anti-retroviral therapy
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
mtDNA
HAPLOGROUPS MODULATE AIDS PROGRESSION
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
mtDNA
HAPLOGRUP J IS PROTECTIVE FOR AIDS
NEURORETINAL DISORDER
•
HR = Hazard Ratio
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
HAPLOGROUPS U5a1 AND H3 AS WELL AS J ARE PROTECTIVE FOR AIDS ASSOCIATED NEURORETINAL
DISORDER
•
Risk of Neuroretinal
disease among patients previously studied for AIDs
progression
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
mtDNA
HAPLOGROUP H IS AT INCREASED FOR HAART-INDUCED LIPOATROPHY
•
HAART = Highly Active Antiretroviral Therapy
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
ENVIRONMENT
CALORIES (Hs)
Carbohydrates
Fatty Acids
STRESSORS
Energy depletion Temperature Hypoxia
Oxidative stress
Infection
BIOENERGETIC SYSTEMS BIOLOGYEnergetics
REDOX
mtDNA10s of genesMUTATIONS
regulation
nDNA1000s of genes
mutationsREGULATION
(EPIGENOMICS)
BIOENERGETICS AS THE INTERFACE BETWEEN GENES & ENVIRONMENT
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
BIOENERGETICS MODULATES THE EPIGENOME & SIGNAL TRANSDUCTION
High Energy Intermediates Mediate Environmental-Cellular Interactions
ATP, Acetyl-CoA, NAD+, SAM, Redox
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
HIGH ENERGY SUBSTRATES MODIFY THE HISTONE
EPIGENOME
List and sites for Histone-Modifying Enzymes, created by Kosi
Gramatikoff, Wikipedia, User:kosigrimPresented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
MITOCHONDRIAL REDOX REGULATES CELLULAR METABOLISM & SIGNAL TRANSDUCTION
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
ENERGY FLUCTUATIONS(SEASONS)
ENERGY ENVIRONMENTS
(REGIONS)
ENERGY RESERVOIRS
(NICHES)
HUMANCOMPLEX DISEASES
EPI-
GENOMEPr
otei
n +
DN
A M
odifi
catio
ns
Chr
omat
in +
Sig
nalin
gH
igh
Ener
gy S
ubst
rate
sAnatomy+
Energy
nDNAQuantizedGenetics
Energy
mtDNAQuantitative
Genetics
BIOENERGETICS IN EVOLUTION & DISEASE
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
Presented at the 1st Int. workshop on HIV & Aging, 4 – 5 Oct. 2010, Baltimore, USA
Thank You
ENERGY IS LIFE
Presented at the 1st
Int. workshop on HIV & Aging, 4 –
5 Oct. 2010, Baltimore, USA
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