mitochondria, aging, & aids...

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


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


THE MITOCHONDRIAL GENOME & ITS GENETICS

THE MITOCHONDRIAL GENOME:~ 1500 nDNA Genes

Dispersed Across the Chromosomes 37 mtDNA

Genes

High Mutation Rate: ROS


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


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


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


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.


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


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


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





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




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





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


mtDNA

HAPLOGROUPS MODULATE AIDS PROGRESSION


mtDNA

HAPLOGRUP J IS PROTECTIVE FOR AIDS

NEURORETINAL DISORDER

•

HR = Hazard Ratio


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


mtDNA

HAPLOGROUP H IS AT INCREASED FOR HAART-INDUCED LIPOATROPHY

•

HAART = Highly Active Antiretroviral Therapy


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


BIOENERGETICS MODULATES THE EPIGENOME & SIGNAL TRANSDUCTION

High Energy Intermediates Mediate Environmental-Cellular Interactions

ATP, Acetyl-CoA, NAD+, SAM, Redox





HIGH ENERGY SUBSTRATES MODIFY THE HISTONE

EPIGENOME

List and sites for Histone-Modifying Enzymes, created by Kosi

Gramatikoff, Wikipedia, User:kosigrimPresented at the 1st



http://en.wikipedia.org/wiki/Histone-Modifying_Enzymes

http://en.wikipedia.org/wiki/User:Kosigrim

http://upload.wikimedia.org/wikipedia/en/5/57/NucleosomeKG.jpg


MITOCHONDRIAL REDOX REGULATES CELLULAR METABOLISM & SIGNAL TRANSDUCTION





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





Thank You

ENERGY IS LIFE




mitochondria, aging, & aids...

Documents