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Mitochondrial Function Decline and Oxidative Stress in Human Aging
(人體老化過程中的粒線體能量代謝功能衰退與氧化壓力 )
Yau-Huei Wei ( 魏耀揮 )Department of Biochemistry and Mol
ecular BiologyNational Yang-Ming University
Taipei, Taiwan 112October 31, 2007
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Biochemical basis of aging
• Accumulation of oxidative damage during aging
• During aging, oxidative damage to biological macromolecules are accumulated. These include:– Peroxidation of lipids– Formation of protein carbonyls– Various forms of damage to DNA
• Macromolecular damage can cause malfunction of organelles, particularly the mitochondria
• It can also lead to necrosis and apoptosis of cells
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The metabolic rate of a species ultimately determines its life
expectancy
Metabolism Aging
This relationship was described about a century ago
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Relationship between body weight (W) and maximum life
span (MLSP) in mammals and birds
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Relationship between MLSP and liver catalase activity
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Relationship between MLSP and liver GPx activity
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Relationship between MLSP and brain selenium-dependent
GSH-peroxidase in vertebrate species including birds
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Relationship between MLSP and lung GSH-reductase activity in vertebrate species
including birds
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Relationship between H2O2 production by liver mitochondria and MLSP in mammalian species
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Overview of mitochondria
100 to 1000 mitochondri
a
2-10 copies of mtDNA
Electron transport chain
Mitochondrial DNA
Cell Mitochondrion
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生
III
IIIIV
V
ROS
e-
H+c
Apoptosis
ATP
Q
c
Mitochondrial theory of agingOxidative phosphorylation 老
病 死Mitochondrial disease
Parkinson’s diseaseAlzheimer’s disease
Diabetes and metabolic syndrome
Cancer
Beta-oxidation of fatty acids
Heme synthesisSteroid hormone synthesis
Urea cycle
ROSOxidative damage
Dysfunctional macromolecules
Vicious cycle
生
III
IIIIV
V
ROS
e-
H+c
Apoptosis
ATP
Q
c
Mitochondrial theory of agingOxidative phosphorylation 老
病 死Mitochondrial disease
Parkinson’s diseaseAlzheimer’s disease
Diabetes and metabolic syndrome
Cancer
Beta-oxidation of fatty acids
Heme synthesisSteroid hormone synthesis
Urea cycle
ROSOxidative damage
Dysfunctional macromolecules
Vicious cycle
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Scientific American 1996
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The majority of intracellular ROS is derived from the mitochondrial
respiratory chain
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Free-radical theory of aging
• First proposed in the mid-1950s
• Proposed by Dr. Denham Harman
• Endogenous oxygen radicals are generated in cells and result in cumulative damage to tissue cells
• Identification of superoxide dismutase (SOD) by Dr. Irwin Fridovich
Metabolism AgingROS
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The targets of ROS and free radicals are random, indiscriminative and
cumulative
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The common deletionthat is related to aging
Naked and compact Maternally inherited
Vulnerable to damage & mutation
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Mitochondria play a role in aging and age-related diseases
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The 4977 bp deletion of mtDNA in aging human liver
Yen TC et al. (1994) Free Radic Biol Med 16:207-214
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A 13-bp direct repeat flanking the 4977 bp deletion of mtDNA
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The strategy for the determination of multiple mtDNA deletions by long-range PCR techniques
Kao SH et al. (1998) Mol. Human Reprod. 7:657-666
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Long-range PCR products amplified from mtDNA with large-scale deletions
Kao SH et al. (1998) Mol. Human Reprod. 7:657-666
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Primer-shift PCR and corresponding products amplified from mtDNA with 4977 bp deletion
Kao SH et al. (1998) Mol. Human Reprod. 7:657-666
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Large-scale deletions of mtDNA are accumulated in old human brain
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Yang JH (1996) Arch. Dermatol. Res. 287:641-648
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1
Yang JH (1996) Arch. Dermatol. Res. 287:641-648
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Fahn HJ et al. (1996) Am. J. Respir. Crit. Care Med. 154:1141-1145
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Large-scale deletion and oxidative damage of mtDNA increase exponentially in the human heart during aging
Age (year)
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Experimental evidence supporting the occurrence and accumulation of different
mtDNA mutations in human skeletal muscle during ageing
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Somatic mtDNA mutations in human aging
• Point mutations, deletions and tandem duplications of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during aging in humans, monkeys and rodents.
• These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle, liver and brain.
• These finding have provided great support of the “mitochondrial theory of aging”.
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Wei YH et al. (1998) Ann. N.Y. Acad. Sci. 854:155-170
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Science (1999) 286,774-779
Science (1999) 286:774-779
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Science (1999)286,774-779
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Science (1999) 286:774-779
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Nature Genet. (2006) 385:515-517.
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Respiratory chain deficiency and analysis of mtDNA deletions in substantia nigra neurons
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Characterization and quantification of mtDNA deletion in substantia nigra neurons from individuals with Parkinso
n disease and from age-matched controls
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Somatic mtDNA mutations
Reactive oxygen species
Oxidative DNA damage
Aging phenotypes
?
Overproduction of ROS results in DNA damage and aging
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Nature (2004) 429:417-423
Hair loss and curvature of the spine in mutant mice
Kyphosis (curvature of the spine)
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Reduced subcutaneous fat in mutant mice
Nature (2004) 429:417-423
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Deletion and depletion of mtDNA in the POLG mutant mice
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Somatic mtDNA mutations
Aging phenotype
sOxidative stress
Oxidative damageMitochondrial dysfunction
Apoptosis
?
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Mitochondrial role in apoptosis
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Science (2005) 309:481-484
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Science (2005) 309:481-484
Hair loss and grayingkyphosis
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Caspase 3 activation in aging
Science (2005) 309:481-484
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Caspase 3 activation in D275A mice
Science (2005) 309: 481-484
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Increased apoptosis in mutant mice
Science (2005) 309:481-484
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Somatic mtDNA mutations
Reactive oxygen species
Oxidative DNA damage
Aging phenotypes
Apoptosis
Apoptosis induced by ROS may also play a role in aging
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Mitochondrial roles in human aging
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Apoptotic features in the mutant cybrid 51-10 harboring 4977 bp-deleted mtDNA after treating with STS or UV
irradiation
Ann. N.Y. Acad. Sci. (2004) 1011:133-145
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Cell viability was decreased in the cybrids with mtDNA deletion compared to the cybrids
harboring wild-type mtDNA after exposure to UV irradiation
Cybrid lines
Lin 0 Lin 2
Viab
ility (%
)
0
10
20
30
40
50
60
70 (A)
Cybrid lines
1-3-16 51-10
Viab
ility (%
)
0
10
20
30
40
50 (B)
Cybrid lines
Lin 0 Lin 2
Viab
ility (%
)
0
10
20
30
40
50
60
70 (A)
Cybrid lines
1-3-16 51-10
Viab
ility (%
)
0
10
20
30
40
50 (B)
Lee CF et al. (2005) Ann. N.Y. Acad. Sci. 1042:429-438Mutant cybrids: 51-10 & Lin 2
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Cybrid clones
1-3-16 51-10
Cas
pase
3 a
ctiv
ity (U
x10
-2/
g pr
otei
n)
0
50
100
150
200
250
ControlQ10
UVQ10+UV *
*
Cybrid clones
Lin 0 Lin 2
Casp
ase
3 ac
tivity
(Ux1
0-2
/g
prot
ein)
0
50
100
150
200
250
300
350
ControlQ10
UVQ10+UV
*
(A) (B)
Coenzyme Q10 attenuates UV-induced apoptosis in cybrids harboring 4977 bp- and 4366 bp-deleted mtDNA
n=3, *p < 0.05
Mutant cybrids: 51-10 & Lin 2 Lee CF et al. (2005) Ann. N.Y. Acad. Sci. 1042:429-438
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Nature (2000) 408:239-247
ROS damages various cell components and triggers the activation of specific signaling
pathways
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Nature (2000) 408:239-247
A number of signaling pathways are tightly regulated by ROS
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cDNA microarray for aging study
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Science (1999) 285:1390-1393
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Science (1999) 285:1390-1393
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Nature Genet (2000) 25:294-297
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Nature Genet (2000) 25:294-297
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Two interventions to reduce the rate of the aging process
• Caloric restriction– Restriction of nutrient intake to 60-70%
that of voluntary levels slows down aging in many organisms
• Alleviation of oxidative stress– Slows down aging by decreasing
oxidative stress
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CCD-966SKSkin fibroblasts
H2O2 treatment for 90 min
incubated for 7 days
Senescence phenotype
Control Senescence
Increase in the proportion of -galactosidase positive skin fibroblasts after H2O2 treatment
A good cell model for molecular biological studies of aging in vitro
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C 24hr 48hr 72hr
GAPDH
p-p53
-actin
p53
p21
MDM2
Rb
MDM2p53
p21
cyclin E
CDK2
Rb
P
PP
P
Rb E2F
H2O2 treatment
Increase in the p53 and p21 protein expression in H2O2-induced cellular senescence-like
phenotype
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Rb
Cyclin A
GAPDH
-actin
p53
p21
MDM2C S
control
24hr
48hr
72hr
Control 24 hr 48 hr 72 hr
Sub G0 1.55 1.37 1.01 0.63
G1 73.13 73.68 75.53 81.95
S 4.55 4.30 5.15 4.11
G2/M 19.10 18.59 16.37 11.75
H2O2-treatment
H2O2-induced cellular senescence resulting in cell cycle arrest at G1 phase
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Oxidative stress effect on mitochondria and nucleus
H2O2
mitochondrion
nucleus
• mitochondrial membrane potential• cytochome c oxidase activity
ROS
p53-dependent cycle arrest at G1 phase
Senescence
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ROS
C 24 hr 48 hr 72 hr
H2O2 treatment
P-PKBThr308
GAPDH
Akt
FOXO3aP
FOXO1P
Catalase
P
MnSOD
p53
FOXO family, the downstream of Akt, regulates the antioxidant enzymes under oxidative stress
ROS Senescence
0
20
40
60
80
100
120
140
160
Control 24hr 48hr 72hr
250 M H2O2 treatment
DC
F r
elat
ive
inte
nsity
n=3
0
20
40
60
80
100
120
140
160
Control 24hr 48hr 72hr
250 M H2O2 treatment
DC
F r
elat
ive
inte
nsity
n=3
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0.0
0.2
0.4
0.6
0.8
1.0
1.2
Control Senescence
The mRNA level of catalase
Rel
ativ
e ra
tio (
%)
C S O A C E
C : controlS : senescenceO : oligomycinA : antimycin AC : CCCPE : EtBr
Down-regulation of catalase in cells with mitochondrial dysfunction
GAPDH
Treatment for 3 Days
catalase
*
n=2 , *: P < 0.05
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Why the expression level of catalase, a crucial
detoxification enzyme is decreased by H2O2?
Catalase promoter assay
Akt-mutated Foxo1-mutated
Down-regulation of catalase by ROS via PKB signaling in mesanglia cells
J. Cell. Physiol. (2007) 211(2):457-467.
Akt
FOXO1P
catalaseexpression
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GAPDH
MnSOD
Catalase
N1 N2 N3 N4 N5 N6
1.0 1.5 1.7 1.3 0.9 0.8
1.0 1.4 1.2 1.1 1.5 1.7
GAPDH
MnSOD
Catalase
N1 M1 M2 M3 M4 M5
1.0 1.2 0.7 0.7 0.9 0.7
1.0 1.7 2.0 2.2 2.5 2.3
Differential expression of antioxidant enzymes in skin fibroblast of different ages
Normal subjects MERRF patients
Age Age
MnSOD was up-regulated but catalase was not changed in such a manner
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When MnSOD is over-expressed without concurrent increase in catalase (CAT) or glutathione peroxidase (GPx), the accumulated H2O2 can be converted to the far more reactive .OH radicals via Fenton reaction in the affected cells.
·OH
NADH .O2- H2O2 2 H2O
2GSH GSSG
MnSOD
CAT
Defective ETC
O2
GPx
H2O + ½ O2
Over-expression of Mn-SOD leads to accumulation of H2O2
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C 24hr 48hr 72hr
GAPDH
C S
PDH
GAPDH
PDH
H2O2 treatment
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Control Senescence
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Control Senescence
The RNA level of PDH
Rel
ativ
e ra
tio (
%)
Rel
ativ
e ra
tio (
%)
Changes in the PDH and PDK expression during cellular senescence
The RNA level of PDK
PDK
The protein level
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Current Opinion in Cell Biology (2006) 18:598-608
Regulation of glucose metabolism by glycolysis and oxidative phosphorylation in human cells
2 ATP / glucose
36 ATP / glucose
Glycolysis
OXPHOS
Plasma membrane
Mitochondria
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Down-regulation of pyruvate dehydrogenase in aging
Acta Biochim. Pol. (2005) 52:759-764
Active
Inactive
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Control Senescence
The mRNA level of PDH
Rel
ativ
e ra
tio (
%)
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Cancer Res. (2006) 66: 8927-8930
Signaling molecules regulating glucose metabolism in cells with mitochondrial dysfunction or mtDNA
mutations
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Metabolic alterations in cells of aging tissues
Mitochondrion
ROS
Nucleus
PI3K/Akt
FOXO1
Catalase
PDH
PDK
Pyruvate HIF
?
Repair system
+ SenescenceLDH
Lactate
Oxidative damage
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Extension of life span by caloric restriction in animals
Scientific American 1996
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Reduction of food intake decelerates aging
Scientific American 1996