Compartmentation of oxidative stress defense in...

Compartmentation of oxidative stress

defense in mitochondria:

Implications of drug toxicity

Dean P. Jones, Ph.D.Department of Medicine/Division of Pulmonary, Allergy

and Critical Care Medicine

Emory University, Atlanta

Emory Clinical Biomarkers Laboratory

EMORYSCHOOL OF

MEDICINE

What actually

happens?What is possible?

Redox Systems Biology applies quantitative principles to the

possibilities within the context of the entire biologic system

Critical transition for mechanistic toxicology:

translation of possibilities (done in vitro in a short time)

into realities (what happens in humans over decades)

Critical transition for mechanistic toxicology: translation of possibilities (done in vitro in a short time)into realities (what happens in humans over decades)

A small fraction of the mitochondrial electron currency

causes toxicity

DP Jones, Chem-Biol Interact 2006

NADH

CoQ

Cyt c

O2

-400

-200

0

+200

+400

+600

Metabolic Redox Circuits

ATP production

Eh

Pyr

Mal

Succinate

MnSOD

Radical-mediated

Macromolecular

damage

A small fraction of the mitochondrial electron currency

causes toxicity


NADH

CoQ

Cyt c

O2

-400

-200

0

+200

+400

+600


ATP production

Eh

Pyr

Mal

Succinate

MnSOD

Radical-mediated

Macromolecular

damage

Concept of ROS as

unavoidable consequence

of aerobic life

A small fraction of the mitochondrial electron currency is

used for signaling and control functions


NADH

CoQ

Cyt c

O2

GR

GSH

-400

-200

0

+200

+400

+600

Redox Signaling and Control Circuits

(low flux)


(high flux)

ATP production

Eh

Pyr

Mal

SuccinateMPT

TR2

Trx2

O2

NADPH

GPx Prx3

H2O2

PrSSGGrx2

Metabolic

substrates

ASK1

MnSOD

Non-Radical

mechanisms of

redox signaling

and control

A small fraction of the mitochondrial electron currency is

used for signaling and control functions


NADH

CoQ

Cyt c

O2

GR

GSH

-400

-200

0

+200

+400

+600


(low flux)


(high flux)

ATP production

Eh

Pyr

Mal

SuccinateMPT

TR2

Trx2

O2

NADPH

GPx Prx3

H2O2

PrSSGGrx2

Metabolic

substrates

ASK1

MnSOD

Non-Radical

mechanisms of

redox signaling

and control

ROS are products of

respiration which

function in signaling

and control

Imbalance in prooxidant and

antioxidant reactions

Macromolecular

damageDisruption of thiol redox

signaling and control

Free Radicals Non-radical Oxidants

Free radical mechanisms

of oxidative stressNon-radical mechanisms

of oxidative stress

1000

900100

9991

99

Efficient

scavenging

Jones 2008 “Radical-Free Biology of Oxidative Stress” AJP Cell Physiol 295:849-868

H3C COOH

H3C

H3C

H3C CO

H3C

H3C

+ CH3

C = O

H3C

H3C

H3C C OH

H3C

H3C

Acetone

t-Butanol

t-Butylhydroperoxide

Methyl radical

2 e-

1 e-

99.98%

0.02%

Tribble et al, Mol Pharm 1988

TBH toxicity involves non-radical mechanisms affecting

mitochondria

Redox Signaling

(Physiologic)

Redox Sensor

Sulfur Switches

ROS/RNS

Redox Messenger

Macromolecular

Targets

ROS/RNS

Toxic Species

Imbalance between

Oxidants/Antioxidants

NADPH oxidase

NO synthase

Oxidative Stress

(Toxicologic)

PhysiologicToxicologic

Thiol redox sensors are sensitive targets of non-radical oxidants

Prooxidants

Antioxidants

1. Imbalance of antioxidants and prooxidants does not explain major

features of oxidative stress

Jones Antiox Redox Signal, 2006

2. Redox signaling and control occurs through discrete molecular circuits

3. Disruption of redox circuitry provides a better conceptual framework to

define oxidative stress

5c

GSH/GSSG(differentiation)

12

9

7a

7b

7c

8

Eh

(mV

)

GSH/GSSG(apoptosis)

4

GSH/GSSG(proliferation)

Trx /SS

-300

-200

-150

-250

-300

-200

-150

-250

Cys/CySS

ROSROS SO, O 2 TO, O 2

3

6

5a

5b

5c

GSH/GSSG(differentiation)

112

9

7a7a

7b7b

7c7c

8

h(m

V)

GSH/GSSG(apoptosis)

4

Electron

donor

Electron

acceptor

NADPH

Redefining Oxidative Stress:

Disruption of thiol systems involved in redox signaling and control

Jones Meth Enzymol 2002

GSHGSSG

Redox states of different couples can be compared in terms of

Nernst redox potentials, i.e., balance can be measured

Eh = Eo + * ln[Ox]_

[Red]

RT

nF

DTT H2O2 0 24 48 h

Ox1

Ox2

Red

Go et al 2007

Trx-1

Calculate from GSH and GSSG, Cys and CySS or redox western

blots of proteins (thioredoxins, PDI, etc)

Biologic Redox Potentials: Steady-state Eh

values from about -400 to +600 mV

-400 0 +200 +600

Most reduced Most oxidized

Mitochondrial ET chain



-400 0 +200 +600



GSH/GSSG



-400 0 +200 +600



Pr-SH

GSH/GSSG



-400 0 +200 +600



Pr-SH

GSH/GSSG

NA

DP

H

NADPH/NADP+

mtGSSG reductase

Prx5 Ask1Prx3 PT pore,

other proteinsGrx2mtGpx1 mtGpx4

NDH, other

proteins

Cyt c

ROOH ROOH ROOHROOH ROOH

GSSGGSH

Trx2(SH)2 Trx2(SS)

TrxR2(red) TrxR2(ox)

Mitochondrial Thiol/Disulfide Redox Pathways

Reduced f

orm

(%

)

100

50

0

TR

2

Trx

2

Prx

3

NA

DP

H

-Glc,-Gln

0 24 h

TrxR2Red

Prx3Red

Trx2Red

Trx2Ox

Reduction

by TCEPTrxR2Red

Vs.TrxR2Red

/totTrxR2

Trx2Red/Trx2Ox

Reduction

by TCEPPrx3Red

Prx3Red

/totPrx3Vs.

Quantitation by redox western blot

100

50

0

TR

2

Trx

2

Prx

3

NA

DP

H

-Glc,-Gln

Reduced f

orm

(%

)

0 24h

Thiol/disulfide redox control pathway

NADPH TrxR2 Trx2 Prx3 H2O2

Redox states of components in pathway provide

information on sites of rate limitation

Reduced f

orm

(%

)

100

50

0

TR

2

Trx

2

Prx

3

NA

DP

H

-Glc,-Gln

0 24 h

TrxR2Red

Prx3Red

Trx2Red

Trx2Ox

Reduction

by TCEPTrxR2Red

Vs.TrxR2Red

/totTrxR2

Trx2Red/Trx2Ox

Reduction

by TCEPPrx3Red

Prx3Red

/totPrx3Vs.

Quantitation by redox western blot

100

50

0

TR

2

Trx

2

Prx

3

NA

DP

H

-Glc,-Gln

Reduced f

orm

(%

)

0 24h

Thiol/disulfide redox control pathway

NADPH TrxR2 Trx2 Prx3 H2O2

v2 v3 v4 v5

Rate

limitation

v1

Trx2 and GSH support parallel, non-redundant functions

in mitochondria

Via

bili

ty (

%)

Mock WT C93S

tBH

Mock WT C93S Mock WT C93S*

TNF TNF +BSO

**

0

20

40

60

80

*

*

*

Trx2C93S to inhibit Trx2, BSO to deplete GSH

Nuc Trx1

Oxidized

Mitochondrial are the most

reduced compartment in cells;

most susceptible to oxidation

Ste

ady-

Sta

te R

edox P

ote

ntial

(Eh

, m

V)

Reduced

-210

-180

-150

-120

-90

-60

-330

-300

-270

-240

-360Mito Trx2

Mito GSH/GSSG

Cyto GSH/GSSG

Cyto Trx1

Cyto Cys/CySS

Plasma GSH/GSSG

Plasma Cys/CySS

ER GSH/GSSG

Chen et al 2006

Kemp et al, 2008; Jones, 2008

µM tBH0 50

Trx1R

Trx1O

Trx2R

Trx2O

Y Chen et al FEBS Lett 2006

Mito

Cyto

143B cells

+ t-Butyl Hydroperoxide

Nuc Trx1

Oxidized

Mitochondrial are the most

reduced compartment in cells;

most susceptible to oxidation

Ste

ady-

Sta

te R

edox P

ote

ntial

(Eh

, m

V)

Reduced

-210

-180

-150

-120

-90

-60

-330

-300

-270

-240

-360Mito Trx2

Mito GSH/GSSG

Cyto GSH/GSSG

Cyto Trx1

Cyto Cys/CySS

Plasma GSH/GSSG

Plasma Cys/CySS

ER GSH/GSSG

Trx-1

(Cyto)

xTrx-2

(Cyto)

Trx-2

(Mito)

H2O2 ( M)

0 20 50 100 200 300

Chen et al 2006

Kemp et al, 2008; Jones, 2008

Nuc Trx1

Oxidized

Redox signaling can occur

selectively in mitochondria

Ste

ady-

Sta

te R

edox P

ote

ntial

(Eh

, m

V)

Reduced

-210

-180

-150

-120

-90

-60

-330

-300

-270

-240

-360Mito Trx2

Mito GSH/GSSG

Cyto GSH/GSSG

Cyto Trx1

Cyto Cys/CySS

Plasma GSH/GSSG

Plasma Cys/CySS

ER GSH/GSSG

TNF (ng/ml)

HeLa cells

Trx1

-280

-260

-240

Eh

(mV

)

Red

0 5 10 20 40 H2O2

Ox

Trx2

0 5 10 20 40 H2O2

-360

-320

-280

RedOx

Eh

(mV

)

J Hansen et al 2006

+TNF

Mitochondrial oxidative stress: Disruption of thiol signaling

and control functions by non-radical oxidants


NADH

CoQ

Cyt c

O2

GR

GSH

-400

-200

0

+200

+400

+600


(low flux)


(high flux)

ATP production

Eh

Pyr

Mal

SuccinateMPT

TR2

Trx2

O2

NADPH

GPx Prx3

H2O2

PrSSGGrx2

Metabolic

substrates

ASK1

MnSOD

Radical-mediated

Macromolecular

damage

Non-Radical

mechanisms:

Altered signaling

and control

Minor

Major

tBH None Mal

Red

OxTrx2

Deficient precursors for NADPH supply causes greater

oxidation of Trx2 than mitochondrial respiratory inhibitors

None AA

Trx

2, E

h (m

V)

Media deficient in

Energy precursors

None AA

-360

-320

-280

-240

Control media

Isolated

Mitochondria

Cells


NADH

CoQ

Cyt c

O2

GR

GSH

-400

-200

0

+200

+400

+600


(low flux)


(high flux)

ATP production

Eh

Pyr

Mal

SuccinateMPT

TR2

Trx2

O2

NADPH

GPx Prx3

H2O2

PrSSGGrx2

Metabolic

substrates

ASK1

MnSOD

Radical-mediated

Macromolecular

damage

Metabolic

substrate

availability

Minor

Major

Inhibition of

respiratory

chain

X

X

Deficient precursors for NADPH supply may be more

critical for toxicity than inhibition of respiration

N Adimora et al (2010) ARS in press

Computational model for metabolism of exogenously added H2O2

100 µM

Jurkat cells, 28 kinetic parameters, 24 molecular species

Catalase

<1%90 nM

Gpx

44%

Prx

32%

Protein

oxidation

23%

% Flux of peroxide

GS-

<1%

-SS-

22%

Redox Signaling

(Physiologic)

Redox Sensor

Sulfur Switches

ROS/RNS

Redox Messenger

Macromolecular

Targets

ROS/RNS

Toxic Species

Imbalance between

Oxidants/Antioxidants

NADPH oxidase

NO synthase

Oxidative Stress

(Toxicologic)

PhysiologicToxicologic

The human genome encodes 214,000 distinct Cys residues

Jones 2008 “Radical-Free Biology of Oxidative Stress” AJP Cell Physiol 295:849-868

Estimated 2000 function in redox signaling and control

Modify

Thiols-L

Redox Proteomics using ICAT-LC/MSMS

Thiol/disulfide

mixtureModify

Thiols-H

Reduce

disulfides

Trypsin

cleavage

Mass spectrometry

m/z

Inte

nsity H

L

Extracellular Eh

Protein Name Peptide Sequence -150 mV 0 mV

Protein metabolism Elongation factor (EF)1- SGDAAIVDOVPGKPMCVESFSDYPPLGR 0.2741 0.1903

DGNASGTTLLEALDCILPPTRPTDKPLR 0.8248 0.3356

NOITGTSQADCAVLIVAAGVGEFEAGISK 1.5961 0.8464

EF-2 ETVSEESNVLCLSK 1.4843 0.9473

EGALCEENOR 1.4196 1.2931

Glu-tRNA synthetase EAPCVLIYIPDGHTK 0.5893 0.3745

Ubiquitin-activating E1 DNPGVVTCLDEAR 0.3381 0.4276

Cofilin HELQANCYEEVK 0.6281 0.2798

Calregulin HEQNIDCGGGIVK 1.6932 1.0689

Signal transduction Tyrosine phosphatase YPLNCSDPTSER 0.2983 0.2843

14-3-3 protein YLAEVACGDDR 0.8484 0.6631

Detoxification Peroxiredoxin 6 DFTPVCTTELGR 0.6783 0.5088

GSH-S-transferase CLDEFPNLK 0.6678 0.4968

Stress Response Hsp 60 AAVEEGIVLGGGCALLR 0.3321 0.2663

CEFQDAYVLLSEK 0.8389 0.2601

CIPALDSLTPANEDQK 0.7340 0.3750

Hsp 90 GFEVVYOTEPIDEYCVOOLK 0.5092 0.3261

Cell Structure/Motility Tubulin EIVHIQAGQCGNQIGAK 0.5351 0.2362

NOOAACDPR 0.6334 0.3395

-tubulin AYHEQLSVAEITNACFEPANQMVK 0.7390 0.3242

ICAT-MS/MS redox proteomics gives ability to measure

percent reduction of 1% of Cys proteome

Y.-M.-Go

Studies of Mitochondrial Redox Proteome

using redox ICAT-mass spectrometry

What happens to mitochondrial proteins with steady-state

generation of H2O2 at low rates in culture medium?

What happens to mitochondrial proteins with

oxidized extracellular Cys/CySS redox potential?

Percent oxidation was determined for peptides representing over 1000

proteins

Total cell protein peptidyl Cys oxidation was measured by Redox ICAT; for

2D LC-MSMS methods, see Go and Jones, 2008; Go and Jones 2009

HT 29 cells were treated with Glc oxidase in culture media to generate

H2O2 at a rate about 1 to 10% of the cellular O2 consumption

Mitochondrial proteins are relatively sensitive to oxidation

Y-M Go and DP Jones, unpublished

Proteins were sorted for subcellular localization, with over 500 proteins

assigned to either cytoplasm, nuclei, mitochondria or plasma membrane

Average mitochondrial protein oxidation was 2-fold

No significant average oxidation occurred in other compartments

Studies of Mitochondrial Redox Proteome

using redox ICAT-mass spectrometry

What happens to mitochondrial proteins with steady-state

generation of H2O2 at low rates in culture medium?

What happens to mitochondrial proteins with oxidized

extracellular Cys/CySS redox potential?

Extracellular Eh Cys/CySS is regulated by human

cells in culture to the value found in human plasma

Jonas et al, FRBM 2002

Extr

acellu

lar

Eh

(Cys/C

yS

S)

(mV

)

0 4 8 12 16 20 24

Time (h)

-120

-100

-80

-60

-40

-20

+200 M Cysteine

+100 M Cystine

CaCo2 cells

Reduced

Oxidized

Go and Jones, Circulation 2005

0-50-100-150-200

120

80

40

0

Eh (mV)

Eh, Cys/CySS

Mean=-72.4

Eh, GSH/GSSG

Mean=-130.9

Fre

quency

Plasma, 740 subjects

Young healthy in RED

OxidizedReduced

Plasma ECys in humans is oxidized in association

with aging, oxidative stress and disease

-400 +600 mV


Aging

Oxidative stress

Chronic disease

ECys = -80 mV

-150

-80

0

Eh, C

ys (

mV

)

Eh,Cys (mV)

-150 -80 0

Bound m

onocyte

s(

% o

f –150 m

V)

0

50

100

150

200

250

300

*

*

Oxidized cysteine (Eh Cys) causes proinflammatory signaling which triggers monocyte binding to aortic endothelial cells

Reduced

Oxidized

Go and Jones, 2005

-150 -80 0 mV

DC

F f

luo

resce

nce

(% o

f –

15

0 m

V)

0

50

100

150

200

250

300

*

Eh, Cys

*


Oxidized extracellular Cys/CySS redox

stimulates H2O2* generation*Signal is blocked by catalase

EhCys/CySS

HS-Pr/

(SS)-PrKinase/

PhosphataseH2O2

IκB

NF-κBNF-κB

DNA binding

Redox

sensor

Transcription

Translation

Protein processing

In secretory pathwayCAMs

Cytoskeletal/Plasma

membrane InteractionsIntegrins

NucleusCytoplasmPlasma

Plasma Cys/CySS redox potential signals H2O2 production

and downstream mechanisms for monocyte adhesion


Oxidized extracellular Cys signals intracellular H2O2

production via cell surface thiol sensors


No. o

f p

ep

tid

es

% of oxidized state

A

143 proteins from membrane

enriched fraction

0 mV (Mean= 41.6 16.2 %)-150 mV (Mean= 33.3 20.2%)

0

50

100

150

200

250

300

350

400

0 20 40 60 80 1000

20

40

60

80

100

120

0 20 40 60 80 100

% of oxidized state

No. o

f p

ep

tid

es

34 actin cytoskeleton-associated

proteins

0 mV (Mean= 41.8 15.3 %)

-150 mV (Mean= 29. 7 14.3 %)

B

Go et al, FRBM 2009

Many specific Cys residues in membrane-associated proteins of

endothelial cells are oxidized

Measured by mass spectrometry-based redox proteomicsMeasured by mass spectrometry-based redox proteomics

-150 -80 0 DTT H2O2

EhCys (mV)

WTTrx2Red

Trx2Ox

Go et al, FRBM 2009

Trx2 is oxidized by

extracellular Eh at 0 mV

NADPH TR Trx2 Prx3 H2O2 metabolismNo effect on cytoplasmic GSH

EhCys/CySS

HS-Pr/

(SS)-PrKinase/

PhosphataseMito

Redox

sensor

Oxidation

Glu

tath

ione

Eh

(mV

)

(2G

SH

/GS

SG

)

-150

-200

-250

-300

EhCys (mV) :

WT

-150

-80 0

0.0

0.4

0.88

12

16

18

(mM

)

-150 -80 0 DTT H2O2

EhCys (mV)

WT

Tg

Trx2Red

Trx2Ox

Trx2Red

Trx2Ox

Trx1Red

NLS-Trx1Red

NLS-Trx1Ox

-150 -80 0 DTT H2O2

EhCys (mV)

Trx1Ox

Glu

tath

ione

Eh

(mV

)

(2G

SH

/GS

SG

)

-150

-200

-250

-300

EhCys (mV) :

WT Tg

-150

-80 0

-150

-80 0

GSHGSSG

0.0

0.4

0.88

12

16

18

(mM

)

WT TgTg

MAECTail

V5-hTrx2

mTrx2

mTrx1

WT Tg

PCR product

of v5-hTrx2

V5-hTrx2

Tg

WT

Go et al, FRBM 2009

Trx2 is oxidized by

extracellular Eh at 0 mV

NADPH TR Trx2 Prx3 H2O2 metabolism

Signaling is blocked in

cells from Trx2 Tg mice

EhCys/CySS

HS-Pr/

(SS)-PrKinase/

PhosphataseH2O2Mito

IκB

NF-κBNF-κB

DNA binding

Redox

sensor

Transcription

Translation

Protein processing


Cytoskeletal/Plasma



Plasma Cys/CySS redox potential signals mitochondrial H2O2

production and downstream mechanisms for monocyte adhesion

A B

EhCys (mV) :

WT Tg

MitoS

OX

(% o

f m

inim

um

)

-150

-80 0

-150

-80 0

1

2

3

50

75

100

125

150

MitoS

OX

(% o

f m

inim

um

)

EhCys (mV) :

-150

-80 0

-150

-80 0

-150

-80 0

None qBBr AMS

C 4

5

6

4

56

*

75

100

125

150

175

200

1

2

3

**

*

N.S

80

100

120

140**

*D

CF

(% o

f m

inim

um

)

EhCys (mV) : -150 -80 0 -150 -80 0

WT Tg

Go et al, FRBM 2009

EhCySS-Dependent Redox Changes in Mitochondrial Proteins are Involved in

Amino Acid Metabolism, Molecular Transport, and Small Molecule Biochemistry

Network 1

Mitochondria proteins from MAEC treated with EhCySS, 0 mV

EhCySS-dependent redox changes in Mitochondrial Proteins are involved in

Cellular Assembly and Organization, Cell Death, and Liver Necrosis

Network 2


EhCySS-dependent redox changes in Mitochondrial Proteins are involved in

Genetic Disorder, Metabolic Disease, and Free Radical Scavenging

Network 3


EhCys

O2∸

H2O2

Trx2 oxidation

PM

Cell adhesion molecules

Cytokine (IL-1 )

Inflammation, vascular disease

OxidationReduction

-150 mV 0 mV

H2O2

Nrf2

H2O2

NF- B

Antioxidants

(NQO1, MAF, FTH1)

Pr-SH Pr-SSPr-SH

MAPK PDGF

Early growth response genes

Eukaryotic translational initiation factor

Cell growth, proliferation Detoxification

Combination of Gene Expression Array and Proteomic Analyses

Extracellular EhCys-dependent cell signaling and control

Go et al Tox Sci 2009

EhCys/CySS

HS-Pr/

(SS)-PrKinase/

PhosphataseH2O2Mito

IκB

NF-κBNF-κB

DNA binding

Redox

sensor

Transcription

Translation

Protein processing


Cytoskeletal/Plasma



Plasma Cys/CySS redox potential signals mitochondrial H2O2

production and downstream mechanisms for monocyte adhesion

Increased Carotid IMT (Ashfaq et al J Am Coll Cardiol 2006)

Chemotherapy/BMT (Jonas et al Am J Clin Nutr 2000)

Cigarette Smoking (Moriarty et al, FRBM 2003)

Type 2 Diabetes (Samiec et al FRBM 1998)

Reversible myocardial perfusion defects (J. Abramson et al J Am Coll Cardiol 2005 (abst))

Pathophysiologic correlation

Low antioxidants, low dietary cysteine (Moriarty-Craige et al Am J

Ophthal 2005; Blanco et al Am J Clin Nutr 2007)

Jones, ARS 2006; Kemp et al 2008

Atrial fibrillation (Neuman et al Clin Chem 2007)

Alcohol abuse (Yeh et al, Am J Resp Crit Care Med 2007)

Aging (Jones et al FRBM 2002)

Oxidized plasma redox states are associated with risk

factors for chronic and age-related disease

Health

-80 mV

-20 mV

(-80 mV)Cys/CySS Redox

(GSH/GSSG Redox)

(-140 mV)-62 mV

(-120 mV)

Lung transplantation (A. Ramirez, unpublished)

Oxidized Eh for GSH and Cys are associated

with persistent atrial fibrillation

Neuman et al , 2007

Odds ratio

Eh GSH*

Eh Cys*

dROMs*

hsCRP

TNFα

IL-1β

IL-6

1 10 100 1000

-90

-80

-70

-60

8:1

5

8:1

5

10

:15

12

:15

14

:15

16

:15

18

:15

20

:15

Time (h)

Cys/C

yS

S E

h (

mV

)

100% SAA + Placebo

100% SAA + APAP

P / A P / A

M

M

*

**

*

*

Mannery et al, 2010 JPET

Acetaminophen induces oxidation of plasma Cys/CySS in humans

2-Day sulfur amino acid insufficiency results in oxidation of plasma

GSH/GSSG in humans taking therapeutic dose of acetaminophen

Mannery et al, 2010 JPET

-150

-140

-130

-120

-110

-100

8:1

5

8:1

5

10

:15

12

:15

14

:15

16

:15

18

:15

20

:15

Time (h)

GS

H/G

SS

G E

h (

mV

)100% SAA + APAP

0% SAA + APAP

A

M

M A

**

Perturbation of the low flux mitochondrial redox circuits activates

cell death machinery and probably underlies mitochondrial

toxicities

Mitochondrial redox proteome is highly responsive to oxidative

conditions—reflects central role of redox mechanisms in regulation

of mitochondrial and cellular functions

Summary: Compartmentation of oxidative stress defense in mitochondria

Implications of drug toxicity

Low flux electron transfer pathways control thiol/disulfide systems

in mitochondria

Acknowledgements: NIEHS

Redox Proteomics

Young-Mi Go

Jan Pohl

Junmin Peng

Cell and molecular

Yan Chen

Smita Iyer

Siobhan Craige

Jason Hansen

Lou Ann Brown

Bill Liang

Hong Zhang

James Roede

Transgenic mice

Jiyang Cai

Redox modeling

Nnenna Adimora

Melissa Kemp

Compartmentation of oxidative stress defense in...

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