J. Duranteau Hôpital de Bicêtre - Université Paris-Sud XI Réponse cellulaire à lhypoxie

J. DuranteauHôpital de Bicêtre - Université Paris-Sud XI

Réponse cellulaire à l’hypoxie

Espèces radicalaires de l’oxygèneEspèces radicalaires de l’oxygène

Dysfonction d’organeDysfonction d’organe

Dysfonction endothélialeDysfonction endothéliale

Réponse cellulaire à l’ hypoxieRéponse cellulaire à l’ hypoxie

HypoxieHypoxie

Métabolisme oxydatifMétabolisme oxydatif

MitochondrieMitochondrie

Duranteau et al. J. Biol. Chem. 273:11619-11624. 1998.


HepatocytesHepatocytes

CardiomyocytesCardiomyocytes

0 60 120 180 240-200

0

200

400

600

800

1000

1200

Hypoxia

Hypoxia

Normoxia 15% 02

Hypoxia 5% 02

Hypoxia 3% 02

Hypoxia 1% 02

DC

FH

(%

of

init

ial

valu

es)

0 60 120 180 2400

10

20

30

40

50

60

70

80

90

100

110

To

tal

mo

tio

n (

% o

f in

itia

l va

lues

)

Times (min)





Cha”ne respiratoire

ComplexeNADH-

dˇshydrog nase(I)

ComplexeNADH-

dˇshydrog nase(I)

ComplexeSuccino-

dˇshydrog nase(II)

ComplexeSuccino-

dˇshydrog nase(II)

Complexeb-c1(III)

Complexeb-c1(III)

Complexecytochrome-

oxidase(IV)

Complexecytochrome-

oxidase(IV)

NAD

NADH

FAD

FADH2H+

H+

H+

H+

H+

H+

cycle de lÕacide citriquepyruvate

§-oxydationnavette malate-aspartate

cycle de lÕacide citrique§-oxydation

e- UQ

e-

transportdÕlectrons

navetteglycˇ rol-phosphate

UQ

e-

e-

ubiquinone

ATP-synthaseATP-synthase

espace inter-membranaire

matrice

UQ

CytochromeC

e-

O2

H2O

H+

H+

membraneinterne

ATPATP+ PiADP +

Pi

ATP


ComplexeNADH-

dˇshydrog nase(I)

ComplexeNADH-

dˇshydrog nase(I)

ComplexeSuccino-

dˇshydrog nase(II)

ComplexeSuccino-

dˇshydrog nase(II)

Complexeb-c1(III)

Complexeb-c1(III)

Complexecytochrome-

oxidase(IV)

Complexecytochrome-

oxidase(IV)

NAD

NADH

FAD

FADH2H+

H+

H+

H+

H+

H+




e- UQ

e-



UQ

e-

e-

ubiquinone



matrice

UQ

CytochromeC

e-

O2

H2O

H+

H+

membraneinterne

ATPATP+ PiADP +

Pi

ATP

NADH / FADH2NADH / FADH2

Flux d’électronsFlux d’électrons

ADPADP

adenine nucleotide translocase

adenine nucleotide translocase

Fuite protonsFuite protons


ComplexeNADH-

dˇshydrog nase(I)

ComplexeNADH-

dˇshydrog nase(I)

ComplexeSuccino-

dˇshydrog nase(II)

ComplexeSuccino-

dˇshydrog nase(II)

Complexeb-c1(III)

Complexeb-c1(III)

Complexecytochrome-

oxidase(IV)

Complexecytochrome-

oxidase(IV)

NAD

NADH

FAD

FADH2H+

H+

H+

H+

H+

H+




e- UQ

e-



UQ

e-

e-

ubiquinone



matrice

UQ

CytochromeC

e-

O2

H2O

H+

H+

membraneinterne

ATPATP+ PiADP +

Pi

ATP

O2.-

Guzy RD et al. Cell Metabolism 2005Guzy RD et al. Cell Metabolism 2005

Hep3B Human Hepatoma Cells

Prolyl hydroxylases

Wheaton W and Chandel NDAm J Physiol Cell Physiol, 2010.


HIF-1-mediated expression of pyruvate dehydrogenase kinase:A metabolic switch required for cellular adaptation to hypoxia

Pyruvate Deshydrogènase(PDH)

Pyruvate Deshydrogènase kinase 1

Lactate deshydrogènase A

Kim JW et al. Cell metabolism 2006Kim JW et al. Cell metabolism 2006



Chen Z et al. Oncogene (2010) 29, 4362–4368Chen Z et al. Oncogene (2010) 29, 4362–4368

Comellas AP et al. Circ Res. 2006;98:1314-1322.Comellas AP et al. Circ Res. 2006;98:1314-1322.

Gusarova AP et al. Molecular and Cellular Biology. 2009.Gusarova AP et al. Molecular and Cellular Biology. 2009.

ATP demand


HypoxieHypoxie

Diminution du métabolisme oxydatifDiminution du métabolisme oxydatif

Retarde la dysoxie cellulaireRetarde la dysoxie cellulaire

Diminue la production d’ERODiminue la production d’ERO


Aragones A et al. Nature Genetics 40, 170 - 180 (2008) Aragones A et al. Nature Genetics 40, 170 - 180 (2008)

HIF prolyl hydroxylase 1-deficient (Egln2-/-) mice

Simerabet M et al.Brain research 2008 Simerabet M et al.Brain research 2008

Piot C et al. NEJM 359;5 2008Piot C et al. NEJM 359;5 2008

Effect of Cyclosporine on Reperfusion Injuryin Acute Myocardial Infarction

58 patients with acute ST-elevation myocardial infarction intravenous bolus of 2.5 mg/kg of cyclosporine

Piot C et al. NEJM 359;5 2008Piot C et al. NEJM 359;5 2008

Effect of Cyclosporine on Reperfusion Injuryin Acute Myocardial Infarction

58 patients with acute ST-elevation myocardial infarction intravenous bolus of 2.5 mg/kg of cyclosporine





HypoxieHypoxie



Inflammation infection

Inflammation infection

Tumor Necrosis Factor Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c OxidaseBovine and murine hepatocyte homogenates

CcO activity

Cytochrome C (μM)Cytochrome C (μM)

60% reduction in CcO activity

60% reduction in CcO activity

Samavati L. et al. J. Biol. Chem.283, pp. 21134–21144, 2008


Tumor Necrosis Factor Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase

ATP (%)100

80

60

40

20

0

TNFαLiver tissue H2.35 cells- + - +

T

T

T

T







HypoxieHypoxie



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J. Duranteau Hôpital de Bicêtre - Université Paris-Sud XI Réponse cellulaire à lhypoxie