Mitochondria nitric oxide synthase in inflammation and septic shock

Tu jie

Nitric Oxidea ubiquitous signaling molecule

Chemical characters

2NO+O2 2NO2

NO2 + NO2 N2O4

NO2 +NO N2O3

[NO+] + OH- HNO2 NO -

2+ H+

[NO -2 ] [NO+] + H2O 2NO -

2+ 2H+

[NO -3 ] [NO+] + H2O NO -

2+ NO -3 + 2H+

Biosynthesis of Nitric Oxide

H2N NH2

+

NH

H+3N COO-

H2N N-OH

NH

H+3N COO-

+ NONADPH

BH4

O2

HEME

Ca2+/CaM

NOS

L-arginine L-citrulline

Three isoforms of NOS

Cellular and mitochondrial production of NO

A fourth type of NOS: mitochondrial NOS (mtNOS)

1. first observed in rat liver mitochondria by Ghafourifar

group and Giulivi group, 1997-1998;

2. localize in the mitochondrial innermembrane

3. mtNOS activity is substantial

and modulated by calcium

4. mtNOS continously controls

mitochondrial respiration

Respiration of IM is markedly inhibited when mtNOS is stimulated （ trace b vs trace a)

Infection SIRS

Sepsis

Trauma

Burns

Pancreatitis

Inflammation and septic shock

• A combination of three clini

cal signs:

vasodilation, hyperthermia,

edema

• Myochondrial dysfunction

The role of mtNOS in inflammation and septic shock

Septic Shock

septic shock: a major cause of death

NO production in inflammation and septic shock• milestone: recognition of NO production by activated

macrophages as part of the inflammatory process

The impairment by high NO concentration in septic sho

ck

• To impair mitochondrial and cellular oxygen uptake with

a simultaneous decrease in the rate of ATP synthesis

• To shift the main mitochondrial O2。－ metabolic route

（ form peroxynitrite (ONOO-), an oxidizing free radical that can c

ause DNA fragmentation and lipid oxidation ）

• Cyclosporin A (CsA) in ameliorating endotoxin-caused myocardial dysfunction and apoptosis in rats (Fauvel H, Marchetti P, Obert G , et al. Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats [J]

Am J Respir Crit Care Med, 2002 ,165(4):449-55)

Mitochondrial played a central role in the intracellula

r event associated with inflammation and septic sho

ck

The contributions of mtNOS and NOS cytosolic isofo

rms to the total production of NO constitute an open

and challenging question

Conclusion