Abstract
Approximately 15 years ago we reported that cytochrome c oxidase (CcO) was persistently inhibited as a consequence of endogenous induction and activation of nitric oxide (•NO) synthase-2 (NOS2) in astrocytes. Furthermore, the reactive nitrogen species implicated was peroxynitrite. In contrast to the reversible inhibition by •NO, which occurs rapidly, in competition with O2, and has signaling regulatory implications, the irreversible CcO damage by peroxynitrite is progressive in nature and follows and/or is accompanied by damage to other key mitochondrial bioenergetic targets. In purified CcO it has been reported that the irreversible inhibition occurs through a mechanism involving damage of the heme a3-CuB binuclear center leading to an increase in the Km for oxygen. Astrocyte survival, as a consequence of peroxynitrite exposure, is preserved due to their robust bioenergetic and antioxidant defense mechanisms. However, by releasing peroxynitrite to the neighboring neurons, whose antioxidant defense can, under certain conditions, be fragile, activated astrocytes trigger bioenergetic stress leading to neuronal cell death. Thus, such irreversible inhibition of CcO by peroxynitrite may be a plausible mechanism for the neuronal death associated with neurodegenerative diseases, in which the activation of astrocytes plays a crucial role.
Highlights
CYTOCHROME C OXIDASE IS PERSISTENTLY INHIBITED BY CONTINUOUS EXPOSURE TO NITRIC OXIDE/PEROXYNITRITE After the discovery of the potential biological roles of nitric oxide (NO) (Ignarro et al, 1987; Palmer et al, 1987), its implication as a key player during glutamatergic neurotransmission was shortly reported (Garthwaite et al, 1988)
DIFFERENT VULNERABILITY BETWEEN NEURONS AND ASTROCYTES AGAINST NITROSATIVE DAMAGE Our own previous data reported that activated atrocytes, which express NOS2 (Murphy et al, 1993), continuously release a considerable amount of NO (Brown et al, 1995), which is responsible for their inhibition of cytochrome c oxidase (CcO) activity (Bolaños et al, 1994)
We found that 24 h after the co-incubation period, neurons showed a NMMA-sensitive inhibition of CcO activity (Bolaños et al, 1996) that, in contrast to the damage to other components www.frontiersin.org of the mitochondrial respiratory chain, was time-dependent and permanent (Stewart et al, 2000), causing a bioernergetic deficiency leading to cell death (Bolaños et al, 1996)
Summary
CYTOCHROME C OXIDASE IS PERSISTENTLY INHIBITED BY CONTINUOUS EXPOSURE TO NITRIC OXIDE/PEROXYNITRITE After the discovery of the potential biological roles of nitric oxide (NO) (Ignarro et al, 1987; Palmer et al, 1987), its implication as a key player during glutamatergic neurotransmission was shortly reported (Garthwaite et al, 1988). In 1994, four independent laboratories reported that NO, either exogenously added to several preparations containing mitochondria, or endogenously produced in intact cells, via the inducible form of NO synthase (NOS2), inhibited cytochrome c oxidase (CcO), the terminal complex of the mitochondrial respiratory chain (Bolaños et al, 1994; Brown and Cooper, 1994; Cleeter et al, 1994; Schweizer and Richter, 1994).
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