Portal de Periódicos da CAPES

Mitochondria, oxidative stress and PARP‐1 network: a new target for neuroprotective effects of tetracyclines?

2008; Wiley; Volume: 586; Issue: 10 Linguagem: Inglês

10.1113/jphysiol.2008.152819

1469-7793

Daniele Orsucci, Michelangelo Mancuso, Gabriele Siciliano,

Mitochondrial Function and Pathology

The Journal of PhysiologyVolume 586, Issue 10 p. 2427-2428 Free Access Mitochondria, oxidative stress and PARP-1 network: a new target for neuroprotective effects of tetracyclines? Daniele Orsucci, Daniele Orsucci Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, ItalyEmail:d.orsucci@sssup.itSearch for more papers by this authorMichelangelo Mancuso, Michelangelo Mancuso Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, ItalyEmail:d.orsucci@sssup.itSearch for more papers by this authorGabriele Siciliano, Gabriele Siciliano Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, ItalyEmail:d.orsucci@sssup.itSearch for more papers by this author Daniele Orsucci, Daniele Orsucci Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, ItalyEmail:d.orsucci@sssup.itSearch for more papers by this authorMichelangelo Mancuso, Michelangelo Mancuso Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, ItalyEmail:d.orsucci@sssup.itSearch for more papers by this authorGabriele Siciliano, Gabriele Siciliano Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, ItalyEmail:d.orsucci@sssup.itSearch for more papers by this author First published: 28 June 2008 https://doi.org/10.1113/jphysiol.2008.152819Citations: 12AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Glutamate excitotoxicity is one of the mechanisms involved in cellular death in neurodegenerative diseases such as Alzheimer's disease or motor neuron disease (MND). In these pathologies, glutamate undergoes an uncontrolled release which causes a massive influx of extracellular Ca2+ in neurons, mainly through N-methy-d-aspartate (NMDA) receptors (Duan et al. 2007). This leads to mitochondrial Ca2+ overload, mitochondrial depolarization and opening of the mitochondrial permeability transition pore (PTP). The opening of the mitochondrial PTP causes the release of cytochrome c and apoptosis-inducing factor (AIF). Further, activation of the glutamate receptors can increase oxidative stress. In this cascade, another critical event is poly(ADP-ribose) polymerase-1 (PARP-1) activation by DNA damage, which is a required event for NMDA-induced neuronal death. PARP-1 favours the translocation of AIF from the mitochondria to the nucleus, and finally promotes cell death and inflammation (Alano et al. 2006). In experimental models, neuronal excitotoxic death is prevented either by eliminating Ca2+ from the culture medium or by genetically knocking out the PARP-1 gene (Duan et al. 2007). A unified scheme linking these two events – the mitochondrial cytochrome c release and PARP-1 activation during glutamate excitotoxicity – was unknown until the very recent work by Duan et al. (2007). They have investigated the relationship between mitochondrial Ca2+ uptake and mitochondrial reactive oxygen species (ROS) generation. These authors found that mitochondrial ROS production is a required signal for PARP-1 activation in cultured rat striatal neurons (Duan et al. 2007). Oxidative damage has an important impact on brain degeneration (Mancuso et al. 2006). The transport of high-energy electrons through the mitochondrial electron transport chain (ETC) is a necessary step for ATP production, but it is also a cause of ROS production. At complex IV of the respiratory chain, the high-energy electrons can react with O2 to form superoxide (O2·−). Up to 2% of the O2 consumed by healthy mitochondria is converted into superoxide, and this amount is higher in damaged and aged mitochondria. The accumulation of ROS can potentially damage several bio-molecules, including lipids, proteins and nucleic acids. Some tissues, such as brain and skeletal muscle, are much more vulnerable to oxidative stress because of their elevated consumption of oxygen (Mancuso et al. 2006). Since superoxide can react with nitric oxide (NO) to form peroxynitrite (ONOO−), which is severely damaging for the DNA, it might serve as a signal for PARP-1 activation. However, the only way to prevent excitotoxicity is to block mitochondrial Ca2+ uptake (Duan et al. 2007). This indicates that ROS produced via mitochondrial pathways exert a ‘privileged’ action on nuclear PARP-1 activation (Duan et al. 2007). Duan et al. (2007) found that in mitochondria, but not in other organelles such as lysosomes and endosomes, there was a significant ROS increase within 30 min of NMDA receptor activation. They obtained the spatial aspect of ROS generation through two redox-sensitive fluorescent indicators and a voltage-sensitive indicator, which accumulates predominantly in the mitochondria. The increased ROS production was blocked by inhibitors of mitochondrial ETC, such as rotenone, but not by the inhibitors of cytosolic phospholipase A2 or xanthine oxidase (two pathways involved in cytosolic ROS generation). Thus, cytosolic pathways do not seem to play a major role in the NMDA-induced ROS production. Mitochondrial ROS generation was also inhibited by removal of Ca2+ from extracellular medium, and by blockage of mitochondrial Ca2+ uptake with a specific inhibitor. Further, the blockage of mitochondrial Ca2+ uptake inhibited both DNA damage (evaluated by comet assay) and PARP-1 activation induced by NMDA (Duan et al. 2007). PARP-1 activation has been examined with immunoblot, analysis which detected the formation of the poly(ADP-ribose) polymer (PAR) product of this enzyme. Antioxidant agents (such as superoxide dismutase mimics and glutathione ethyl ester) also inhibited DNA damage and PARP-1 activation. These observations suggest that the increase of mitochondrial ROS is a signal for PARP-1 activation, and that concomitant mitochondrial Ca2+ uptake and PARP-1 activation constitute a unified mechanism for excitotoxic neuronal death. The exact mechanism of Ca2+ stimulation in ROS production inside mitochondria remains unclear. Possible mechanisms could be the inhibition of respiratory activity and the release of cytochrome c from mitochondria via the Ca2+-induced PTP. Conversely, ROS generation can occur even earlier than cytochrome c release from mitochondria. Further studies are needed to clarify this aspect. An intriguing implication of the Duan study is related to the mechanism of action of tetracyclines as neuroprotective agents. This class of antibiotics, especially minocycline, seems to have a therapeutic role in several neurological disorders, at least in animal models (Yong et al. 2004). In animal models of ischaemic and haemorrhagic stroke, minocycline decreases the size of infarct. In Parkinson's disease models, it protects the nigrostriatal pathway; in Huntington and MND models, it seems to delay the progression of the disease and to extend lifespan (Yong et al. 2004). In human diseases, such as stroke and multiple sclerosis, tetracyclines play some neuroprotective role as well (Yong et al. 2004; Lampl et al. 2007). The main biological effects of tetracyclines are inhibition of microglial activation, attenuation of apoptosis, and suppression of ROS production (Yong et al. 2004). These mechanisms are involved in the pathogenesis of several neurological diseases, mainly neurodegenerative ones (Mancuso et al. 2006). It is still unclear whether tetracyclines have a single major mode of action or several modes of action. The anti-apoptotic effect of tetracyclines might involve the mitochondrion. Until now, studies reported that minocycline reduces mitochondrial Ca2+ uptake, stabilizes mitochondrial membranes, inhibits MPT-mediated release of cytochrome c into the cytosol, and reduces the release into the cytoplasm of other apoptotic factors, such as AIF. Other effects include up-regulation of mitochondrial bcl-2 (an anti-apoptotic protein), direct scavenging of ROS, and inhibition of mitogen-activated protein kinases (Alano et al. 2006). It is still unclear which of these mechanisms plays the pivotal role in neuroprotective properties of tetracyclines. The paper of Duan and coworkers describes a complex cascade that links mitochondria, oxidative stress, PARP-1 and apoptosis. The major target for minocycline in neurodegeneration could lie within this network. Interestingly, Alano et al. (2006) reported that minocycline and other tetracyclines inhibited PARP-1 at nanomolar concentrations. Furthermore, the same group found that minocycline protected neurons against PARP-1-mediated toxicity. Finally, these authors observed a direct correlation between the potency of these agents as PARP-1 inhibitors and their neuroprotective effect. Therefore, it could be hypothesized that the neuroprotective effect of tetracyclines could be related to PARP-1 inhibition, at least in part. Because of the epidemiological relevance of the neurodegenerative diseases, and considering that, to date, there are no effective treatments for these pathologies, further studies are needed to clarify the role of tetracyclines in the complex network described by Duan and coworkers. Furthermore, these studies may help elucidate the mechanism behind the mitochondrial dysfunction detectable in neurodegeneration, and may be of relevance for the development of strategies in the treatment of these devastating disorders. References Alano CC, Kauppinen TM, Valls AV & Swanson RA (2006). Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci U S A 103, 9685– 9690. Duan Y, Gross RA & Sheu SS (2007). Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol 585, 741– 558. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M & Sadeh M (2007). Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69, 1404– 1410. Mancuso M, Coppede F, Migliore L, Siciliano G & Murri L (2006). Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis 10, 59– 73. Yong VW, Wells J, Giuliani F, Casha S, Power C & Metz LM (2004). The promise of minocycline in neurology. Lancet Neurol 3, 744– 751. Citing Literature Volume586, Issue10May 2008Pages 2427-2428 ReferencesRelatedInformation