Date published:

Discovery of endogenous nitroxyl

It has been 30 years since Science recognized nitric oxide (*NO) as the Molecule of the Year 1992. Since then our knowledge on *NO has been considerably broadened, showing that this gaseous free radical is an important regulator in many physiological processes at various biological organization levels. Cellular redox reactions in response to various developmental stimuli or stressors lead to the conversion of *NO to other reactive nitrogen species (RNS), which may affect biological systems in many diverse ways. As a consequence, different nitric oxide derivatives present in the cellular environment determine a broad spectrum of physiological effects, which are frequently ascribed only to the *NO radical form. As has been indicated by recently conducted pharmacological studies, the protonated and reduced form of nitric oxide, i.e. nitroxyl (HNO), exhibits unique physico-chemical properties compared to the radical form as well as a different biological activity. Nevertheless, to date endogenous production of this molecule has not been observed in any experimental system. Results of our studies published in Nature Plants in the publicationDiscovery of endogenous nitroxyl as a new redox player in Arabidopsis thaliana, M. Arasimowicz-Jelonek , J. Floryszak-Wieczorek, S. Suarez ,F. Doctorovich, E. Sobieszczuk-Nowicka, S. Bruce King, G. Milczarek, T. Rębiś, J. Gajewska, P. Jagodzik, M. Żywicki, for the first time have documented that HNO is formed endogenously in living organisms, as shown in Arabidopsis leaf cells. Sources of HNO synthesis include, among other things, non-enzymatic reactions of NO*/HNO interconversion in the presence of key cellular reductants. Using Arabidopsis mutants with impaired *NO biosynthesis (nia1nia2, Atnoa1, nia1nia2noa1) and applying high performance measurement techniques facilitating real-time HNO detection it was shown that the kinetics of the formation of this molecule is dependent on the cell redox potential. Under physiological conditions the endogenous production of HNO is very low, at the level of nanomoles. In turn, a decrease or increase of nitroxyl formation may be observed in various developmental processes and responses of plants to adverse environmental factors. These phenomena are accompanied by marked shifts in the cellular redox potential towards oxidation (e.g. the senescence process) or reduction (e.g. hypoxia stress). Moreover, the transcriptomic analysis of Arabidopsis leaf cells, pharmacologically depleted of endogenous nitroxyl, revealed the participation of HNO e.g. in the ethylene regulation process, which may play a key role in plant adaptation to hypoxia conditions. Nitroxyl production and its biological activity in the cellular environment documented in our study make it possible to verify the effects up to date ascribed solely to nitric oxide and indicate the potential for an alternative signaling pathway in plants, competitive in relation to *NO. This discovery allows also to include HNO, next to NO, H2S and CO, in the group of gasotransmitters. Obviously, the occurrence of HNO is not limited to the world of plants. For many years research has been conducted on the therapeutic potential of HNO donors in medicine, thus our results provide an incentive for further intensive studies in search of sources and functionality of nitroxyl in various biological systems.