The labile iron pool attenuates peroxynitrite-dependent damage and can no longer be considered solely a pro-oxidative cellular iron source

Author(s)

Damasceno, Fernando Cruvinel ^[1] ; Condeles, Andre Luis ^[1] ; Bueno Lopes, Angelica Kodama ^[1] ; Facci, Romulo Rodrigues ^{[1, 2]} ; Linares, Edlaine ^[2] ; Truzzi, Daniela Ramos ^[2] ; Augusto, Ohara ^[2] ; Toledo, Jr., Jose Carlos ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, BR-14040901 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo - Brazil

• Document type: Journal article
• Source: Journal of Biological Chemistry; v. 293, n. 22, p. 8530-8542, JUN 1 2018.
• Web of Science Citations: 5

Abstract

The ubiquitous cellular labile iron pool (LIP) is often associated with the production of the highly reactive hydroxyl radical, which forms through a redox reaction with hydrogen peroxide. Peroxynitrite is a biologically relevant peroxide produced by the recombination of nitric oxide and superoxide. It is a strong oxidant that may be involved in multiple pathological conditions, but whether and how it interacts with the LIP are unclear. Here, using fluorescence spectroscopy, we investigated the interaction between the LIP and peroxynitrite by monitoring peroxynitrite-dependent accumulation of nitrosated and oxidized fluorescent intracellular indicators. We found that, in murine macrophages, removal of the LIP with membrane-permeable iron chelators sustainably accelerates the peroxynitrite-dependent oxidation and nitrosation of these indicators. These observations could not be reproduced in cell-free assays, indicating that the chelator-enhancing effect on peroxynitrite-dependent modifications of the indicators depended on cell constituents, presumably including LIP, that react with these chelators. Moreover, neither free nor ferrous-complexed chelators stimulated intracellular or extracellular oxidative and nitrosative chemistries. On the basis of these results, LIP appears to be a relevant and competitive cellular target of peroxynitrite or its derived oxidants, and thereby it reduces oxidative processes, an observation that may change the conventional notion that the LIP is simply a cellular source of pro-oxidant iron. (AU)

• FAPESP's process: 10/00550-2 - Mechanisms of cellular s-nitrosation from free nitric oxide. Involviment of transition metals and reactive species
• Grantee: José Carlos Toledo Junior
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC