Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis
| Autor: | Varsha P. Daswani, Patrick J. Doonan, Yefim Manevich, Brian J. Hawkins, Krishna M. Irrinki, Bruce A. Cameron, Muniswamy Madesh, Subbiah Ramasamy, Christiana Davis, Khalid Islam |
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| Rok vydání: | 2010 |
| Předmět: |
Indoles
Bioenergetics Mitochondrion Biology Nitric Oxide Biochemistry Mitochondrial apoptosis-induced channel Article Cell Line Mice Necrosis chemistry.chemical_compound Physiology (medical) Animals Humans RNA Small Interfering Reactive nitrogen species Membrane Potential Mitochondrial chemistry.chemical_classification Reactive oxygen species Electron Transport Complex I Superoxide Macrophages Imidazoles RNA-Binding Proteins Fibroblasts Mitochondria Rats Cell biology Nuclear Pore Complex Proteins Protein Subunits Microscopy Fluorescence chemistry Receptor-Interacting Protein Serine-Threonine Kinases DNAJA3 Endothelium Vascular ATP–ADP translocase |
| Zdroj: | Free Radical Biology and Medicine. 48:306-317 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2009.11.001 |
| Popis: | Nitric oxide (NO) and other reactive nitrogen species target multiple sites in the mitochondria to influence cellular bioenergetics and survival. Kinetic imaging studies revealed that NO from either activated macrophages or donor compounds rapidly diffuses to the mitochondria, causing a dose-dependent progressive increase in NO-dependent DAF fluorescence, which corresponded to mitochondrial membrane potential loss and initiated alterations in cellular bioenergetics that ultimately led to necrotic cell death. Cellular dysfunction is mediated by an elevated 3-nitrotyrosine signature of the mitochondrial complex I subunit NDUFB8, which is vital for normal mitochondrial function as evidenced by selective knockdown via siRNA. Overexpression of mitochondrial superoxide dismutase substantially decreased NDUFB8 nitration and restored mitochondrial homeostasis. Further, treatment of cells with either necrostatin-1 or siRNA knockdown of RIP1 and RIP3 prevented NO-mediated necrosis. This work demonstrates that the interaction between NO and mitochondrially derived superoxide alters mitochondrial bioenergetics and cell function, thus providing a molecular mechanism for reactive oxygen and nitrogen species-mediated alterations in mitochondrial homeostasis. |
| Databáze: | OpenAIRE |
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