Mitochondrial nitric oxide in the signaling of cell integrated responses.
Mitochondria are the specialized organelles for energy metabolism, but, as a typical example of system biology, they also activate a multiplicity of pathways that modulate cell proliferation and mitochondrial biogenesis or oppositely promote cell arrest and programmed cell death by a limited number of oxidative or nitrosative reactions. These reactions are influenced by matrix nitric oxide (NO) steady-state concentration, either from local production or by gas diffusion to mitochondria from the canonical sources. Likewise, in a range of approximately 30-200 nM, NO turns mitochondrial O(2) utilization down by binding to cytochrome oxidase and elicits a burst of superoxide anion and hydrogen peroxide that diffuses outside mitochondria. Depending on NO levels and antioxidant defenses, more or less H(2)O(2) accumulates in cytosol and nucleus, and the resulting redox grading contributes to dual activation of proliferating and proapoptotic cascades, like ERK1/2 or p38 MAPK. Moreover, these sequential activating pathways participate in rat liver and brain development and in thyroid modulation of mitochondrial metabolism and contribute to hypothyroid phenotype through complex I nitration. On the contrary, lack of NO disrupts pathways like S-nitrosylation or H(2)O(2) production and likewise is a gateway to disease in amyotrophic lateral sclerosis with superoxide dismutase 1 mutations or to cancer proliferation.
Carreras
Maria Cecilia
MC
Laboratory of Oxygen Metabolism, University Hospital of Buenos Aires, Cordoba 2351, 1120 Buenos Aires, Argentina. carreras@ffyb.uba.ar
Poderoso
Juan José
JJ
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007037:Hypothyroidism / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D020928:Mitogen-Activated Protein Kinases