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INVITED REVIEW

Mitochondrial nitric oxide in the signaling of cell integrated responses

¹Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, and ²Department of Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

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 30–200 nM, NO turns mitochondrial O₂ 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 H₂O₂ 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 H₂O₂ production and likewise is a gateway to disease in amyotrophic lateral sclerosis with superoxide dismutase 1 mutations or to cancer proliferation.

peroxynitrite; hydrogen peroxide; mitochondrial nitric oxide synthase; mitogen-activated protein kinase

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