This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Galli, S. Articles by Poderoso, J. J. Search for Related Content PubMed PubMed Citation Articles by Galli, S. Articles by Poderoso, J. J.

Decreased Mitochondrial Nitric Oxide Synthase Activity and Hydrogen Peroxide Relate Persistent Tumoral Proliferation to Embryonic Behavior¹

Laboratory of Oxygen Metabolism, University Hospital, Córdoba 2351, CP 1120, University of Buenos Aires [S. G., M. I. L., M. C. C., J. J. P.], and Institute of Oncology Ángel H. Roffo, CP 1417 [E. B. d. K. J.], University of Buenos Aires, 1120 Buenos Aires, Argentina

Differential expression and activity of constitutive mitochondrial nitric oxide synthase (mtNOS) in the mitochondrial compartment is followed by significant variations in matrix nitric oxide (NO) steady-state concentration. The mitochondrial utilization of NO involves the production of superoxide anion and H₂O₂, a species freely diffusible outside the mitochondria that participates in the modulation of cell proliferation and apoptosis and in cell transformation and cancer. On these bases, we analyzed the modulation of mtNOS in the frame of cellular redox state in M3, MM3, and P07 murine tumors and their respective cell lines, as compared with normal proliferating and quiescent tissues. The results showed that: (a) tumoral and proliferating mitochondria only retain 10–50% of the activity of complexes I, II-III, and IV and Mn-SOD of quiescent tissues; (b) normal proliferating tissues, like embryonic liver or pregnant mammary gland, have 10–20% of mtNOS expression and activity and mitochondrial H₂O₂ yield than quiescent nonproliferating tissues; (c) similarly but irrespective of mtNOS expression, tumoral mitochondria have no >5% of mtNOS activity and H₂O₂ yield of mature tissues; and (d) in opposition to stable tissues, both tumoral and normal proliferating cells exhibit high cyclin D1 expression and low pro-apoptotic p38mitogen-activated protein kinase activity. Dually, H₂O₂ stimulated tumor cell proliferation (<10 µM) or markedly inhibited it (>10 µM) with parallel variations of cyclin D1, phospho-extracellular-regulated kinase1/2, and phospho-p38mitogen-activated protein kinase. It is surmised that decreased oxidative phosphorylation, defective tumoral mtNOS, and low mitochondrial NO-dependent H₂O₂ may be a platform to link persistent tumoral growth to embryonic behavior.

This article has been cited by other articles:

				M. C. Carreras and J. J. Poderoso Mitochondrial nitric oxide in the signaling of cell integrated responses Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1569 - C1580. [Abstract] [Full Text] [PDF]

				T. Zaobornyj, L. B. Valdez, P. La Padula, L. E. Costa, and A. Boveris Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. II. mtNOS activity J Appl Physiol, June 1, 2005; 98(6): 2370 - 2375. [Abstract] [Full Text] [PDF]