Mitochondrial nitric oxide synthase drives redox signals for proliferation and quiescence in rat liver development

Carreras, Marı́a Cecilia; Converso, Daniela P.; Lorenti, Alicia; Barbich, Mariana; Levisman, Damián; Jaitovich, Ariel; Arciuch, Valeria G. Antico; Galli, Soledad; Poderoso, Juan José

doi:10.1002/hep.20255

Cited by 58 publications

(54 citation statements)

References 37 publications

(43 reference statements)

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“…Low NO levels were associated with low H 2 O 2 yields, high proliferation rate, and activation of ERK1/2, a pattern resembling that shown in embryonic development (32,44). Because proapoptotic p38 or JNK1/2 did not become phosphorylated, we surmise the results are part of the "reciprocal dance between cancer and fetal development."…”

Section: The Lack Of Cell and Mitochondrial No: A New Gateway To Pathsupporting

confidence: 60%

“…In contrast, NOS II is not constitutive and does not depend on Ca 2ϩ concentration; NOS II gene expression is modulated by inflammatory mediators, like cytokines TNF-␣, IFN-␥, and LPS that activate transcription factors like NF-B or AP-1 (59). The mtNOS is nNOS-␣ translocated to mitochondria with specific posttranslational modifications such as myristoylation and phosphorylation of Ser-1412 in an Akt-dependent motif (RXRXXS/T); it is constitutively expressed and Ca 2ϩ dependent, and it is subjected to modulation by drugs or hormones or during development (21,32,34,119).…”

Section: Nitric Oxide In Mitochondriamentioning

confidence: 99%

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Mitochondrial nitric oxide in the signaling of cell integrated responses

Carreras¹,

Poderoso²

2007

American Journal of Physiology-Cell Physiology

116

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Carreras MC, Poderoso JJ. Mitochondrial nitric oxide in the signaling of cell-integrated responses. Am J Physiol Cell Physiol 292: C1569 -C1580, 2007; doi:10.1152/ajpcell.00248.2006.-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 ϳ30 -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 2O2 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 2O2 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; mitogenactivated protein kinase MITOCHONDRIA PLAY A PIVOTAL role in cell physiology, producing the cellular energy and acting as signaling organelles. A mitochondria-based network elicits a multiplicity of effects and responses, depending on the course of cell life and on the environmental stimuli. This organization resulted from the selective pressure applied on eukaryotes to evolve the original endosymbiont process between bacteria, i.e., Cyanobacteria sp., and the primordial prokaryote structure. Accordingly, contribution of mitochondria includes several cohorts of integrated biochemical pathways shared with nucleus and mainly directed to execute the different cell programs or with the plasma membrane to elicit the responses to environmental challenges. Interestingly, mitochondrial pathways involve a limited number of reactions; depending on the steady-state concentrations of substrates and products and on the rate of oxidative reactions, there exist dual or even opposite effects on cell responses. NITRIC OXIDE IN MITOCHONDRIAMitochondria are the central organelles in cell bioenergetics. Most available oxygen is consumed in the electron transfer chain, placed in the inner membrane of the two membranes that limit the differentiated mitochondrial compartment. Electron transfer through mitochondrial complexes I, III, and IV is joined to proton pumping across the inner membrane, creat...

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Section: The Lack Of Cell and Mitochondrial No: A New Gateway To Pathsupporting

confidence: 60%

Section: Nitric Oxide In Mitochondriamentioning

confidence: 99%

Mitochondrial nitric oxide in the signaling of cell integrated responses

Carreras¹,

Poderoso²

2007

American Journal of Physiology-Cell Physiology

116

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“…At present, mitochondrial NO (10,34,35) and H 2 O 2 (2, 10) are considered together as signals that are able to regulate genes involved in the control of cell metabolism and proliferation. In particular, NO was found to trigger mitochondrial biogenesis in diverse cell types (35,36), an effect observed during chronic exposure to hypobaric hypoxia (12).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments

Zaobornyj¹,

Valdez²,

Iglesias³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Zaobornyj T, Valdez LB, Iglesias DE, Gasco M, Gonzales GF, Boveris A. Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments. Am J Physiol Heart Circ Physiol 296: H1741-H1747, 2009. First published April 3, 2009 doi:10.1152/ajpheart.00422.2008.-Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, PO2 ϭ 12.2 kPa) for up to 84 days showed a physiological adaptive response with decreased body weight gain (15%), increased right ventricle weight (100%), and increased hematocrit (40%) compared with sea level animals. These classical parameters of adaptation to high altitude were accompanied by an increase in heart mitochondrial enzymes: complexes I-III activity by 34% and mitochondrial nitric oxide synthase (mtNOS) activity and expression by Ͼ75%. The hyperbolic increase for mtNOS activity during adaptation to high altitude was similar to the observed pattern for hematocrit. Hematocrit and mtNOS activity mean values correlated linearly (r 2 ϭ 0.75, P Յ 0.05). Chronic treatment for 28 days with sildenafil (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) decreased the response of mtNOS to high altitude by 25%. Conversely, N Gnitro-L-arginine methyl ester treatment (8.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) increased such response by 40%, whereas L-arginine treatment (106 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) had no effect. Nitric oxide (NO) production by mtNOS accounts for ϳ49% of total cellular NO production in sea level rats and for ϳ54% in rats exposed to high altitude for 84 days. It is concluded that mtNOS is a substantial source of cardiac NO, a factor in the adaptive response to sustained heart hypoxia that is susceptible to be modified by pharmacological treatments. mitochondrial nitric oxide synthase activity; mitochondrial nitric oxide synthase expression; mitochondrial respiratory complexes; hematocrit; nitro-L-arginine methyl ester HIGH ALTITUDE IS A MULTIFACTORIAL source of stress in which hypobaric hypoxia is the most important component. The O 2 gradient between atmospheric air and cells decreases from 105 mmHg at sea level to 49 mmHg at high altitude (20). There are a number of adaptive responses that are triggered by this situation, such as increased ventilation (28), pulmonary hypertension (40), erythropoiesis (39), and heart work load. The adaptation to high altitude constitutes a situation that has both advantageous and disadvantageous consequences for human health. The main long term effects are decreased physical activity and life span. Among the beneficial effects, there is a recognized cardioprotection with improvement of the myocardial tolerance to ischemic episodes. A number of studies involving exposure to natural (22) or simulated (29) hypobaric hypoxia reported that this adaptation is associated to lower incidence and smaller size of myocardial infarction (30).Although the mechanism by which adaptation to hypoxia has cardioprotective effects remains not elucidated, nitric oxide (NO) has been extensively proposed as one of the molecular messengers inv...

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“…27 The existence of a mitochondrial-specific form of NOS (mtNOS) has been proposed in recent years. 28,29 However, it is still unclear whether this mitochondrial NOS enzyme is functionally distinguishable from eNOS, nNOS and iNOS. Studies conducted in NOS-deficient mice suggested that eNOS deficiency has the most profound effect on mitochondrial biogenesis and energy metabolism.…”

Section: Mitochondrial Mass In Primary Cll Cells Is Significantly Cormentioning

confidence: 99%

Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine

Carew

Nawrocki

et al. 2004

Leukemia

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B cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western hemisphere, yet many biological and molecular features of the disease remain undefined. CLL cells generate increased levels of radical species such as superoxide and nitric oxide (NO), which is associated with mitochondrial DNA mutations. Considering that NO levels can affect mitochondrial biogenesis, we hypothesized that the inherent nitrosative stress in CLL cells may lead to hyperactive mitochondrial biogenesis. Here we report that primary CLL cells contained significantly more mitochondria than normal lymphocytes and that their mitochondrial mass was significantly related to endogenous NO levels. Expression of the mitochondrial biogenesis factors nuclear respiratory factor-1 and mitochondrial transcription factor A was elevated in most CLL specimens examined and appeared to be related to cellular NO levels. Treatment of B cells with exogenous NO caused a substantial increase in mitochondrial mass. In vitro sensitivity of CLL cells to fludarabine was highly related to mitochondrial mass in that cells with greater mitochondrial mass were less sensitive to the drug. Taken together, our results suggest that NO is a key mediator of mitochondrial biogenesis in CLL and that modulation of mitochondrial biogenesis by NO may alter cellular sensitivity to fludarabine.

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Mitochondrial nitric oxide synthase drives redox signals for proliferation and quiescence in rat liver development

Cited by 58 publications

References 37 publications

Mitochondrial nitric oxide in the signaling of cell integrated responses

Mitochondrial nitric oxide in the signaling of cell integrated responses

Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments

Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine

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