J J Poderoso

University of Buenos Aires, Buenos Aires, Buenos Aires F.D., Argentina

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Publications (102)360.39 Total impact

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    ABSTRACT: Sepsis-associated multiple organ failure is a major cause of mortality characterized by a massive increase of reactive oxygen and nitrogen species (ROS/RNS) and mitochondrial dysfunction. Despite intensive research, determining events in the progression or reversal of the disease are incompletely understood. Herein, we studied two prototype sepsis models: endotoxemia and cecal ligation and puncture (CLP)-which showed very different lethality rates (2.5% and 67%, respectively)-, evaluated iNOS, ROS and respiratory chain activity, and investigated mitochondrial biogenesis and dynamics, as possible processes involved in sepsis outcome. Endotoxemia and CLP showed different iNOS, ROS/RNS, and complex activities time-courses. Moreover, these alterations reverted after 24-h endotoxemia but not after CLP. Mitochondrial biogenesis was not elicited during the first 24 h in either model but instead, 50% mtDNA depletion was observed. Mitochondrial fusion and fission were evaluated using real-time PCR of mitofusin-2 (Mfn2), dynamin-related protein-1 (Drp1), and using electron microscopy. During endotoxemia, we observed a decrease of Mfn2-mRNA levels at 4-6 h, and an increase of mitochondrial fragmentation at 6 h. These parameters reverted at 24 h. In contrast, CLP showed not only decreased Mfn2-mRNA levels at 12-18 h but also increased Drp1-mRNA levels at 4 h, and enhanced and sustained mitochondrial fragmentation. The in vivo pretreatment with mdivi-1 (Drp1 inhibitor) significantly attenuated mitochondrial dysfunction and apoptosis in CLP. Therefore, abnormal fusion-to-fission balance, probably evoked by ROS/RNS secondary to iNOS induction, contributes to the progression of sepsis. Pharmacological targeting of Drp1 may be a potential novel therapeutic tool for sepsis.
    Free Radical Research 04/2014; · 3.28 Impact Factor
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    ABSTRACT: Background Hepatocyte apoptosis, the hallmark of Non-alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases.Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH. Methods: C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan.ResultsMice fed a HFD diet demonstrate a 5-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum AST and ALT levels, NAS histologic score and IL 1-β, TNF-α, MCP-1 and CXCL2 qPCR. These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for HSC activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR.In Conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive anti-fibrotic therapy in NASHThis article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 04/2014; · 3.87 Impact Factor
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    ABSTRACT: Introducción. El estrés oxidativo es una de las causas subya- centes de la disfunción miocardica en sepsis. Reciente evidencia demuestra el papel importante de trx1 como regulador antioxidan- te. Por tanto el objetivo fue estudiar si la trx1 ejerce un rol protector en la reserva contractil miocárdica y en el estrés oxidativo durante la sepsis. Métodos. Se utilizaron ratones machos transgenicos con sobreexpresión especifica de trx1 en corazón (trx1k-in) y sus wildtype (wt). Se les realizó ligadura y doble punción cecal o laparotomía. Se realizó análisis de sobrevida. Después de 6, 18 o 24 h, en tejido cardiaco fue determinada la expresión y actividad de enzimas antioxidantes, detección de grupos carbonilos, actividad de complejos mitocondriales y producción de peroxido de hidrógeno (H2O2) mitocondrial. Se evaluó el inotropismo, a través de la presión desarrollada del ventrículo izquierdo (PDVI), y la reserva contráctil frente a estímulo b-adrenérgico (isoproterenol 1μM) en corazones aislados e isovolúmicos (Langendorff). Re- sultados. Trx1 incrementó la esperanza de vida media (trx1k-in: 36, wt: 28 h; p=0.0204). Los valores de PDVI antes del estímulo b-adrenérgico fueron similares entre los grupos estudiados. Sin embargo a las 6 hs después de la sepsis, la respuesta a isoproterenol fue mayor en trx1k-in comparado con los wt (wt: 5,6 ± 1,39; trx1k-in: 14,9 ± 1,39 mmHg p=0.0012). En trx1k-in, la actividad de trx1 fue significantemente incrementada, la expresión de trx2 y actividad y expresión de MnSOD se prolongó hasta las 24 h, y sólo la actividad del complejo II-III fue inhibida tardíamente. Se observó menor oxidación proteica en trx1k-in en relación a menor producción mitocondrial de H2O2. Conclusion. Trx1 atenuó la caída de la reserva contráctil a las 6 hs de producida la sepsis y retrasó el daño oxidativo mitocondrial durante la disfunción miocárdica inducida por sepsis.
    Medicina 11/2013; 73(supl. III):201. · 0.42 Impact Factor
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    ABSTRACT: Progesterone is a neuroprotective, promyelinating and antiinflammatory factor for the nervous system. Here we discuss progesterone effects in models of motoneuron degeneration and neuroinflammation. In neurodegeneration of the Wobbler mouse, a subset of spinal cord motoneurons showed increased activity of nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of respiratory chain complexes and decreased activity and protein expression of Mn-superoxide dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several degrees of motor impairment. Progesterone treatment restored the expression of neuronal markers, decreased the activity of NOS and enhanced complex I respiratory activity and MnSOD2. Long-term treatment with progesterone increased muscle strength, biceps weight and survival. Collectively, these data supported that progesterone prevented neurodegeneration. To study progesterone effects in neuroinflammation, we employed mice with experimental autoimmune encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of the inflammatory mediators tumour necrosis factor α (TNFα) and its receptor TNFR1, the microglial marker CD11b, iNOS and the toll-like receptor 4 (TLR4). Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells became targets of progesterone anti-inflammatory effects. These results open the ground for testing the usefulness of neuroactive steroids for neurological disorders. This article is protected by copyright. All rights reserved.
    Journal of Neuroendocrinology 05/2013; · 3.51 Impact Factor
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    ABSTRACT: In the Wobbler mouse, a mutation of the Vps54 protein increases oxidative stress in spinal motoneurons, associated to toxic levels of nitric oxide and hyperactivity of nitric oxide synthase (NOS). Progesterone neuroprotection has been reported for several CNS diseases, including the Wobbler mouse neurodegeneration. In the present study, we analyzed progesterone effects on mitochondrial-associated parameters of symptomatic Wobbler mice. The activities of mitochondrial respiratory chain complexes I, II-III and IV and protein levels of mitochondrial and cytosolic NOS were determined in cervical and lumbar cords from control, Wobbler and Wobbler mice receiving a progesterone implant for 18 days. We found a significant reduction of complex I and II-III activities in mitochondria and increased protein levels of mitochondrial, but not cytosolic nNOS, in the cervical cord of Wobbler mice. Progesterone treatment prevented the reduction of complex I in the cervical region and the increased level of mitochondrial nNOS. Wobbler motoneurons also showed accumulation of amyloid precursor protein immunoreactivity and decreased activity and immunostaining of MnSOD. Progesterone treatment avoided these abnormalities. Therefore, administration of progesterone to clinically afflicted Wobblers (i) prevented the abnormal increase of mitochondrial nNOS and normalized respiratory complex I; (ii) decreased amyloid precursor protein accumulation, a sign of axonal degeneration, and (iii) increased superoxide dismutation. Thus, progesterone neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal cord.
    Journal of Neurochemistry 04/2012; 122(1):185-95. · 3.97 Impact Factor
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    ABSTRACT: Eukaryotic mitochondria resulted from symbiotic incorporation of α-proteobacteria into ancient archaea species. During evolution, mitochondria lost most of the prokaryotic bacterial genes and only conserved a small fraction including those encoding 13 proteins of the respiratory chain. In this process, many functions were transferred to the host cells, but mitochondria gained a central role in the regulation of cell proliferation and apoptosis, and in the modulation of metabolism; accordingly, defective organelles contribute to cell transformation and cancer, diabetes, and neurodegenerative diseases. Most cell and transcriptional effects of mitochondria depend on the modulation of respiratory rate and on the production of hydrogen peroxide released into the cytosol. The mitochondrial oxidative rate has to remain depressed for cell proliferation; even in the presence of O₂, energy is preferentially obtained from increased glycolysis (Warburg effect). In response to stress signals, traffic of pro- and antiapoptotic mitochondrial proteins in the intermembrane space (B-cell lymphoma-extra large, Bcl-2-associated death promoter, Bcl-2 associated X-protein and cytochrome c) is modulated by the redox condition determined by mitochondrial O₂ utilization and mitochondrial nitric oxide metabolism. In this article, we highlight the traffic of the different canonical signaling pathways to mitochondria and the contributions of organelles to redox regulation of kinases. Finally, we analyze the dynamics of the mitochondrial population in cell cycle and apoptosis.
    Antioxidants & Redox Signaling 10/2011; 16(10):1150-80. · 8.20 Impact Factor
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    ABSTRACT: Hemorrhage (H) is associated with a left ventricular (LV) dysfunction. However, the diastolic function has not been studied in detail. The main goal was to assess the diastolic function both during and 120 min after bleeding, in the absence and in the presence of L-NAME. Also, the changes in mRNA and protein expression of nitric oxide synthase (NOS) isoforms were determined. New Zealand rabbits were divided into three groups: Sham group, H group (hemorrhage 20% blood volume), and H L-NAME group (hemorrhage treated with L-NAME). We evaluated systolic and diastolic ventricular functions in vivo and in vitro (Langendorff technique). Hemodynamic parameters and LV function were measured before, during, and at 120 min after bleeding. We analyzed the isovolumic relaxation using t ½ in vivo (closed chest). After that, hearts were excised and perfused in vitro to measure myocardial stiffness. Samples were frozen to measure NOS mRNA and protein expression. The t½ increased during bleeding and returned to basal values 120 min after bleeding. L-NAME blunted this effect. Data from the H group revealed a shift to the left in the LV end diastolic pressure-volume curve at 120 min after bleeding, which was blocked by L-NAME. iNOS and nNOS protein expression and mRNA levels increased at 120 min after the hemorrhage. Acute hemorrhage induces early and transient isovolumic relaxation impairment and an increase in myocardial stiffness 120 min after bleeding. L-NAME blunted the LV dysfunction, suggesting that NO modulates ventricular function through iNOS and nNOS isoforms.
    Molecular and Cellular Biochemistry 08/2011; 359(1-2):169-76. · 2.33 Impact Factor
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    ABSTRACT: Obesity arises on defective neuroendocrine pathways that increase energy intake and reduce mitochondrial metabolism. In the metabolic syndrome, mitochondrial dysfunction accomplishes defects in fatty acid oxidation and reciprocal increase in triglyceride content with insulin resistance and hyperglycemia. Mitochondrial inhibition is attributed to reduced biogenesis, excessive fission, and low adipokine-AMP-activated protein kinase (AMPK) level, but lateness of the respiratory chain contributes to perturbations. Considering that nitric oxide (NO) binds cytochrome oxidase and inhibits respiration, we explored NO as a direct effector of mitochondrial dysfunction in the leptin-deficient ob/ob mice. A remarkable three- to fourfold increase in neuronal nitric oxide synthase (nNOS) expression and activity was detected by western blot, citrulline assay, electronic and confocal microscopy, flow cytometry, and NO electrode sensor in mitochondria from ob/ob mice. High NO reduced oxygen uptake in ob/ob mitochondria by inhibition of complex IV and nitration of complex I. Low metabolic status restricted β-oxidation in obese mitochondria and displaced acetyl-CoA to fat synthesis; instead, small interference RNA nNOS caused a phenotype change with fat reduction in ob/ob adipocytes. We evidenced that leptin increases mitochondrial respiration and fat utilization by potentially inhibiting NO release. Accordingly, leptin administration to ob/ob mice prevented nNOS overexpression and mitochondrial dysfunction in vivo and rescued leptin-dependent effects by matrix NO reduction, whereas leptin-Ob-Rb disruption increased the formation of mitochondrial NO in control adipocytes. We demonstrated that in ob/ob, hypoleptinemia is associated with critically low mitochondrial p-AMPK and that, oppositely to p-Akt2, p-AMPK is a negative modulator of nNOS. Thereby, defective leptin-AMPK pathway links mitochondrial NO to obesity with complex I syndrome and dysfunctional mitochondria.
    Antioxidants & Redox Signaling 04/2011; 15(9):2395-406. · 8.20 Impact Factor
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    ABSTRACT: The subcellular localization and physiological functions of biomolecules are closely related and thus it is crucial to precisely determine the distribution of different molecules inside the intracellular structures. This is frequently accomplished by fluorescence microscopy with well-characterized markers and posterior evaluation of the signal colocalization. Rigorous study of colocalization requires statistical analysis of the data, albeit yet no single technique has been established as a standard method. Indeed, the few methods currently available are only accurate in images with particular characteristics. Here, we introduce a new algorithm to automatically obtain the true colocalization between images that is suitable for a wide variety of biological situations. To proceed, the algorithm contemplates the individual contribution of each pixel's fluorescence intensity in a pair of images to the overall Pearsońs correlation and Manders' overlap coefficients. The accuracy and reliability of the algorithm was validated on both simulated and real images that reflected the characteristics of a range of biological samples. We used this algorithm in combination with image restoration by deconvolution and time-lapse confocal microscopy to address the localization of MEK1 in the mitochondria of different cell lines. Appraising the previously described behavior of Akt1 corroborated the reliability of the combined use of these techniques. Together, the present work provides a novel statistical approach to accurately and reliably determine the colocalization in a variety of biological images.
    PLoS ONE 01/2011; 6(4):e19031. · 3.53 Impact Factor
  • Medicina 06/2010; 70(3):233-239. · 0.42 Impact Factor
  • Journal of Hepatology - J HEPATOL. 01/2010; 52.
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    ABSTRACT: In order to evaluate the relationship between systemic inflammatory response and mortality in the older hospitalized patient, we developed a prospective cohort study in which we evaluated a nutritional score (SGA), years of instruction, functional status, organic failure (Marshall), presence of sepsis, comorbidities (Charlson), cognitive state (MMSE), albumin, erythrocyte sedimentation rate and mortality. Fifty two patients were included, 19 men (36.5%) and 33 women (63.5%), mean age was 80 (Interquartile Range 12.5) years. 29 (55.8%) patients were well-nourished and 23 (44.2%) malnourished, 53.8% of patients developed sepsis at admission or during hospitalization. Total nosocomial mortality was 7.7 % (n = 4) and one-year mortality was 31.8% (n = 14). Comparative analyses showed older age (80 vs. 78; p = 0.012), less years of instruction (7 vs. 8; p = 0.027), lower MMST (14 vs. 27; p = 0.017), lower previous functional status (21 vs. 32; p < 0.0001), lower albumin (3 vs. 3.35; p = 0.014) and higher organic failure score at admission (3 vs. 1; p = 0.01) with more number of affected organs (2 vs. 1; p = 0.003) in malnourished patients compared to well nourished ones. Higher incidence of sepsis -at admission or during hospitalization- (73.9% vs. 37.9%; p = 0.01) and more severe stages of sepsis were also observed in malnourished patients. One-year mortality was significantly higher in malnourished (52.2% vs. 9.5%, log rank test = 0.002). In conclusion, malnourished patients presented greater systemic inflammatory response.
    Medicina 01/2010; 70(3):233-9. · 0.42 Impact Factor
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    ABSTRACT: Phylogenetic studies had shown that evolution of mitochondria occurred in parallel with the maturation of kinases implicated in growth and final size of modern organisms. In the last years, different reports confirmed that MAPKs, Akt, PKA and PKC are present in mitochondria, particularly in the intermembrane space and inner membrane where they meet mitochondrial constitutive upstream activators. Although a priori phosphorylation is the apparent aim of translocation, new perspectives indicate that kinase activation depends on redox status as determined by the mitochondrial production of oxygen species. We observed that the degree of mitochondrial oxidation of ERK Cys38 and Cys214 discriminates the kinase to be phosphorylated and determines translocation to the nuclear compartment and proliferation, or accumulation in mitochondria and arrest. Otherwise, transcriptional gene regulation by Akt depends on Cys60 and Cys310 oxidation to sulfenic and sulfonic acids. It is concluded that the interactions between kinases and mitochondria control cell signaling pathways and participate in the modulation of cell proliferation and arrest, tissue protection, tumorigenesis and cancer progression.
    Advanced drug delivery reviews 11/2009; · 11.96 Impact Factor
  • Medicina 10/2009; 69(4):460-465. · 0.42 Impact Factor
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    ABSTRACT: Mitochondria are specialized organelles that control energy metabolism and also activate a multiplicity of pathways that modulate cell proliferation and mitochondrial biogenesis or, conversely, promote cell arrest and programmed cell death by a limited number of oxidative or nitrative reactions. Nitric oxide (NO) regulates oxygen uptake by reversible inhibition of cytochrome oxidase and the production of superoxide anion from the mitochondrial electron transfer chain. In this sense, NO produced by mtNOS will set the oxygen uptake level and contribute to oxidation-reduction reaction (redox)-dependent cell signaling. Modulation of translocation and activation of neuronal nitric oxide synthase (mtNOS activity) under different physiologic or pathologic conditions represents an adaptive response properly modulated to adjust mitochondria to different cell challenges.
    Experimental Biology and Medicine 07/2009; 234(9):1020-8. · 2.80 Impact Factor
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    ABSTRACT: In order to achieve the goal of this article, as an example we will describe the strategies followed to analyze the presence of the multi-kinase complex at the mitochondria and the posttranslational modification of two key mitochondrial proteins, which participate in the regulation of cholesterol transport across the mitochondrial membranes and in the regulation of steroid biosynthesis. Hormones, ions or growth factors modulate steroid biosynthesis by the posttranslational phosphorylation of proteins. The question still remains on how phosphorylation events transmit a specific signal to its mitochondrial site of action. Cholesterol transport requires specific interactions in mitochondria between several proteins including a multi-kinase complex. The presence of this multi-kinase complex at the mitochondria reveals the importance of the posttranslational modification of mitochondrial proteins for its activity and functions. The activation of PKA triggers the posttranslational modification of the mitochondrial acyl-CoA thioesterase (Acot2), which releases arachidonic acid (AA) in the mitochondria, and the activation of a kinase cascade that leads to the phoshorylation of the steroidogenic acute regulatory (StAR) protein. The function of StAR is to facilitate the access of cholesterol to the first enzyme of the biosynthesis process and its induction is dependent on Acot2 and intramitochondrial AA release. Truncation of the StAR protein is associated with the steroid deficiency disease, congenital lipoid adrenal hyperplasia.
    Methods in enzymology 02/2009; 457:169-92. · 1.90 Impact Factor
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    ABSTRACT: Extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) are members of the MAPK family and participate in the transduction of stimuli in cellular responses. Their long-term actions are accomplished by promoting the expression of specific genes whereas faster responses are achieved by direct phosphorylation of downstream effectors located throughout the cell. In this study we determined that hERK1 translocates to the mitochondria of HeLa cells upon a proliferative stimulus. In the mitochondrial environment, hERK1 physically associates with (i) at least 5 mitochondrial proteins with functions related to transport (i.e. VDAC1), signalling, and metabolism; (ii) histones H2A and H4; and (iii) other cytosolic proteins. This work indicates for the first time the presence of diverse ERK-complexes in mitochondria and thus provides a new perspective for assessing the functions of ERK1 in the regulation of cellular signalling and trafficking in HeLa cells.
    PLoS ONE 01/2009; 4(10):e7541. · 3.53 Impact Factor
  • Juan J. Poderoso
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    ABSTRACT: Mitochondria require nitric oxide (NO) to exert a delicate control of metabolic rate as well as to regulate life functions, cell cycle activation and arrest, and apoptosis. All activities depend on the matrical NO steady state concentration as provided by mitochondrial (mtNOS) and cytosolic sources (eNOS) and reduced by forming superoxide anion and H2O2 and a low peroxynirite (ONOO−) yield. We review herein the biochemical pathways involved in the control of NO mitochondrial level and its biological and physiological significance in hormone effects and aging. At high NO, the cost of this physiological regulation is that ONOO− excess will lead to nitrosation/nitration and oxidization of mitochondrial and cell proteins and lipids. The disruption of NO modulation of mitochondrial respiration supports then, a platform for prevalent neurodegenerative and metabolic diseases.
    Archives of Biochemistry and Biophysics 01/2009; · 3.37 Impact Factor
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    ABSTRACT: Akt is a serine/threonine kinase involved in cell proliferation, apoptosis, and glucose metabolism. Akt is differentially activated by growth factors and oxidative stress by sequential phosphorylation of Ser(473) by mTORC2 and Thr(308) by PDK1. On these bases, we investigated the mechanistic connection of H(2)O(2) yield, mitochondrial activation of Akt1 and cell cycle progression in NIH/3T3 cell line with confocal microscopy, in vivo imaging, and directed mutagenesis. We demonstrate that modulation by H(2)O(2) entails the entrance of cytosolic P-Akt1 Ser(473) to mitochondria, where it is further phosphorylated at Thr(308) by constitutive PDK1. Phosphorylation of Thr(308) in mitochondria determines Akt1 passage to nuclei and triggers genomic post-translational mechanisms for cell proliferation. At high H(2)O(2), Akt1-PDK1 association is disrupted and P-Akt1 Ser(473) accumulates in mitochondria in detriment to nuclear translocation; accordingly, Akt1 T308A is retained in mitochondria. Low Akt1 activity increases cytochrome c release to cytosol leading to apoptosis. As assessed by mass spectra, differential H(2)O(2) effects on Akt1-PDK interaction depend on the selective oxidation of Cys(310) to sulfenic or cysteic acids. These results indicate that Akt1 intramitochondrial-cycling is central for redox modulation of cell fate.
    PLoS ONE 01/2009; 4(10):e7523. · 3.53 Impact Factor

Publication Stats

3k Citations
360.39 Total Impact Points

Institutions

  • 1983–2013
    • University of Buenos Aires
      • • Faculty of Medicine
      • • Department of Medicine
      • • Clinical Hospital (UDH)
      Buenos Aires, Buenos Aires F.D., Argentina
  • 2009
    • THE UNIVERSITY OF BAMENDA
      Bamenda, North-West Province, Cameroon
  • 2008
    • IntraMed
      Buenos Aires, Buenos Aires F.D., Argentina
  • 1999–2006
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2003
    • Hospital de Clínicas (Argentina)
      Buenos Aires, Buenos Aires F.D., Argentina
  • 1998–2001
    • University of Southern California
      • School of Pharmacy
      Los Angeles, CA, United States