Julio César Cárdenas
Profesor Asociado
J. Cesar Cárdenas obtuvo su Ph.D. de la Universidad de Chile, donde estudió el mecanismo que regulaba el Ca2 + nuclear bajo la tutoría del Dr. Enrique Jaimovich. Luego se trasladó a la Facultad de Medicina de la Universidad de Pensilvania, donde exploró el canal de Ca2 + del receptor 1,4,5-trisfosfato (InsP3R) de localización nuclear utilizando microscopía electrónica de alta resolución y criofractura como becario postdoctoral con la Dra. Clara Franzini-Armstrong. Motivado a comprender mejor el papel fisiológico del InsP3R, se unió al laboratorio del Dr. Kevin Foskett también en UPENN, donde desarrolló un gran interés en la regulación del metabolismo celular y las bioenergéticas por Ca2 +. Fue el primero en demostrar que la señalización de Ca2 + constitutivo basal bajo por InsP3R es esencial para mantener la producción mitocondrial suficiente de NADH para apoyar la fosforilación oxidativa en células en reposo. En ausencia de esta señalización de calcio, las células se comprometen metabólicamente y se activa una autofagia independiente de mTOR dependiente de AMPK para la supervivencia.
Se unió al Departamento de Anatomía y Programa de Biología del Desarrollo Celular en el Instituto de Ciencias Biomédicas de la Facultad de Medicina de la Universidad de Chile en marzo de 2012.
PUBLICACIONES
MTOR-independent autophagy induced by interrupted endoplasmic reticulum-mitochondrial Ca2+ communication: a dead end in cancer cells. Ahumada-Castro, U., Silva-Pavez, E., Pardo, E., Lovy, A., and Cárdenas, C. Autophagy. (Accepted).
FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway. Urra FA, Muñoz F, Córdova-Delgado M, Ramírez MP, Peña-Ahumada B, Rios M, Cruz P, Ahumada-Castro U, Bustos G, Silva-Pavez E, Pulgar R, Morales D, Varela D, Millas-Vargas JP, Retamal E, Ramírez-Rodríguez O, Pessoa-Mahana H, Pavani M, Ferreira J, Cárdenas C, Araya-Maturana R. Scientific Report. 8(1):13190, 2018
Mitochondrial Regulation by Calcium as Basis of Neurodegeneration Associated to Aging. Müller, M., Ahumada-Castro, U., Gonzalez-Billault, C., Court, F.A., and Cárdenas, C. Frontiers in Neuroscience. 12:470, 2018
Hepatic Glutaminase activity and glutamine flux contributes to glucagon-stimulated gluconeogenesis and systemic glucose homeostasis. Miller, R.A., Shi, Y., Lu,W., Pirman, D.A., Jatkar, A., Blatnik, M., Wu, H., Cárdenas, C., Wan, M., Foskett, J.K., Park, J.O., Zhang, Y., Holland, W.L., Rabinowitz, J.D., Birnbaum, M.J. Nature Medicine. 24(4):518-524, 2018.
Mouse Tc17 cells display memory T cell-like traits. Flores-Santibáñez, F., Cuadra, B., Fernández, D., Rosemblatt, M., Núñez, S., Cruz, P., Gálvez-Cancino, F., Cárdenas, C., Lladser, A., Rosemblatt, M., Bono, M.R., and Sauma, D. Frontiers Immunology. 9:209, 2018.
Editorial: Inter- Organelle Calcium Communication in Cancer. Cardenas, C., Pinton, P., and Bultynck, G. Frontiers in Oncology. 8:14, 2018.
Calcium and Mitochondrial Metabolism in Cancer, a Novel Potential Target? Bustos, G., Cruz, P., Lovy, A., and Cárdenas C. Frontiers in Oncology. 7:199, 2017.
The mitochondrial complex(I)ty of cancer. Urra, FA., Muñoz, F., Lovy, A., Cárdenas, C. Frontiers in Oncology. 7:118, 2017.
Diabetic concentrations of Metformin inhibit platelet-mediated ovarian cancer cell
progression. Erices, R., Cubillos, S., Aravena, R., Santoro, F., Marquez, M., Orellana, R., Ramírez, C., González, P., Fuenzalida, P., Bravo, ML., Oliva, B., Kato, S., Ibañez, C., Brañes, J., Bravo, E., Alonso, C., García, K., Arab, C., Torres, VA., Godoy, A., Pereira, J., Bustos, G., Cardenas, C., Cuello, MA., and Owen, GI. Oncotarget. 8 (13): 20865-20880, 2017.
The Paraguayan Rhinella toad venom: Implications in the traditional medicine and proliferation of breast cancer cells. Schmeda-Hirschmann, G., Gomez, CV., de Arias, AR., Burgos-Edwards, A., Alfonso J., Rolon, M., Brusquetti, F., Netto, F., Urra, FA., Cárdenas, C. J Ethnopharmacology. 199: 106–118, 2017.
Prolonged Activation of the Htr2b Serotonin Receptor Impairs Glucose Stimulated Insulin Secretion and Mitochondrial Function in MIN6 Cells. Cataldo, L., Mizgier, ML., Bravo, R., Jaña F., Cardenas, C., Llanos, P., Olmos PR., Galgani JE., Santos JL. and Cortés VA. PLOS One. 12(1):e0170213, 2017.
Antiproliferative activity and chemical composition of the venom from the Amazonian toad Rhinella marina (Anura: Bufonidae). Schmeda-Hirschmann, G., Quispe, C., Arana, GV., Theoduloz, C., Urra, FA. and Cárdenas C. Toxicon. 121:119-129, 2016.
InsP3R, the Calcium Whisperer: Maintaining Mitochondrial Function in Cancer. Lovy, A. Foskett, J.K. and Cardenas C. Molecular Cellular Oncology. 3(4):e1185563. 2016
Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria. Cardenas, C., Muller, M, McNeal, A., Lovy, A., Jaňa, F., Bustos, G., Smith, N., Molgo, J., Diehl, A., Ridky, TW., and Foskett J.K. Cell Rep. 14(10):2313-24. 2016
Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease. Herrera A., Muñoz, P., Paris, I., Díaz-Veliz, G., Mora, S., Inzunza, J., Hultenby, K., Cardenas, C., Jaña, F., Raisman-Vozari, R., Gysling, K., Abarca, J., Steinbusch, HW. and Segura-Aguilar, J. Cell Mol Life Sci. 73(18):3583-972016, 2016
LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. Doonan, P.J., Chandramoorthy, H.C., Hoffman, N.E., Zhang X., Cárdenas, C., Shanmughapriya, S., Rajan, S., Vallem S., Mallilankaraman, K., Chen, X., Foskett, J.K., Cheung J.Y., Houser, S.R., and Madesh, M. FASEB J. 28(11):4936-49, 2014.
MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Mallilankaraman, K1., Doonan, P1., Cárdenas, C1., Chandramoorthy, Müller, M., Miller, R., H.C., Hoffman, N.E., Gandhirajan, R., Molgó, J., Birnbaum, M., Rothberg, B., Mak, D., Foskett, J.K. and Madesh, M. Cell 151:630-644, 2012. 1These authors contributed equally to this manuscript.
MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Mallilankaraman, K., Cárdenas, C., Doonan, P., Irrinki, K.M., Chandramoorthy, H.C., Madireddi, P., Yang, Y., Miller, R., Molgó, J., Kaufman, B., Foskett, J.K. and Madesh, M. Nature Cell Biol. 12:1336-1343, 2012.
Mitochondrial Ca2+ signals in autophagy. Cárdenas, C., and Foskett, J.K Cell Calcium 52: 44-51, 2012.
Constitutive activation of CREB by Alzheimer’s disease presenilin-driven InsP3R Ca2+ signaling. Müller, M., Cárdenas, C., Cheung, K.H. Mei, L., and Foskett, J.K. Proc Natl Acad Sci U S A. 108:13293-13298, 2011.
Structural evidence for perinuclear calcium microdomains in cardiac myocytes. Escobar, M., Cárdenas, C., Colavita, K., Petrenko, N.B. and Franzini-Armstrong. C. J. Mol Cell Car. 50:451-459, 2011.
Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cárdenas, C., Miller, R.A., Smith, I., Bui, T., Molgo, J., Müller, M., Vais, H., Cheung, K.H., Yang, J., Parker, I., Thompson, C., Birnbaum, M., Hallows, K.R. and Foskett J.K. Cell 142:270-283, 2010.
Visualization of inositol 1,4,5-trisphospate receptors on the nuclear envelope outer membrane by deep etching electron microscopy. Cárdenas, C., Escobar, M., Foskett, J.K., and Franzini-Armstrong, C. J. Structural Biology 171:372-381, 2010.
Abnormal distribution of inositol 1,4,5-trisphosphate receptors in human muscle can be related to altered calcium signals and gene expression in Duchenne dystrophy derived cells. Cárdenas, C., Juretić, N., Bevilacqua, J.A., García, I., Figueroa, R., Hartley, R., Taratuto, A.L., Gejman, R., Riveros, N., Molgó J. and Jaimovich E. FASEB J. 24:3210-3221, 2010.
Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Cheung, K.H., Shineman, D., Müller, M., Cárdenas, C., Mei, L., Yang, J., Tomita, T., Iwatsubo, T., Lee, V.M. and Foskett, J.K. Neuron 58:871-883, 2008.
Increase in IP3 mass levels and intracellular Ca2+ induced by Brevetoxin (Pbtx-3) depends on the membrane potential change in rat skeletal myotubes. Liberona, J.L., Cárdenas, C., Reyes, R., Molgó J. And Jaimovich E. Cell Calcium 44:289-297, 2008.
Single-channel recording of inositol trisphosphate receptor in the isolated nucleus of a muscle cell line. Kusnier C., Cardenas, C., Hidalgo, J., and Jaimovich E. Biol. Res. 39:541-553, 2006.
Nuclear inositol 1,4,5 triphosphate receptor isoforms regulate local Ca2+ transients and modulate cAMP response element binding protein phosphorylation. Cárdenas, C., Liberona J.L., Molgó, J., Colasante, C., Mignery G.A. and Jaimovich, E. J.Cell Sci. 118: 3131-3140, 2005
Xestospongin B, a competitive inhibitor of IP3-mediated Ca2+ signalling in cultured rat myotubes, isolated myonuclei, and neuroblastoma (NG108-15) cells. Jaimovich, E., Mattei, C., Liberona, J.L., Cárdenas, C., Estrada, M., Barbier, J., Debitus, C., Laurent, D. And Molgó J. FEBS Letts. 579: 2051-2057, 2005.
Depolarization induces CREB phosphorylation via calcium and PKCα dependent pathways in skeletal muscle cells. Cárdenas C., Müller M., Jaimovich E., Pérez F., Buchuk D.,Quest A.F.G and Carrasco M.A. J. Biol. Chem. 279:39122-39131, 2004.
Insulin-like growth factor-1 induces an inositol 1,4,5-trisphosphate-dependent increase in nuclear and cytosolic calcium in cultured rat cardiac myocytes. Ibarra, C., Estrada, M., Carrasco, L., Chiong, M., Liberona, J.L., Cardenas, C., Diaz-Araya, G., Jaimovich, E., and Lavandero, S. J. Biol. Chem. 279:7554-7565, 2004.
Dihydropiridine receptors as voltage sensors for a depolarization-evoked, IP3R-mediated, slow calcium signal in skeletal muscle muscle cells. Araya, R., Liberona, J.L., Cárdenas, C., Riveros, N., Estrada, M., Powell, J., Carrasco M.A., and Jaimovich, E. J.Gen.Physiol. 121: 3-16, 2003.
Calcium transients in 1B5 myotubes lacking ryanodine receptors are related to IP3 receptors. Estrada, M., Cárdenas, C., Liberona, J.L., Carrasco, M.A., Mignery, G. Allen, P.D. and Jaimovich, E. J.Biol.Chem. 276: 22868-22874, 2001.
LíNEAS DE INVESTIGACIÓN
Cancer metabolism
Mechanisms that regulate cell metabolism are a fundamental requirement for cell viability. Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes. In tumor cells, it has historically been assumed that mitochondrial metabolism is significantly diminished while aerobic glycolysis is enhanced so that it becomes the major ATP source to fuel cancer cell proliferation, a phenomenon known as the Warburg effect. Nevertheless, recent studies have shown that the mitochondrial tricarboxylic acid (TCA) cycle is both functional and essential for tumor growth, because provide the cells, in addition to energy, building blocks for the synthesis of macromolecules (proteins, lipids and nucleotides), and reducing equivalent which among other functions, regulate the redox state of the cell. Therefore, we focus our research in understand how mitochondrial activity is regulate and how we can modulate it in cancer cells. We discover that Ca2+ transfer from the endoplasmic reticulum (ER) mediate trough the inositol trisphosphate receptor (InsP3R) channel (InsP3R) to mitochondria maintain normal mitochondrial activity and the absence of this signal generate a bioenergetic crisis that induce selective cancer cell death. We demonstrate that Ca2+ transfer to mitochondria is essential to maintain the activity of pyruvate, α-ketoglutarate and isocitrate dehydrogenases, key rate limiting enzymes of the TCA cycle. In this scenario, we hypothesize that in the absence of Ca2+, tumor cells are unable to use glutamine and the TCA cycle to generate the building blocks needed to proliferate and maintain homeostasis. We expect that a deeper understanding of the regulation of mitochondria bioenergetics by InsP3R-released Ca2+ will result in the identification of new therapeutic targets.
Cellular senescence
By 2050, close to one fifth of the Chilean population will be over 60 years old, making Chile one of the countries with the highest number of elderly people. Aging is one of the main risk factors for cancer, heart and neurodegenerative diseases. Cellular senescence, an irreversible cell cycle arrest, play a big role in the decline of the regenerative potential and function of tissues, inflammation, and tumorigenesis in aged organisms. Thus, the identification, characterization, and pharmacological elimination of senescent cells have gained attention in the field of aging. Since cellular senescence is accompanied by change in metabolism and Ca2+ homeostasis, we aim to understand the role of mitochondria in the generation and maintenance of senescence cells and determine if the modulation of it activity can be use as a therapeutical tool.
Mitochondrial calcium in Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia, affecting millions of people worldwide and still incurable. It is characterized clinically as a decline of intellectual and cognitive functions and irreversible memory loss as major features. Altered Ca2+ signaling and mitochondrial dysfunction are observed early in the development of the disease, long before the onset of measurable histopathology or cognitive deficits. However, the involvement of exaggerated Ca2+ signaling on mitochondrial dysfunction remain poorly understood. A molecular mechanism underlying exaggerated Ca2+ signaling is mediated in part by Ca2+ release from the endoplasmic reticulum (ER) through inositol 1,4,5-trisphosphate receptors (IP3R). IP3R are in close proximity with the mitochondrial Ca2+ uniporter (MCU), the ion channel responsible for sequestering Ca2+ into the mitochondrial matrix. We aim to study the relation InsP3R-MCU in an AD context and determine weather the normalization of Ca2+ signaling by decreasing IP3R activity will restore or prevent mitochondrial crisis and synaptic dysfunction in AD models.
Mitochondrial function in Dysferlinophathies
The dysferlinopathies include different muscular dystrophy phenotypes; all of which are autosomal recessive, and are consequence of mutations in the dysferlin gene (DYSF). Miyoshi’s distal myopathy (MM) and limb girdle muscular dystrophy 2B (LGMD2B), are the two more common dysferlinopathy phenotypes, and correspond to allelic disorders. The functionality of dysferlin in muscle cells is under active investigation. Pathogenesis of dysferlinopahy is attributed to impaired calcium-mediated muscle-membrane repair after normal stress injury. Abnormal mitochondria have been observed in myophaties like Pompe and Danon’s disease. Accumulation of damaged mitochondria usually reflects an autophagy malfunction, which generates a bioenergetic crisis sensed by AMPK, the master energy regulator of the cell. In the dysferlinopathies context is unknow weather the mitochondria are functional or not and which is the bioenergetic state of the cells. Thus, we aim to explore the signal pathway that regulate cellular bioenergetic in this pathophysiological context and determine is potential as a therapeutical target.
PROYECTOS
Nombre: FONDECYT
Título: Mitochondrial uptake of constitutive InsP3R-released Ca2+ is essential to maintain mitochondrial metabolism and sustain breast cancer cell migration, invasion and metastasis.
Institución que financia: CONICYT
Investigador responsable: César Cárdenas
Fecha de ejecución: 2016-2019
Nombre: FONDAP Título: Geroscience Center for Brain Health and Metabolism
Institución que financia: CONICYT:
Investigador responsable: Cardenas C, González-Billault C, Slachevsky A and Court F.
Fecha de ejecución: 2015-2019
Nombre: FONDECYT
Título: Autophagy as a possible pathophysiological mechanism in dysferlinopathy
Institución que financia: CONICYT
Investigador responsable: Jorge Bevilacqua, Co-Principal Investigator; Cardenas C
Fecha de ejecución: 2015-2018
EQUIPO
Eduardo E. Silva Pavez
Postdoctoral Fellow
Bioquímica de la Pontificia Universidad Católica de Valparaiso y Ph.D en Farmacología de la Universidad de Chile. Estudia los mecanismos de la muerte celulcar en cáncer y su relación con el estado mtabólico de la célula y el rol mitocondrial en la progresión de los tumores.
Sergio Linsambarth
Posdoctoral Fellow
Biotecnólogo, PhD en Molecular Bioscience, estudiando el impacto de una dieta cetogénica en la disferlinopatía
Hernan Huerta
Postdoctoral Fellow
Bioquímico, Dr. en Ciencias Biomédicas, estudia el efecto de una dieta cetogénica en la senescencia inducida por la quimioterapia.
Galdo Bustos Cisterna
Biomedical Science Ph.D. Candidate and Lab Manager
Tecnólogo médico de la Universidad de Chile, trabajando en la comunicación del calcio retículo endoplásmico-mitocondrial en la migración de células cancerosas
Ulises Ahumada-Castro
Biomedical Science Ph.D. Candidate
Se enfoca en biologia celular y metabolismo de las células cancerosas y senescencia, con particular énfasis en el retículo endoplasmático e interacciones de organelos mitocondriales.
Marioly Muller
Biomedical Science Ph.D. Candidate
Tecnólogo Médico y Msc en Ciencias Biológicas de la Universidad de Chile y Profesor Asistente de del departamento de Tecnología Médica de la Universidad de Chile. Estudia el metabolismo mitocondrial en la neurodegeneración.
Sandra Espinoza
Research Assistant
Biotecnóloga, estudia el impacto de una dieta cetogénica en la disferlinopatía y el envejecimiento.
Andrea Puebla
Undergraduate
Bioquímica estudiando el papel de la absorción de calcio mitocondrial en la senescencia celular.
RED
Nacional
Dr. Jorge Bevilacqua, Hospital Jose Joaquin Aguirre, Universidad de Chile, Santiago Chile
Dr. Claudio Hetz, School of Medicine, Universidad de Chile, Santiago Chile
Dr. Felipe Court, Center for Integrative Biology, Universidad Mayor, Santiago, Chile
Dr. Pablo Caviedes, School of Medicine, Universidad de Chile, Santiago Chile
Dr. Ramiro Araya-Maturana, Instituto of Chemistry and Natural Resources, Universidad de Talca, Talca, Chile.
Dr. Jose Galgani, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago Chile
Dr. Daniela Sauma, School of Science, Universidad de Chile, Santiago Chile
Dr. Diego Garcia, School of Medicine, Universidad de Chile, Santiago Chile
Internacional
Dr. Kevin Foskett, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Dr. Armen Zakarian, Department of Chemistry, University of California, Santa Barbara, USA.
Dr. Judith Campisi, The Buck Institute for Research on Aging, Novato, USA.
Dr. Madesh Muniswamy, Lewis Katz School of Medicine, Temple University, Philadelphia, USA.
Dr. Amalia Dolga, Faculty of Science and Engineering, Groningen University, Groningen, Netherland
Dr. Jordi Molgo, Institute de Neurobiologie Alfred Fessard, CNRS, Gif-sur-Yvette, France
Dr. Jimmy Crott, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, USA