Cesar Cardenas

Julio César Cárdenas

Associate Professor


JULIO.CARDENAS@UMAYOR.CL


J. Cesar Cardenas earned his Ph.D. from the University of Chile, where he studied the mechanism that regulated nuclear Ca2+ under Dr. Enrique Jaimovich’s mentoring. Then he moved to the University of Pennsylvania Medical School where he explored the nuclear localization 1,4,5-trisphosphate receptor (InsP3R) Ca2+channel by using high resolution electron microscopy and cryofracture as a postdoctoral fellow with Dr. Clara Franzini-Armstrong. Motivate in gain a better understanding of the physiological role of the InsP3R he joined Dr. Kevin Foskett’s lab also at UPENN, where he developed a strong interest in the regulation of cellular metabolism and bioenergetics by Ca2+. He was the first to show that basal constitutive low-level Ca2+ signaling by the InsP3R, is essential to maintain the sufficient mitochondrial NADH production to support oxidative phosphorylation in resting cells. In the absence of this calcium signaling, cells become metabolically compromised and a pro-survival AMPK-dependent mTOR-independent autophagy is turned on.

He joined the Department of Anatomy and Cell Developmental Biology Program at the Institute of Biomedical Science of the University of Chile School of Medicine in March of 2012.



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.

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.


Name: FONDECYT

Title: Mitochondrial uptake of constitutive InsP3R-released Ca2+ is essential to maintain mitochondrial metabolism and sustain breast cancer cell migration, invasion and metastasis

Funding institution: CONICYT

Responsible Investigator: César Cárdenas

Date ofimplementation: 2016-2019

Name: FONDAP

Title: Geroscience Center for Brain Health and Metabolism

Funding institution: CONICYT

Responsible investigator: González-Billault

Date of implementation: 2015-2019

Name: FONDECYT

Title: Autophagy as a possible pathophysiological mechanism in dysferlinopathy

Funding institution CONICYT

Responsible investigator: Jorge Bevilacqua

Date of implementation: 2015-2018

Eduardo E. Silva Pavez
Postdoctoral Fellow

Biochemist of the Pontificia Universidad Católica de Valparaíso and Ph.D. in Pharmacology of the University of Chile. study mechanisms of cell death in cancer and their relation with the metabolic state of the cell and the role of mitochondrial dynamics in tumor progression.

Sergio Linsanbarth
Postdoctoral Fellow

Biotechnologist, PhD in Molecular Bioscience, studing the impact of a ketogenic diet on dysferlinopathy.

Hernan Huerta
Postdoctoral Fellow

Biochemist, PhD in Biomedical Science, studying the effect of a ketogenic diet in the senescence induce by chemotherapy.

Galdo Bustos Cisterna
Biomedical Science Ph.D. Candidate and Lab Manager

Medical Technologist from the University of Chile, working in the endoplasmic reticulum-mitochondrial calcium communication in cancer cell migration.

Ulises Ahumada-Castro
Biomedical Science Ph.D. Candidate

Medical Technologist from the University of Chile focus in the cellular biology and metabolism of cancer and senescence cells, with particular emphasis in endoplasmic reticulum and mitochondria organelle interactions.

Marioly Muller
Biomedical Science Ph.D. Candidate

Medical Technologist and MSc in Biological Sciences from the University of Chile and Assistant Professor of the Medical Technology Department at the University of Chile.

Studying mitochondrial metabolism in neurodegeneration.

Sandra Espinoza
Research Assistant

Biotechnologist, studing the impact of a ketogenic diet on dysferlinopathy and aging.

Andrea Puebla
Undergraduate

Biochemistry studying the role of mitochondrial calcium uptake in cellular senescence.

National

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

International

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