Antonio Zorzano

Publications (4)16.66 Total impact

• Article: Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration.

  Roberto Bravo, Valentina Parra, Damián Gatica, Andrea E Rodriguez, Natalia Torrealba, Felipe Paredes, Zhao V Wang, Antonio Zorzano, Joseph A Hill, Enrique Jaimovich, Andrew F G Quest, Sergio Lavandero
  [show abstract] [hide abstract]
  ABSTRACT: The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.
  International review of cell and molecular biology 01/2013; 301:215-90. · 4.48 Impact Factor
• Source

  Available from: Rodrigo Troncoso

  Article: Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress.

  Roberto Bravo, Jose Miguel Vicencio, Valentina Parra, Rodrigo Troncoso, Juan Pablo Munoz, Michael Bui, Clara Quiroga, Andrea E Rodriguez, Hugo E Verdejo, Jorge Ferreira, Myriam Iglewski, Mario Chiong, Thomas Simmen, Antonio Zorzano, Joseph A Hill, Beverly A Rothermel, Gyorgy Szabadkai, Sergio Lavandero
  [show abstract] [hide abstract]
  ABSTRACT: Increasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabolic events that occur during the adaptive phase of ER stress, before the cell death response, remain unknown. Here, we show that, during the onset of ER stress, the reticular and mitochondrial networks are redistributed towards the perinuclear area and their points of connection are increased in a microtubule-dependent fashion. A localized increase in mitochondrial transmembrane potential is observed only in redistributed mitochondria, whereas mitochondria that remain in other subcellular zones display no significant changes. Spatial re-organization of these organelles correlates with an increase in ATP levels, oxygen consumption, reductive power and increased mitochondrial Ca²⁺ uptake. Accordingly, uncoupling of the organelles or blocking Ca²⁺ transfer impaired the metabolic response, rendering cells more vulnerable to ER stress. Overall, these data indicate that ER stress induces an early increase in mitochondrial metabolism that depends crucially upon organelle coupling and Ca²⁺ transfer, which, by enhancing cellular bioenergetics, establishes the metabolic basis for the adaptation to this response.
  Journal of Cell Science 07/2011; 124(Pt 13):2143-52. · 6.11 Impact Factor
• Article: Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis.

  Valentina Parra, Veronica Eisner, Mario Chiong, Alfredo Criollo, Francisco Moraga, Alejandra Garcia, Steffen Härtel, Enrique Jaimovich, Antonio Zorzano, Cecilia Hidalgo, Sergio Lavandero
  [show abstract] [hide abstract]
  ABSTRACT: In cells, mitochondria are organized as a network of interconnected organelles that fluctuate between fission and fusion events (mitochondrial dynamics). This process is associated with cell death. We investigated whether activation of apoptosis with ceramides affects mitochondrial dynamics and promotes mitochondrial fission in cardiomyocytes. Neonatal rat cardiomyocytes were incubated with C(2)-ceramide or the inactive analog dihydro-C(2)-ceramide for up to 6 h. Three-dimensional images of cells loaded with mitotracker green were obtained by confocal microscopy. Dynamin-related protein-1 (Drp-1) and mitochondrial fission protein 1 (Fis1) distribution and levels were studied by immunofluorescence and western blot. Mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c (cyt c) distribution were used as indexes of early activation of apoptosis. Cell viability and DNA fragmentation were determined by propidium iodide staining/flow cytometry, whereas cytotoxicity was evaluated by lactic dehydrogenase activity. To decrease the levels of the mitochondrial fusion protein mitofusin 2, we used an antisense adenovirus (AsMfn2). C(2)-ceramide, but not dihydro-C(2)-ceramide, promoted rapid fragmentation of the mitochondrial network in a concentration- and time-dependent manner. C(2)-ceramide also increased mitochondrial Drp-1 and Fis1 content, Drp-1 colocalization with Fis1, and caused early activation of apoptosis. AsMfn2 accentuated the decrease in DeltaPsi(m) and cyt c redistribution induced by C(2)-ceramide. Doxorubicin, which induces cardiomyopathy and apoptosis through ceramide generation, also stimulated mitochondrial fragmentation. Ceramides stimulate mitochondrial fission and this event is associated with early activation of cardiomyocyte apoptosis.
  Cardiovascular Research 02/2008; 77(2):387-97. · 6.06 Impact Factor
• Article: Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis

  Valentina María Parra Ortiz, Verónica Eisner, Mario Chiong Lay, Alfredo Criollo Céspedes, Francisco Moraga, Alejandra García, Steffen Haertel, Enrique Jaimovich P, Antonio Zorzano, Cecilia Hidalgo, Sergio Lavandero
  [show abstract] [hide abstract]
  ABSTRACT: Aims In cells, mitochondria are organized as a network of interconnected organelles that fluctuate between fission and fusion events (mitochondrial dynamics). This process is associated with cell death. We investigated whether activation of apoptosis with ceramides affects mitochondrial dynamics and promotes mitochondrial fission in cardiomyocytes. Methods and results Neonatal rat cardiomyocytes were incubated with C-2-ceramide or the inactive analog dihydro-C-2-ceramide for up to 6 h. Three-dimensional images of cells loaded with mitotracker green were obtained by confocal microscopy. Dynamin-retated protein-1 (Drp-1) and mitochondrial fission protein 1 (Fis1) distribution and levels were studied by immunofluorescence and western blot. Mitochondrial membrane potential (Delta Psi(m)) and cytochrome c (cyt c) distribution were used as indexes of early activation of apoptosis. Cell viability and DNA fragmentation were determined by propidium iodide staining/flow cytometry whereas cytotoxicity was evaluated by tactic dehydrogenase activity. To decrease the levels of the mitochondrial fusion protein mitofusin 2, we used an antisense adenovirus (AsMfn2). C-2-ceramide, but not dihydro-C2-ceramide, promoted rapid fragmentation of the mitochondrial network in a concentration- and time-dependent manner. C2-ceramide also increased mitochondrial Drp-1 and Fis1 content, Drp-1 colocalization with Fis1, and caused early activation of apoptosis. AsMfn2 accentuated the decrease in Delta Psi(m) and cyt c redistribution induced by C2-ceramide. Doxorubicin, which induces cardiomyopathy and apoptosis through ceramide generation, also stimulated mitochondrial fragmentation. Conclusion Ceramides stimulate mitochondrial fission and this event is associated with early activation of cardiomyocyte apoptosis.