DSpace Angular :: Browsing by Author "Parra, Valentina"

Browsing by Author "Parra, Valentina"

Now showing 1 - 12 of 12

Down syndrome critical region 1 gene, rcan1, helps maintain a more fused mitochondrial network
(2018) Parra, Valentina; Altamirano, Francisco; Hernández Fuentes, Carolina P.; Tong, Dan; Kyrychenko, Victoriia; Rotter, David; Pedrozo, Zully; Hill, Joséph A.| Eisner Sagüés, Verónica Raquel; Lavandero, Sergio; Schneider, Jay W.; Rothermel, Beverly A.
Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy
(2012) Troncoso, Rodrigo; Vicencio, Jose Miguel; Parra, Valentina; Nemchenko, Andriy; Kawashima, Yuki; Del Campo, Andrea; Toro, Barbra; Battiprolu, Pavan K.; Aranguiz, Pablo; Chiong, Mario; Yakar, Shoshana; Gillette, Thomas G.; Hill, Joseph A.; Abel, Evan Dale; LeRoith, Derek; Lavandero, Sergio
HERPUD1 governs tumor cell mitochondrial function via inositol 1,4,5-trisphosphate receptor-mediated calcium signaling
(2024) Paredes, Felipe; Navarro-Marquez, Mario; Quiroga, Clara; Jimenez-Gallegos, Danica; Yeligar, Samantha M.; Parra, Valentina; Mueller, Marioly; Chiong, Mario; Quest, Andrew F. G.; San Martin, Alejandra; Lavandero, Sergio
The intricate relationship between calcium (Ca2+) homeostasis and mitochondrial function is crucial for cellular metabolic adaptation in tumor cells. Ca2+-initiated signaling maintains mitochondrial respiratory capacity and ATP synthesis, influencing critical cellular processes in cancer development. Previous studies by our group have shown that the homocysteine-inducible ER Protein with Ubiquitin-Like Domain 1 (HERPUD1) regulates inositol 1,4,5-trisphosphate receptor (ITPR3) levels and intracellular Ca2+ signals in tumor cells. This study explores the role of HERPUD1 in regulating mitochondrial function and tumor cell migration by controlling ITPR3-dependent Ca2+ signals.We found HERPUD1 levels correlated with mitochondrial function in tumor cells, with HERPUD1 deficiency leading to enhanced mitochondrial activity. HERPUD1 knockdown increased intracellular Ca2+ release and mitochondrial Ca2+ influx, which was prevented using the ITPR3 antagonist xestospongin C or the Ca2+ chelator BAPTA-AM. Furthermore, HERPUD1 expression reduced tumor cell migration by controlling ITPR3-mediated Ca2+ signals. HERPUD1-deficient cells exhibited increased migratory capacity, which was attenuated by treatment with xestospongin C or BAPTA-AM. Additionally, HERPUD1 deficiency led to reactive oxygen species -dependent activation of paxillin and FAK proteins, which are associated with enhanced cell migration.Our findings highlight the pivotal role of HERPUD1 in regulating mitochondrial function and cell migration by controlling intracellular Ca2+ signals mediated by ITPR3. Understanding the interplay between HERPUD1 and mitochondrial Ca2+ regulation provides insights into potential therapeutic targets for cancer treatment and other pathologies involving altered energy metabolism.
Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress
(COMPANY BIOLOGISTS LTD, 2011) Bravo, Roberto; Miguel Vicencio, Jose; Parra, Valentina; Troncoso, Rodrigo; Pablo Munoz, Juan; Bui, Michael; Quiroga, Clara; Rodriguez, Andrea E.; Verdejo, Hugo E.; Ferreira, Jorge; Iglewski, Myriam; Chiong, Mario; Simmen, Thomas; Zorzano, Antonio; Hill, Joseph A.; Rothermel, Beverly A.; Szabadkai, Gyorgy; Lavandero, Sergio
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.
Insulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NF kappa B-Opa-1 Signaling Pathway
(AMER DIABETES ASSOC, 2014) Parra, Valentina; Verdejo, Hugo E.; Iglewski, Myriam; del Campo, Andrea; Troncoso, Rodrigo; Jones, Deborah; Zhu, Yi; Kuzmicic, Jovan; Pennanen, Christian; Lopez Crisosto, Camila; Jana, Fabian; Ferreira, Jorge; Noguera, Eduard; Chiong, Mario; Bernlohr, David A.; Klip, Amira; Hill, Joseph A.; Rothermel, Beverly A.; Abel, Evan Dale; Zorzano, Antonio; Lavandero, Sergio
Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFB pathway.
Mitochondrial Dynamics: a Potential New Therapeutic Target for Heart Failure
(EDICIONES DOYMA S A, 2011) Kuzmicic, Jovan; del Campo, Andrea; Lopez Crisosto, Camila; Morales, Pablo E.; Pennanen, Christian; Bravo Sagua, Roberto; Hechenleitner, Jonathan; Zepeda, Ramiro; Castro, Pablo F.; Verdejo, Hugo E.; Parra, Valentina; Chiong, Mario; Lavandero, Sergio
Mitochondria are dynamic organelles able to vary their morphology between elongated interconnected mitochondrial networks and fragmented disconnected arrays, through events of mitochondrial fusion and fission, respectively. These events allow the transmission of signaling messengers and exchange of metabolites within the cell. They have also been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy. Although the majority of these studies have been confined to noncardiac cells, emerging evidence suggests that changes in mitochondrial morphology could participate in cardiac development, the response to ischemia-reperfusion injury, heart failure, and diabetes mellitus. In this article, we review how the mitochondrial dynamics are altered in different cardiac pathologies, with special emphasis on heart failure, and how this knowledge may provide new therapeutic targets for treating cardiovascular diseases. Full English text available from: www.revespcardiol.org (C) 2011 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, SI. All rights reserved.
mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage
(Springer Nature, 2025) Verdejo Pinochet, Hugo; Parra, Valentina; Campo Sfeir, Andrea del; Vasquez-Trincado, Cesar; Gatica, Damian; Lopez-Crisosto, Camila; Kuzmicic Previtali, Jovan Paolo; Venegas-Zamora, Leslye; Zuñiga-Cuevas, Ursula; Troncoso, Mayarling F.; Troncoso, Rodrigo; Rothermel, Beverly A.; Chiong L., Mario; Abel, E. D.; Lavandero, Sergio
Introduction Cardiac mitochondrial function is intricately regulated by various processes, ultimately impacting metabolic performance. Additionally, protein turnover is crucial for sustained metabolic homeostasis in cardiomyocytes. Objective Here, we studied the role of mTOR in OPA-1 cleavage and its consequent effects on mitochondrial dynamics and energetics in cardiomyocytes. Results Cultured rat cardiomyocytes treated with rapamycin for 6–24 h showed a significant reduction in phosphorylation of p70S6K, indicative of sustained inhibition of mTOR. Structural and functional analysis revealed increased mitochondrial fragmentation and impaired bioenergetics characterized by decreases in ROS production, oxygen consumption, and cellular ATP. Depletion of either the mitochondrial protease OMA1 or the mTOR regulator TSC2 by siRNA, coupled with an inducible, cardiomyocyte-specific knockout of mTOR in vivo, suggested that inhibition of mTOR promotes mitochondrial fragmentation through a mechanism involving OMA1 processing of OPA-1. Under homeostatic conditions, OMA1 activity is kept under check through an interaction with microdomains in the inner mitochondrial membrane that requires prohibitin proteins (PHB). Loss of these microdomains releases OMA1 to cleave its substrates. We found that rapamycin both increased ubiquitination of PHB1 and decreased its abundance, suggesting proteasomal degradation. Consistent with this, the proteasome inhibitor MG-132 maintained OPA-1 content in rapamycin-treated cardiomyocytes. Using pharmacological activation and inhibition of AMPK our data supports the hypothesis that this mTOR-PHB1-OMA-OPA-1 pathway impacts mitochondrial morphology under stress conditions, where it mediates dynamic changes in metabolic status. Conclusions These data suggest that mTOR inhibition disrupts mitochondrial integrity in cardiomyocytes by promoting the degradation of prohibitins and OPA-1, leading to mitochondrial fragmentation and metabolic dysfunction, particularly under conditions of metabolic stress.
Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism
(SPRINGERNATURE, 2022) Avalos, Yenniffer; Paz Hernandez-Caceres, Maria; Lagos, Pablo; Pinto-Nunez, Daniela; Rivera, Patricia; Burgos, Paulina; Diaz-Castro, Francisco; Joy-Immediato, Michelle; Venegas-Zamora, Leslye; Lopez-Gallardo, Erik; Kretschmar, Catalina; Batista-Gonzalez, Ana; Cifuentes-Araneda, Flavia; Toledo-Valenzuela, Lilian; Rodriguez-Pena, Marcelo; Espinoza-Caicedo, Jasson; Perez-Leighton, Claudio; Bertocchi, Cristina; Cerda, Mauricio; Troncoso, Rodrigo; Parra, Valentina; Budini, Mauricio; Burgos, Patricia, V; Criollo, Alfredo; Morselli, Eugenia
Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.
Palmitic and Stearic Acids Inhibit Chaperone-Mediated Autophagy (CMA) in POMC-like Neurons In Vitro
(2022) Espinosa, Rodrigo; Gutierrez, Karla; Rios, Javiera; Ormeno, Fernando; Yanten, Liliana; Galaz-Davison, Pablo; Ramirez-Sarmiento, Cesar A.; Parra, Valentina; Albornoz, Amelina; Alfaro, Ivan E.; Burgos, Patricia, V; Morselli, Eugenia; Criollo, Alfredo; Budini, Mauricio
The intake of food with high levels of saturated fatty acids (SatFAs) is associated with the development of obesity and insulin resistance. SatFAs, such as palmitic (PA) and stearic (SA) acids, have been shown to accumulate in the hypothalamus, causing several pathological consequences. Autophagy is a lysosomal-degrading pathway that can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Previous studies showed that PA impairs macroautophagy function and insulin response in hypothalamic proopiomelanocortin (POMC) neurons. Here, we show in vitro that the exposure of POMC neurons to PA or SA also inhibits CMA, possibly by decreasing the total and lysosomal LAMP2A protein levels. Proteomics of lysosomes from PA- and SA-treated cells showed that the inhibition of CMA could impact vesicle formation and trafficking, mitochondrial components, and insulin response, among others. Finally, we show that CMA activity is important for regulating the insulin response in POMC hypothalamic neurons. These in vitro results demonstrate that CMA is inhibited by PA and SA in POMC-like neurons, giving an overview of the CMA-dependent cellular pathways that could be affected by such inhibition and opening a door for in vivo studies of CMA in the context of the hypothalamus and obesity.
Polycystin-1 regulates cardiomyocyte mitophagy
(2021) Ramirez-Sagredo, Andrea; Quiroga, Clara; Garrido-Moreno, Valeria; Lopez-Crisosto, Camila; Leiva-Navarrete, Sebastian; Norambuena-Soto, Ignacio; Ortiz-Quintero, Jafet; Diaz-Vesga, Magda C.; Perez, William; Hendrickson, Troy; Parra, Valentina; Pedrozo, Zully; Altamirano, Francisco; Chiong, Mario; Lavandero, Sergio
Polycystin-1 (PC1) is a transmembrane protein found in different cell types, including cardiomyocytes. Alterations in PC1 expression have been linked to mitochondrial damage in renal tubule cells and in patients with autosomal dominant polycystic kidney disease. However, to date, the regulatory role of PC1 in cardiomyocyte mitochondria is not well understood. The analysis of mitochondrial morphology from cardiomyocytes of heterozygous PC1 mice (PDK1(+/-)) using transmission electron microscopy showed that cardiomyocyte mitochondria were smaller with increased mitochondria density and circularity. These parameters were consistent with mitochondrial fission. We knocked-down PC1 in cultured rat cardiomyocytes and human-induced pluripotent stem cells (iPSC)-derived cardiomyocytes to evaluate mitochondrial function and morphology. The results showed that downregulation of PC1 expression results in reduced protein levels of sub-units of the OXPHOS complexes and less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production). This mitochondrial dysfunction activates the elimination of defective mitochondria by mitophagy, assessed by an increase of autophagosome adapter protein LC3B and the recruitment of the Parkin protein to the mitochondria. siRNA-mediated PC1 knockdown leads to a loss of the connectivity of the mitochondrial network and a greater number of mitochondria per cell, but of smaller sizes, which characterizes mitochondrial fission. PC1 silencing also deregulates the AKT-FoxO1 signaling pathway, which is involved in the regulation of mitochondrial metabolism, mitochondrial morphology, and processes that are part of cell quality control, such as mitophagy. Together, these data provide new insights about the controls that PC1 exerts on mitochondrial morphology and function in cultured cardiomyocytes dependent on the AKT-FoxO1 signaling pathway.
Polycystin-2 Is Required for Starvation- and Rapamycin-Induced Atrophy in Myotubes
(2019) Kretschmar, Catalina; Pena-Oyarzun, Daniel; Hernando, Cecilia; Hernandez-Moya, Nadia; Molina-Berrios, Alfredo; Paz Hernandez-Caceres, Maria; Lavandero, Sergio; Budini, Mauricio; Morselli, Eugenia; Parra, Valentina; Troncoso, Rodrigo; Criollo, Alfredo
Muscle atrophy involves a massive catabolism of intracellular components leading to a significant reduction in cellular and tissue volume. In this regard, autophagy, an intracellular mechanism that degrades proteins and organelles, has been implicated with muscle breakdown. Recently, it has shown that polycystin-2 (PC2), a membrane protein that belongs to the transient receptor potential (TRP) family, is required for the maintenance of cellular proteostasis, by regulating autophagy in several cell types. The role of PC2 in the control of atrophy and autophagy in skeletal muscle remains unknown. Here, we show that PC2 is required for the induction of atrophy in C2C12 myotubes caused by nutrient deprivation or rapamycin exposure. Consistently, overexpression of PC2 induces atrophy in C2C12 myotubes as indicated by decreasing of the myogenic proteins myogenin and caveolin-3. In addition, we show that inhibition of mTORC1, by starvation or rapamycin is inhibited in cells when PC2 is silenced. Importantly, even if PC2 regulates mTORC1, our results show that the regulation of atrophy by PC2 is independent of autophagy. This study provides novel evidence regarding the role of PC2 in skeletal muscle cell atrophy.
The complex interplay between mitochondrial dynamics and cardiac metabolism
(2011) Parra, Valentina; Verdejo Pinochet, Hugo; Del Campo, Andrea; Pennanen, Christian; Kuzmicic, Jovan; Iglewski, Myriam; Hill, Joséph A; Rothermel, Beverly A.; Lavandero, Sergio

Browsing by Author "Parra, Valentina"

Results Per Page

Sort Options