Browsing by Author "Bravo-Sagua, Roberto"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state?
    (2018) Pena-Oyarzun, Daniel; Bravo-Sagua, Roberto; Diaz-Vega, Alexis; Aleman, Larissa; Chiong, Mario; Garcia, Lorena; Bambs S., Claudia; Troncoso, Rodrigo; Cifuentes, Mariana; Morselli, Eugenia; Ferreccio Readi, Catterina; Quest, Andrew F. G.; Criollo, Alfred
  • No Thumbnail Available
    Item
    Endoplasmic reticulum-mitochondria coupling increases during doxycycline-induced mitochondrial stress in HeLa cells
    (2021) Lopez-Crisosto, Camila; Diaz-Vegas, Alexis; Castro, Pablo F.; Rothermel, Beverly A.; Bravo-Sagua, Roberto; Lavandero, Sergio
    Subcellular organelles communicate with each other to regulate function and coordinate responses to changing cellular conditions. The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca2+ between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER-mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial-ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C/EBP beta, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2 h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca2+ uptake. This was followed by the rise in the rate of oxygen consumption at 4 h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial-ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.
  • Thumbnail Image
    Item
    Enfermedades cardiovasculares y cáncer: ¿dos entidades mutuamente relacionadas?
    (2019) Mendoza-Torres, Evelyn; Bravo-Sagua, Roberto; Villa, Mónica; Flores, Nancy; Olivares, María José; Calle, Ximena; Riquelme, Jaime A.; Bambs S., Claudia; Castro Gálvez, Pablo Federico; Lavandero, Sergio
    Las enfermedades cardiovasculares y el cáncer son enfermedades crónicas transmisibles culturalmente, y las dos causas principales de mortalidad en el mundo. Además del gran impacto sobre la mortalidad y morbilidad, estas enfermedades han mostrado un alto grado de relación entre ellas debido, entre otras razones, a que comparten factores de riesgo y mecanismos biológicos. La alta incidencia de enfermedad cardiovascular en pacientes con cáncer es un fenómeno conocido que ha orientado el desarrollo del campo interdisciplinario de la cardio-oncología. Sin embargo, en la última década han surgido evidencias que muestran el papel que desempeñan las enfermedades cardiovasculares en el desarrollo de cáncer. Un estudio reciente publicado por Meijers y cols, en agosto de 2018 en Circulation, mostró que la insuficiencia cardiaca post-infarto del miocardio contribuye significativamente al desarrollo del cáncer de colón, apoyando lo obtenido en estudios epidemiológicos anteriores. Este estudio también sugiere que el crecimiento tumoral podría producirse por factores secretados por el corazón insuficiente abriendo un amplio grupo de posibilidades de investigación en lo que sería un nuevo campo de la medicina cuyo propósito sería el desarrollo de nuevas estrategias para el seguimiento y tratamiento del cáncer en pacientes con enfermedades cardiovasculares. El presente artículo revisa los factores de riesgo, y mecanismos celulares y moleculares, que son comunes en las enfermedades cardiovasculares y el cáncer, la contribución del trabajo de Meijers y cols hacia un mayor entendimiento de la interrelación entre estas patologías y las perspectivas futuras con respecto a los nuevos hallazgos.
  • No Thumbnail Available
    Item
    Glucocorticoid Receptor β Overexpression Has Agonist-Independent Insulin-Mimetic Effects on HepG2 Glucose Metabolism
    (2022) Sepulveda-Quinenao, Claudia; Rodriguez, Juan M.; Diaz-Castro, Francisco; del Campo, Andrea; Bravo-Sagua, Roberto; Troncoso, Rodrigo
    Glucocorticoids (GC) are steroids hormones that drive circulating glucose availability through gluconeogenesis in the liver. However, alternative splicing of the GR mRNA produces two isoforms, termed GR alpha and GR beta. GR alpha is the classic receptor that binds to GCs and mediates the most described actions of GCs. GR beta does not bind GCs and acts as a dominant-negative inhibitor of GR alpha. Moreover, GR beta has intrinsic and GR alpha-independent transcriptional activity. To date, it remains unknown if GR beta modulates glucose handling in hepatocytes. Therefore, the study aims to characterize the impact of GR beta overexpression on glucose uptake and storage using an in vitro hepatocyte model. Here we show that GR beta overexpression inhibits the induction of gluconeogenic genes by dexamethasone. Moreover, GR beta activates the Akt pathway, increases glucose transports mRNA, increasing glucose uptake and glycogen storage as an insulin-mimetic. Our results suggest that GR beta has agonist-independent insulin-mimetic actions in HepG2 cells.