Browsing by Author "Eisner, Veronica"

Now showing 1 - 13 of 13
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    beta-Hydroxybutyrate Increases Exercise Capacity Associated with Changes in Mitochondrial Function in Skeletal Muscle
    (MDPI, 2020) Monsalves Alvarez, Matias; Morales, Pablo Esteban; Castro Sepulveda, Mauricio; Sepulveda, Carlos; Rodriguez, Juan Manuel; Chiong, Mario; Eisner, Veronica; Lavandero, Sergio; Troncoso, Rodrigo
    beta-hydroxybutyrate is the main ketone body generated by the liver under starvation. Under these conditions, it can sustain ATP levels by its oxidation in mitochondria. As mitochondria can modify its shape and function under different nutritional challenges, we study the chronic effects of beta-hydroxybutyrate supplementation on mitochondrial morphology and function, and its relation to exercise capacity. Male C57BL/6 mice were supplemented with beta-hydroxybutyrate mineral salt (3.2%) or control (CT, NaCl/KCl) for six weeks and submitted to a weekly exercise performance test. We found an increase in distance, maximal speed, and time to exhaustion at two weeks of supplementation. Fatty acid metabolism and OXPHOS subunit proteins declined at two weeks in soleus but not in tibialis anterior muscles. Oxygen consumption rate on permeabilized fibers indicated a decrease in the presence of pyruvate in the short-term treatment. Both the tibialis anterior and soleus showed decreased levels of Mitofusin 2, while electron microscopy assessment revealed a significant reduction in mitochondrial cristae shape in the tibialis anterior, while a reduction in the mitochondrial number was observed only in soleus. These results suggest that short, but not long-term, beta-hydroxybutyrate supplementation increases exercise capacity, associated with modifications in mitochondrial morphology and function in mouse skeletal muscle.
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    Cytosolic and Mitochondrial Ca2+ Transients in Mitochondrial Fission Protein MiD49-Defficient
    (CELL PRESS, 2021) Lopez, Erik A.; Troncoso, Diego; Cartes Saavedra, Benjamin; Lagos, Daniel A.; Eisner, Veronica
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    Doxorubicin induced senescence affects the integrity of the inner mitochondrial membrane in human iPS derived cardiomyocytes and primary rat cardiomyocytes
    (ELSEVIER, 2022) Morris, Silke; Molina-Riquelme, Isidora; Barrientos, Gonzalo; Bravo, Francisco; Aedo, Geraldine; Gomez, Wileidy; Psathaki, Katherina; Peischard, Stefan; Seebohm, Guiscard; Eisner, Veronica; Busch, Karin B.
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    Hyperosmotic stress-dependent NFκB activation is regulated by reactive oxygen species and IGF-1 in cultured cardiomyocytes
    (2006) Eisner, Veronica; Criollo, Alfredo; Quiroga, Clara; Olea-Azar, Claudio; Santibanez, Juan Francisco; Troncoso, Rodrigo; Chiong, Mario; Diaz-Araya, Guillermo; Foncea, Rocio; Lavandero, Sergio
    We have recently shown that hyperosmotic stress activates p65/RelB NF kappa B in cultured cardiomyocytes with dichotomic actions on caspase activation and cell death. It remains unexplored how NFKB is regulated in cultured rat cardiomyocytes exposed to hyperosmotic stress. We study here: (a) if hyperosmotic stress triggers reactive oxygen species (ROS) generation and in turn whether they regulate NFKB and (b) if insulin-like growth factor-1 (IGF-1) modulates ROS production and NF kappa B activation in hyperosmotically-stressed cardiomyocytes. The results showed that hyperosmotic stress generated ROS in cultured cardiac myocytes, in particular the hydroxyl and superoxide species, which were inhibited by N-acetylcysteine (NAC). Hyperosmotic stress-induced NFKB activation as determined by I kappa B alpha degradation and NF kappa B DNA binding. NFKB activation and procaspase-3 and -9 fragmentation were prevented by NAC and IGF-1. However, this growth factor did not decrease ROS generation induced by hyperosmotic stress, suggesting that its actions over NFKB and caspase activation may be due to modulation of events downstream of ROS generation. We conclude that hyperosmotic stress induces ROS, which in turn activates NF kappa B and caspases. IGF-1 prevents NFKB activation by a ROS-independent mechanism. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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    Inner mitochondrial membrane ultrastructure adaptations in the aging heart
    (ELSEVIER, 2022) Molina-Riquelme, Isidora; Gomez, Wileidy; Barrientos, Gonzalo; Diaz-Castro, Francisco; del Campo-Sefir, Andrea; Garrido, Luis; Morris, Silke; Breitsprecher, Leonhard; Psathaki, Katherina; Verdejo, Hugo; Busch, Karin B.; Eisner, Veronica
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    Mitochondrial cristae ultrastructure adaptations in the senescent heart
    (CELL PRESS, 2022) Barrientos, Gonzalo; Molina, Isidora E.; Gomez, Wileidy; Diaz-Castro, Francisco; delCampo-Sefir, Andrea; Garrido, Luis; Morris, Silke; Psathaki, Katherina; Verdejo, Hugo; Busch, Karin B.; Eisner, Veronica
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    Mitochondrial function in spinal cord injury and regeneration
    (SPRINGER BASEL AG, 2022) Slater, Paula G.; Dominguez-Romero, Miguel E.; Villarreal, Maximiliano; Eisner, Veronica; Larrain, Juan
    Many people around the world suffer from some form of paralysis caused by spinal cord injury (SCI), which has an impact on quality and life expectancy. The spinal cord is part of the central nervous system (CNS), which in mammals is unable to regenerate, and to date, there is a lack of full functional recovery therapies for SCI. These injuries start with a rapid and mechanical insult, followed by a secondary phase leading progressively to greater damage. This secondary phase can be potentially modifiable through targeted therapies. The growing literature, derived from mammalian and regenerative model studies, supports a leading role for mitochondria in every cellular response after SCI: mitochondrial dysfunction is the common event of different triggers leading to cell death, cellular metabolism regulates the immune response, mitochondrial number and localization correlate with axon regenerative capacity, while mitochondrial abundance and substrate utilization regulate neural stem progenitor cells self-renewal and differentiation. Herein, we present a comprehensive review of the cellular responses during the secondary phase of SCI, the mitochondrial contribution to each of them, as well as evidence of mitochondrial involvement in spinal cord regeneration, suggesting that a more in-depth study of mitochondrial function and regulation is needed to identify potential targets for SCI therapeutic intervention.
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    Mitochondrial nucleoid dynamics perturbation by OPA1 disease-causing mutants
    (CELL PRESS, 2022) Eisner, Veronica; Macuada, Josefa; Vidal, Gonzalo; Aedo, Geraldine; Cartes-Saavedra, Benjamin; Rudge, Timothy
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    OPA1 disease-causing mutants perturb mitochondrial nucleoid cluster distribution
    (ELSEVIER, 2022) Eisner, Veronica; Macuada, Josefa; Vidal, Gonzalo; Molina-Riquelme, Isidora; Aedo, Geraldine; Lagos, Daniel; Perez, Nicolas; Rudge, Timothy; Cartes-Saavedra, Benjamin
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    OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling
    (FRONTIERS MEDIA SA, 2022) Cartes Saavedra, Benjamin; Macuada, Josefa; Lagos, Daniel; Arancibia, Duxan; Andres, Maria E.; Yu Wai Man, Patrick; Hajnoczky, Gyoergy; Eisner, Veronica
    Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+](mito)). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1(-/-) MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+](cyto)) needed for a prompt [Ca2+](mito) rise. Finally, OPA1 mutants' overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1(-/-) MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.
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    Role of OPA1 ADOA-Causing Mutants in Mitochondrial Nucleoid Distribution
    (CELL PRESS, 2021) Macuada, Josefa; Aedo, Geraldine; Vidal, Gonzalo; Rudge, Timothy; Cartes Saavedra, Benjamin; Eisner, Veronica
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    Semi-Automated Method for Image Analysis of mtDNA Nucleoids Dynamics
    (CELL PRESS, 2021) Aedo, Geraldine; Macuada, Josefa; Cartes Saavedra, Benjamin; Vidal, Gonzalo; Rudge, Timothy; Eisner, Veronica
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    Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system
    (SPRINGER BASEL AG, 2022) Peischard, Stefan; Moeller, Melina; Disse, Paul; Huyen Tran Ho; Verkerk, Arie O.; Strutz-Seebohm, Nathalie; Budde, Thomas; Meuth, Sven G.; Schweizer, Patrick A.; Morris, Silke; Mucher, Lena; Eisner, Veronica; Thomas, Dierk; Klingel, Karin; Busch, Karin; Seebohm, Guiscard
    The enterovirus Coxsackievirus B3 (CVB3) is known to be a major source for the development of cardiac dysfunctions like viral myocarditis (VMC) and dilatative cardiomyopathy (DCM), but also results in bradycardia and fatal cardiac arrest. Besides clinical reports on bradycardia and sudden cardiac death, very little is known about the influence of CVB3 on the activity of human cardiac pacemaker cells. Here, we address this issue using the first human induced pluripotent stem cell (hiPSC)-derived pacemaker-like cells, in which the expression of a transgenic non-infectious variant of CVB3 can be controlled dose- and time-dependently. We found that CVB3 drastically changed hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) distribution and function in hiPSC-derived pacemaker-like tissue. In addition, using HCN4 cell expression systems, we found that HCN4 currents were decreased with altered voltage dependency of activation when CVB3 was expressed. Increased autophagosome formation and autophagosomal HCN4 insertion was observed in hiPSC-derived pacemaker-like cells under CVB3 expression as well. Individual effects of single, non-structural CVB3 proteins were analyzed and demonstrated that CVB3 proteins 2C and 3A had the most robust effect on HCN4 activity. Treatment of cells with the Rab7 inhibitor CID 106770 or the CVB3-3A inhibitor GW5074 led to the recovery of the cytoplasmatic HCN4 accumulation into a healthy appearing phenotype, indicating that malfunctioning Rab7-directed autophagosome transport is involved in the disturbed, cytoplasmatic HCN4 accumulation in CVB3-expressing human pacemaker-like cells. Summarizing, the enterovirus CVB3 inhibits human cardiac pacemaker function by reducing the pacemaker channel plasma membrane density, an effect that can be corrected by pharmacological intervention of endocytic vesicle trafficking.