The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes

Oxidative stress is a common event in most hepatopathies, leading to mitochondrial permeability transition pore (MPTP) formation and further exacerbation of both oxidative stress from mitochondrial origin and cell death. Intracellular Ca2+ elevations play a permissive role in these events, but th...

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Autores principales: Toledo, Flavia D., Pérez, Leonardo Martín, Basiglio, Cecilia Lorena, Ochoa, Justina E., Sánchez Pozzi, Enrique Juan, Roma, Marcelo Gabriel
Formato: article artículo publishedVersion
Lenguaje:Inglés
Publicado: Springer 2018
Materias:
Oxidative Stress
tert-Butyl Hydroperoxide
Ca2+/calmodulin-dependent Protein Kinase II
Mitochondrial Permeability Transition Pore
Apoptosis
Cytochrome c
Caspasas
Acceso en línea:http://hdl.handle.net/2133/10485
http://hdl.handle.net/2133/10485
Aporte de:
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) de Universidad Nacional de Rosario
id I15-R121-2133-10485
record_format dspace
institution Universidad Nacional de Rosario
institution_str I-15
repository_str R-121
collection Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR)
language Inglés
topic Oxidative Stress
tert-Butyl Hydroperoxide
Ca2+/calmodulin-dependent Protein Kinase II
Mitochondrial Permeability Transition Pore
Apoptosis
Cytochrome c
Caspasas
spellingShingle Oxidative Stress
tert-Butyl Hydroperoxide
Ca2+/calmodulin-dependent Protein Kinase II
Mitochondrial Permeability Transition Pore
Apoptosis
Cytochrome c
Caspasas
Toledo, Flavia D.
Pérez, Leonardo Martín
Basiglio, Cecilia Lorena
Ochoa, Justina E.
Sánchez Pozzi, Enrique Juan
Roma, Marcelo Gabriel
The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
topic_facet Oxidative Stress
tert-Butyl Hydroperoxide
Ca2+/calmodulin-dependent Protein Kinase II
Mitochondrial Permeability Transition Pore
Apoptosis
Cytochrome c
Caspasas
description Oxidative stress is a common event in most hepatopathies, leading to mitochondrial permeability transition pore (MPTP) formation and further exacerbation of both oxidative stress from mitochondrial origin and cell death. Intracellular Ca2+ elevations play a permissive role in these events, but the underlying mechanisms are poorly known. We examined in primary cultured rat hepatocytes whether the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) signalling pathway is involved in this process, by using tert-butyl hydroperoxide (tBOOH) as a pro-oxidizing, model compound. tBOOH (500 µM, 15 min) induced MPTP formation, as assessed by measuring mitochondrial membrane depolarization as a surrogate marker, and increased lipid peroxidation in a clyclosporin A (CsA)-sesitive manner, revealing the involvement of MPTPs in tBOOH-induced ROS formation. Intracellular Ca2+ sequestration with BAPTA/AM, CaM blockage with W7 or trifluoperazine, and CaMKII inhibition with KN-62 all fully prevented tBOOH-induced MPTP opening and reduced tBOOH-induced lipid peroxidation to a similar extent to CsA, suggesting that Ca2+/CaM/CaMKII signaling pathway fully mediates MPTP-mediated mitochondrial ROS generation. tBOOH induced apoptosis, as shown by flow cytometry of annexin V/propidium iodide, mitochondrial release of cytochrome c, activation of caspase-3 and increase in the Bax-to-Bcl-xL ratio, and the Ca2+/CaM/CaMKII signaling antagonists fully prevented these effects. Intramitochondrial CaM and CaMKII were partially involved in tBOOH-induced MPTP formation, since W7 and KN-62 both attenuated the tBOOH-induced, MPTP-mediated swelling of isolated mitochondria. We concluded that Ca2+/CaM/CaMKII signaling pathway is a key mediator of oxidative stress-induced induced MPTP formation, and the subsequent exacerbation of oxidative stress from mitochondrial origin and apoptotic cell death.
format article
artículo
publishedVersion
author Toledo, Flavia D.
Pérez, Leonardo Martín
Basiglio, Cecilia Lorena
Ochoa, Justina E.
Sánchez Pozzi, Enrique Juan
Roma, Marcelo Gabriel
author_facet Toledo, Flavia D.
Pérez, Leonardo Martín
Basiglio, Cecilia Lorena
Ochoa, Justina E.
Sánchez Pozzi, Enrique Juan
Roma, Marcelo Gabriel
author_sort Toledo, Flavia D.
title The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
title_short The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
title_full The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
title_fullStr The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
title_full_unstemmed The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
title_sort ca2+-calmodulin-ca2+/calmodulin-dependent protein kinase ii pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes
publisher Springer
publishDate 2018
url http://hdl.handle.net/2133/10485
http://hdl.handle.net/2133/10485
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