The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/106217 https://doi.org/10.3390/ijms21144896 |
Resumo: | Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD+-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I/R injury. |
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The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Functionmitochondriaischemia/reperfusionliversoluble adenylyl cyclaseLRE1sirtuin 3Adenosine DiphosphateAdenylyl Cyclase InhibitorsAdenylyl CyclasesAnimalsConstrictionDisease Models, AnimalGene Expression RegulationHepatic ArteryHormesisLiver FailureMaleMembrane Potential, MitochondrialMitochondria, LiverOxygen ConsumptionPhosphorylationPortal VeinPremedicationPyrimidinesRandom AllocationRatsRats, WistarReactive Oxygen SpeciesReperfusion InjurySolubilityThiophenesHepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD+-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I/R injury.MDPI2020-07-11info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/106217http://hdl.handle.net/10316/106217https://doi.org/10.3390/ijms21144896eng1422-0067Teodoro, João S.Amorim, João A.Machado, Ivo F.Castela, Ana C.Steegborn, ClemensSinclair, David ARolo, Anabela P.Palmeira, Carlos M.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-03-27T20:33:29Zoai:estudogeral.uc.pt:10316/106217Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:22:42.367613Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
title |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
spellingShingle |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function Teodoro, João S. mitochondria ischemia/reperfusion liver soluble adenylyl cyclase LRE1 sirtuin 3 Adenosine Diphosphate Adenylyl Cyclase Inhibitors Adenylyl Cyclases Animals Constriction Disease Models, Animal Gene Expression Regulation Hepatic Artery Hormesis Liver Failure Male Membrane Potential, Mitochondrial Mitochondria, Liver Oxygen Consumption Phosphorylation Portal Vein Premedication Pyrimidines Random Allocation Rats Rats, Wistar Reactive Oxygen Species Reperfusion Injury Solubility Thiophenes |
title_short |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
title_full |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
title_fullStr |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
title_full_unstemmed |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
title_sort |
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function |
author |
Teodoro, João S. |
author_facet |
Teodoro, João S. Amorim, João A. Machado, Ivo F. Castela, Ana C. Steegborn, Clemens Sinclair, David A Rolo, Anabela P. Palmeira, Carlos M. |
author_role |
author |
author2 |
Amorim, João A. Machado, Ivo F. Castela, Ana C. Steegborn, Clemens Sinclair, David A Rolo, Anabela P. Palmeira, Carlos M. |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Teodoro, João S. Amorim, João A. Machado, Ivo F. Castela, Ana C. Steegborn, Clemens Sinclair, David A Rolo, Anabela P. Palmeira, Carlos M. |
dc.subject.por.fl_str_mv |
mitochondria ischemia/reperfusion liver soluble adenylyl cyclase LRE1 sirtuin 3 Adenosine Diphosphate Adenylyl Cyclase Inhibitors Adenylyl Cyclases Animals Constriction Disease Models, Animal Gene Expression Regulation Hepatic Artery Hormesis Liver Failure Male Membrane Potential, Mitochondrial Mitochondria, Liver Oxygen Consumption Phosphorylation Portal Vein Premedication Pyrimidines Random Allocation Rats Rats, Wistar Reactive Oxygen Species Reperfusion Injury Solubility Thiophenes |
topic |
mitochondria ischemia/reperfusion liver soluble adenylyl cyclase LRE1 sirtuin 3 Adenosine Diphosphate Adenylyl Cyclase Inhibitors Adenylyl Cyclases Animals Constriction Disease Models, Animal Gene Expression Regulation Hepatic Artery Hormesis Liver Failure Male Membrane Potential, Mitochondrial Mitochondria, Liver Oxygen Consumption Phosphorylation Portal Vein Premedication Pyrimidines Random Allocation Rats Rats, Wistar Reactive Oxygen Species Reperfusion Injury Solubility Thiophenes |
description |
Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD+-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I/R injury. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-07-11 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/106217 http://hdl.handle.net/10316/106217 https://doi.org/10.3390/ijms21144896 |
url |
http://hdl.handle.net/10316/106217 https://doi.org/10.3390/ijms21144896 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1422-0067 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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