Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage

Bibliographic Details
Main Author: Cardoso, Susana Maria Batista Tieres Tomé
Publication Date: 2013
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: https://hdl.handle.net/10316/23651
Summary: Tese de doutoramento em Biologia, na especialidade de Biologia Celular, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra.
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spelling Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damageTese de doutoramento em Biologia, na especialidade de Biologia Celular, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra.Diabetes mellitus (DM) is one of the most important and prevalent chronic diseases, and its epidemic proportions has placed it in the frontline of public health challenges. In fact, it is a priority concern due to the associated complications. In this context, achieving a nearly normal glycemia is one of the most prevalent goals. However, it is consensual that achieving this tight control leads very frequently to the occurrence of hypoglycemic episodes. Some of the most serious consequences of hypoglycemia are those related with brain changes, which include loss of cognitive functions, coma, and even death. Since mitochondrial dysfunction play a key role in diabetic complications, our main goals were to evaluate the consequences of blood glucose fluctuations in brain mitochondria function and oxidative status, to unravel the role of mitochondrial uncoupling proteins (UCPs) under those situations, and the behavior and cognitive implications. Our studies were performed in the well-characterized and widely used animal model of T1DM, the streptozotocin (STZ)-induced diabetic rodent, and the effects of a short-term hyperglycemia (one month of duration) and a long-term hyperglycemia (three months of duration) were assessed. Hyperglycemic animals were randomly divided and some were submitted to blood glucose fluctuations achieved with the subcutaneous administration of insulin and consequent induction of acute (insulin given one hour prior to sacrifice) or recurrent (twice or daily injections of insulin during one or two weeks) hypoglycemia. The impact of these metabolic insults with different durations/severity were analysed in two brain regions associated with learning and memory processes, the cortex and hippocampus. The bioenergetics and oxidative status of brain cortical and hippocampal mitochondria obtained from short-term hyperglycemic and/or insulin-induced acute hypoglycemic animals (Chapter 4) were analysed. Both short-term hyperglycemia and insulin-induced acute hypoglycemia promoted an increase in oxidative stress together with a decrease in the antioxidant defenses in brain cortical and hippocampal mitochondria, although the profile of changes was regionspecific. Interestingly, the acute episode of insulin-induced hypoglycemia potentiated the effects of STZ-induced diabetes leading to detrimental effects in cortical mitochondria (Chapter 4). Those metabolic insults also led to a higher calcium-independent release of glutamate from cortical synaptosomes (Chapter 5), and the acute episode of hypoglycemia caused a significant increase in plasma levels of the excitatory amino acids aspartate and glutamate and a decrease in the inhibitory amino acid -aminobutyric acid (Chapter 5). Interestingly, long-term hyperglycemia and insulin-induced recurrent hypoglycemia affected both brain cortical and hippocampal mitochondria, although the effects were more pronounced in hippocampal mitochondria (Chapter 6). Also, insulin-induced recurrent hypoglycemia potentiated the effects of long-term hyperglycemia (Chapter 6). The decreased mitochondrial function was accompanied by increased levels of caspase-9 activity and loss of synaptic integrity, as evaluated through the protein expression of synaptophysin (Chapter 6). In addition, long-term hyperglycemia rendered brain cortical mitochondria more susceptible to adenine nucleotide translocator (ANT) mediated proton-leak; whereas UCP-mediated uncoupling prevailed after recurrent hypoglycemic episodes (Chapter 7). Proton-leak modulation mediated by UCPs is believed to play a critical role in cell protection against oxidative stress. Thus, to clarify the role of UCP2, which is expressed in the brain, experiments were carried out in wild-type (WT) and UCP2 knockout mice (UCP2KO) submitted to recurrent hypoglycemia and/or short-term hyperglycemia. In this study, the cognitive behavior and hippocampal mitochondrial function were analysed (Chapter 8). In the WT animals, both metabolic insults exerted detrimental effects in exploratory behavior and memory, as observed in the open-field and Y maze behavioral tests. UCP2KO control (CT) mice showed the most drastic decline in cognitive function in comparison with WT CT mice while in some behavioral aspects, UCP2KO mice subjected to recurrent hypoglycemia behaved poorly in comparison with UCP2KO CT and WT hypoglycemic mice. Hippocampal mitochondrial respiratory function remained unchanged between WT and UCP2KO CT mice whereas higher levels of reactive oxygen species (ROS) were produced by UCP2KO CT animals. Similar results were found between UCP2KO CT and UCP2KO STZ mice. In opposite, hippocampal mitochondria from UCP2KO hypoglycemic mice showed a decreased respiratory capacity when compared with UCP2KO CT and WT hypoglycemic mice that was not associated with changes in ROS production, which may suggest the involvement of other neuronal UCPs. In summary, the results presented herein demonstrate that mitochondrial (dys)function have a central role in hypoglycemiaand/ or hyperglycemia-related brain impairment predisposing to excitotoxicity and synaptic loss. In this scenario, UCPs seem to play a role. However, further studies must be done to clarify this issue.2013-07-16doctoral thesisinfo:eu-repo/semantics/publishedVersionhttps://hdl.handle.net/10316/23651https://hdl.handle.net/10316/23651engCARDOSO, Susana Maria Batista Tieres Tomé - Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage. Coimbra : [s.n.], 2013. Tese de doutoramentoCardoso, Susana Maria Batista Tieres Toméinfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2021-12-13T21:51:29Zoai:estudogeral.uc.pt:10316/23651Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T05:16:20.231807Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
title Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
spellingShingle Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
Cardoso, Susana Maria Batista Tieres Tomé
title_short Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
title_full Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
title_fullStr Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
title_full_unstemmed Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
title_sort Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage
author Cardoso, Susana Maria Batista Tieres Tomé
author_facet Cardoso, Susana Maria Batista Tieres Tomé
author_role author
dc.contributor.author.fl_str_mv Cardoso, Susana Maria Batista Tieres Tomé
description Tese de doutoramento em Biologia, na especialidade de Biologia Celular, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra.
publishDate 2013
dc.date.none.fl_str_mv 2013-07-16
dc.type.driver.fl_str_mv doctoral thesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://hdl.handle.net/10316/23651
https://hdl.handle.net/10316/23651
url https://hdl.handle.net/10316/23651
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv CARDOSO, Susana Maria Batista Tieres Tomé - Exploring the role of mithocondria and uncopling proteins in hypoglycemia and/or hypoglycemia-induced brain damage. Coimbra : [s.n.], 2013. Tese de doutoramento
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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