Roger F. Castilho

Universidade Estadual de Campinas (UNICAMP)

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Anı́bal E. Vercesi

Universidade Estadual de Campinas (UNICAMP)

Alicia J. Kowaltowski

Universidade de São Paulo

Tiago R. Figueira

Universidade de São Paulo

Annelise Francisco

Universidade Estadual de Campinas (UNICAMP)

Moacır Wajner

Universidade Federal do Rio Grande do Sul

Helena C.F. Oliveira

Universidade Estadual de Campinas (UNICAMP)

Alexandre Umpierrez Amaral

Universidade Regional Integrada do Alto Uruguai e das Missões

Oskar Hansson

Lund University

Edilene S. Siqueira‐Santos

Universidade Estadual de Campinas (UNICAMP)

Claudia D.C. Navarro

Universidade Estadual de Campinas (UNICAMP)

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Universidade Estadual de Campinas (UNICAMP)

181

Universidade de São Paulo

Universidade Federal do Rio Grande do Sul

Hospital de Clínicas da Unicamp

Universidade Federal do Rio de Janeiro

Charles University

Inserm

University College London

University of Coimbra

Centre National de la Recherche Scientifique

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Redox properties of the adenoside triphosphate‐sensitive K⁺ channel in brain mitochondria

Journal of Neuroscience Research (2008)

Maynara Fornazari Juliana G. de Paula Roger F. Castilho Alicia J. Kowaltowski

Brain mitochondrial ATP-sensitive K+ channel (mitoK(ATP)) opening by diazoxide protects against ischemic damage and excitotoxic cell death. Here we studied the redox properties of brain mitoK(ATP) . MitoK(ATP) activation during excitotoxicity in cultured cerebellar granule neurons prevented the accumulation of reactive oxygen species (ROS) and cell death. Furthermore, mitoK(ATP) activation in isolated brain mitochondria significantly prevented H2O2 release by these organelles but did not change Ca2+ accumulation capacity. Interestingly, the activity of mitoK(ATP) was highly dependent on redox state. The thiol reductant mercaptopropionylglycine prevented mitoK(ATP) activity, whereas exogenous ROS activated the channel. In addition, the use of mitochondrial substrates that led to higher levels of endogenous mitochondrial ROS release closely correlated with enhanced K+ transport activity through mitoK(ATP). Altogether, our results indicate that brain mitoK(ATP) is a redox-sensitive channel that controls mitochondrial ROS release.

Diazoxide

Excitotoxicity

Adenosine triphosphate

10.1002/jnr.21614

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Citations (52)

Disfunção mitocondrial induzida por metilmalonato e 3-nitropropionato

Sandra R. Mirandola Roger F. Castilho

A acidemia metilmalonica (MMAemia) e uma desordem metabolica hereditaria do metabolismo de aminoacidos com cadeia ramificada e de acidos graxos com cadeia impar, envolvendo um defeito na conversao de metilmalonil-CoA a succinil-CoA. Manifestacoes sistemicas e neurologicas nesta doenca sao relacionadas com o acumulo de metilmalonato (MMA) em tecidos e fluidos biologicos e com o comprometimento do metabolismo energetico. Neste trabalho, verificou-se que o MMA inibiu com grande intensidade a conversao de lactato a piruvato catalisada pela enzima lactato desidrogenase (LDH) em homogenatos de figado e cerebro de rato. A conversao de piruvato a lactato, catalisada pela LDH, foi menos sensivel a inibicao por MMA. Estudos de cinetica enzimatica sobre a inibicao da LDH de cerebro, utilizando-se lactato como substrato, indicaram que o MMA inibe esta enzima competitivamente (Ki = 3,02 ± 0,59 mM). Propos-se que a inibicao da conversao lactato/piruvato por MMA contribui para a fisiopatologia da MMAemia, resultando, dentre outras alteracoes, em acumulo de lactato e acidemia metabolica. Mostrou-se que, em mitocondrias isoladas de cerebro e musculo de rato, concentracoes milimolares de MMA inibiram o consumo de O2 mantido por succinato, enquanto nenhum efeito inibitorio foi observado quando substratos para os complexos I ou IV foram utilizados. Notadamente, o efeito inibitorio de MMA, mas nao de malonato, no consumo mitocondrial de O2 mantido por succinato foi minimizado quando uma permeabilizacao nao-seletiva das mitocondrias foi induzida por alameticina. Em adicao, o MMA apresentou apenas um pequeno efeito inibitorio no consumo de O2 por particulas submitocondriais invertidas na presenca de succinato. Nao se obteve evidencia de producao de malonato nas mitocondrias tratadas com MMA. Conclui-se que o MMA inibe o consumo mitocondrial de O2 na presenca de succinato por interferir na captacao deste substrato pela mitocondria. A inibicao do transporte mitocondrial de substratos, induzida pelo MMA, atraves do carreador de dicarboxilatos, pode ter importantes implicacoes fisiopatologicas na MMAemia. Comparou-se a suscetibilidade de mitocondrias isoladas de figado, rim e coracao de rato, assim como de diferentes subregioes cerebrais quanto a transicao de permeabilidade mitocondrial (MPT) induzida por 3-nitropropionato (3-NP) e Ca2+. A MPT foi estimada pela queda do potencial eletrico transmembrana e inchamento mitocondrial sensiveis a ciclosporina A. Mitocondrias de cerebro e coracao foram mais suscetiveis a MPT induzida por 3-NP e Ca2+ que organelas isoladas de figado e rim. A comparacao de mitocondrias de diferentes regioes cerebrais indicou que uma inibicao parcial da respiracao por 3-NP resultou em MPT mais rapidamente em organelas estriatais que corticais ou cerebelares. Em ratos tratados sistemicamente com 3-NP, verificou-se uma inibicao de mesma magnitude da succinato desidrogenase em todos os tecidos estudados. Notadamente, mitocondrias isoladas de cerebro de ratos tratados sistemicamente com 3-NP apresentaram uma maior suscetibilidade a MPT induzida por Ca2+ quanto comparadas a controles. Propos-se que a maior suscetibilidade do estriado a neurodegeneracao induzida por 3-NP pode ser, pelo menos em parte, explicada por uma maior vulnerabilidade desta regiao cerebral a MPT, juntamente com a vulnerabilidade desta regiao ao influxo de Ca2+ citosolico mediado pelo estimulo de receptores de glutamato. Abstract

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Abstract: P279 CONTRIBUTION OF NITRIC OXIDE TO THE MITOCHONDRIAL OXIDATIVE STRESS IN HYPERCHOLESTEROLEMIC MICE

Atherosclerosis Supplements (2009)

Leite Ac Renata Porto Alegre Garcia Fabiane Leonel Utino Roger F. Castilho Adriana Cassina

Nitrotyrosine

Peroxynitrous acid

10.1016/s1567-5688(09)70574-4

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Lack of NAD(P)+ transhydrogenase activity in patients with primary adrenal insufficiency due to NNT variants

European Journal of Endocrinology (2024)

Annelise Francisco Ayşe Mine Yılmaz Claudia D.C. Navarro Aşan Önder Melek Yıldız

Pathogenic variants in the nicotinamide nucleotide transhydrogenase gene (NNT) are a rare cause of primary adrenal insufficiency (PAI), as well as functional impairment of the gonads. Despite the description of different homozygous and compound heterozygous NNT variants in PAI patients, the extent to which the function and expression of the mature protein are compromised remains to be clarified. The activity and expression of mitochondrial NAD(P)+ transhydrogenase (NNT) were analyzed in blood samples obtained from patients diagnosed with PAI due to genetically confirmed variants of the NNT gene (n = 5), heterozygous carriers as their parents (n = 8), and healthy controls (n = 26). NNT activity was assessed by a reverse reaction assay standardized for digitonin-permeabilized peripheral blood mononuclear cells (PBMCs). The enzymatic assay was validated in PBMC samples from a mouse model of NNT absence. Additionally, the PBMC samples were evaluated for NNT expression by western blotting and reverse transcription quantitative polymerase chain reaction and for mitochondrial oxygen consumption. NNT activity was undetectable (<4% of that of healthy controls) in PBMC samples from patients, independent of the pathogenic genetic variant. In patients' parents, NNT activity was approximately half that of the healthy controls. Mature NNT protein expression was lower in patients than in the control groups, while mRNA levels varied widely among genotypes. Moreover, pathogenic NNT variants did not impair mitochondrial bioenergetic function in PBMCs. The manifestation of PAI in NNT-mutated patients is associated with a complete lack of NNT activity. Evaluation of NNT activity can be useful to characterize disease-causing NNT variants.

10.1093/ejendo/lvae011

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Citations (2)

Evaluation of mitochondrial respiratory function in highly glycolytic glioma cells reveals low ADP phosphorylation in relation to oxidative capacity

Journal of Neuro-Oncology (2017)

Erika Rodrigues-Silva Edilene S. Siqueira‐Santos Juliana S. Ruas Raffaela Silvestre Ignarro Tiago R. Figueira

Protonophore

10.1007/s11060-017-2482-0

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Citations (7)

Disturbance of mitochondrial functions associated with permeability transition pore opening induced by cis-5-tetradecenoic and myristic acids in liver of adolescent rats

Mitochondrion (2019)

Cristiane Cecatto Alexandre Umpierrez Amaral Alessandro Wajner Simone Magagnin Wajner Roger F. Castilho

Bioenergetics

Myristic acid

Homeostasis

10.1016/j.mito.2019.09.008

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Mitochondrial membrane potential and hydroethidine‐monitored superoxide generation in cultured cerebellar granule cells

FEBS Letters (1997)

Samantha L. Budd Roger F. Castilho David G. Nicholls

Mitochondrial depolarisation has been reported to enhance the generation of superoxide anion (O2.-) in a number of cell preparations while an inhibition has been observed with isolated mitochondria. Cerebellar granule cells equilibrated with > 1 microM hydroethidine (dihydroethidium) which is oxidised to the fluorescent ethidium cation by O2.- showed a large increase in fluorescence on protonophore addition. However, controls showed the fluorescent enhancement to be a consequence of release of unbound preformed ethidium from the mitochondrial matrix within the cell with resultant fluorescent enhancement. This ambiguity was removed by the use of low (1 microM) concentrations of dye in which case generated ethidium remained bound within the mitochondria. Under these conditions antimycin A, but not protonophore addition, produced an increase in fluorescence. It is concluded that excess ethidium acts as an indicator of mitochondrial membrane potential obscuring the monitoring of O2.- and that certain experiments employing this indicator in cells may require re-evaluation.

Protonophore

Antimycin A

Ethidium bromide

Rotenone

Granule (geology)

10.1016/s0014-5793(97)01088-0

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Citations (225)

Diazoxide protects against methylmalonate-induced neuronal toxicity

Experimental Neurology (2006)

Alicia J. Kowaltowski Evelise N. Maciel Maynara Fornazari Roger F. Castilho

Diazoxide

Oligomycin

10.1016/j.expneurol.2006.04.004

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Citations (31)

NEK10 kinase ablation affects mitochondrial morphology, function and protein phosphorylation status

Proteome Science (2024)

Andressa Peres de Oliveira Claudia D.C. Navarro Pedro Rafael F Dias Tania Arguello Brittni R. Walker

NEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels.

Morphology

10.1186/s12953-024-00234-z

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Citations (1)

Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma

Nature Medicine (2003)

Gustav Mattiasson Mehrdad Shamloo Gunilla Gidö Kavitha Mathi Gregor Tomasevic

10.1038/nm903

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Citations (510)