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1.
iScience ; 26(3): 106296, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36936788

RESUMO

Mitochondrial calcium overload contributes to neurodegenerative disease development and progression. We recently reported that loss of the mitochondrial sodium/calcium exchanger (NCLX), the primary mechanism of mCa2+ efflux, promotes mCa2+ overload, metabolic derangement, redox stress, and cognitive decline in models of Alzheimer's disease (AD). However, whether disrupted mCa2+ signaling contributes to neuronal pathology and cognitive decline independent of pre-existing amyloid or tau pathology remains unknown. Here, we generated mice with neuronal deletion of the mitochondrial sodium/calcium exchanger (NCLX, Slc8b1 gene), and evaluated age-associated changes in cognitive function and neuropathology. Neuronal loss of NCLX resulted in an age-dependent decline in spatial and cued recall memory, moderate amyloid deposition, mild tau pathology, synaptic remodeling, and indications of cell death. These results demonstrate that loss of NCLX-dependent mCa2+ efflux alone is sufficient to induce an Alzheimer's disease-like pathology and highlights the promise of therapies targeting mCa2+ exchange.

2.
Biochim Biophys Acta Gen Subj ; 1861(1 Pt A): 2942-2955, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27663234

RESUMO

Apoptosis Inducing Factor (AIF), a phylogenetically conserved mitochondrial inter-membrane space flavoprotein has an important role in caspase independent cell death. Nevertheless, AIF is also essential for cell survival. It is required for mitochondrial organization and energy metabolism. Upon apoptotic stimulation, AIF induces DNA fragmentation after its mitochondrio-nuclear translocation. Although it executes critical cellular functions in a coordinated manner, the exact mechanism still remains obscure. The present study aims to understand AIF's role in cell survival, growth and development by its down-regulation in an interesting unicellular eukaryote, D. discoideum which exhibits multicellularity upon starvation. Constitutive AIF down-regulated (dR) cells exhibited slower growth and delayed developmental morphogenesis. Also, constitutive AIF dR cells manifested high intracellular ROS, oxidative DNA damage and calcium levels with lower ATP content. Interestingly, constitutive AIF dR cells showed amelioration in cell growth upon antioxidant treatment, strengthening its role as ROS regulator. Under oxidative stress, AIF dR cells showed early mitochondrial membrane depolarization followed by AIF translocation from mitochondria to nucleus and exhibited necrotic cell death as compared to paraptoptic cell death of control cells. Thus, the results of this study provide an exemplar where AIF is involved in growth and development by regulating ROS levels and maintaining mitochondrial function in D. discoideum, an evolutionarily significant model organism exhibiting caspase independent apoptosis.


Assuntos
Fator de Indução de Apoptose/metabolismo , Evolução Biológica , Dictyostelium/citologia , Dictyostelium/metabolismo , Trifosfato de Adenosina/metabolismo , Anexina A5/metabolismo , Cálcio/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Citosol/efeitos dos fármacos , Citosol/metabolismo , Dictyostelium/crescimento & desenvolvimento , Dictyostelium/ultraestrutura , Regulação para Baixo/efeitos dos fármacos , Citometria de Fluxo , Fluoresceína-5-Isotiocianato/metabolismo , Fluorometria , Glucose/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , NAD/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Propídio/metabolismo , Transporte Proteico/efeitos dos fármacos , RNA Antissenso/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Coloração e Rotulagem
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