Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Nat Cell Biol ; 26(8): 1261-1273, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38969763

RESUMO

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.


Assuntos
Retículo Endoplasmático , Ácidos Graxos , Inflamação , Gotículas Lipídicas , Metabolismo dos Lipídeos , Macrófagos , Mitocôndrias , Macrófagos/metabolismo , Animais , Retículo Endoplasmático/metabolismo , Gotículas Lipídicas/metabolismo , Mitocôndrias/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Ácidos Graxos/metabolismo , Peroxissomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Organelas/metabolismo
2.
Nat Metab ; 4(7): 856-866, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35864246

RESUMO

Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB-Irg1-itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32-BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB's role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.


Assuntos
Lisossomos , Succinatos , Autofagia/fisiologia , Lisossomos/metabolismo , Macrófagos/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA