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1.
Nature ; 622(7983): 627-636, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37821702

RESUMO

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.


Assuntos
Apoptose , Senescência Celular , Citosol , DNA Mitocondrial , Mitocôndrias , Animais , Camundongos , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria , Estudo de Prova de Conceito , Inflamação/metabolismo , Fenótipo , Longevidade , Envelhecimento Saudável
2.
EMBO J ; 40(9): e106048, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33764576

RESUMO

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.


Assuntos
Lesão Pulmonar Aguda/imunologia , Tetracloreto de Carbono/efeitos adversos , Neutrófilos/citologia , Espécies Reativas de Oxigênio/metabolismo , Encurtamento do Telômero , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Linhagem Celular , Senescência Celular , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Neutrófilos/metabolismo , Estresse Oxidativo , Comunicação Parácrina
4.
FEMS Yeast Res ; 13(6): 518-28, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23692511

RESUMO

Deletion of SIT4 phosphatase decreased the pyruvate decarboxylase activity, which is essential for directing the glucose flux to ethanol production. Concomitantly, a reduction in the fermentative capacity was observed. As pyruvate decarboxylase expression was not altered, its post-translational phosphorylation was studied. Immunoblot analyses using anti-phosphoserine antibodies against the affinity-purified Pdc1p showed that Pdc1p is a phosphoenzyme. Dephosphorylation of Pdc1p by alkaline phosphatase inhibited activity by 50%. Moreover, phosphorylation of Pdc1p was dependent on the growth phase, being hyperphosphorylated in the logarithmic phase, which showed to be dependent on the presence of SIT4. A comparison of the kinetic parameters of pyruvate decarboxylase in total protein extracts from WT yeast and the Δsit4 mutant revealed that the apparent K(m) values of the cofactor thiamin pyrophosphate (TPP) were 81 and 205 µM, respectively, with V(max) values of 0.294 and 0.173 µmol mg⁻¹ min⁻¹, respectively. Treatment of the purified enzyme with alkaline phosphatase increased the K(m) for TPP from 20 to 84 µM and for pyruvate from 2.3 to 4.6 mM, while the V(max) changed from 0.806 to 0.673 µmol mg⁻¹ min⁻¹. These results suggest that the Pdc1p phosphorylation dependent on SIT4 occurs at residues that change the apparent affinity for TPP and pyruvate.


Assuntos
Regulação Fúngica da Expressão Gênica , Proteína Fosfatase 2/metabolismo , Piruvato Descarboxilase/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Coenzimas/metabolismo , Deleção de Genes , Cinética , Fosforilação , Ligação Proteica , Ácido Pirúvico/metabolismo , Saccharomyces cerevisiae/genética , Tiamina Pirofosfato/metabolismo
5.
PLoS One ; 5(6): e11163, 2010 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-20567505

RESUMO

The genome of Saccharomyces cerevisiae is arguably the best studied eukaryotic genome, and yet, it contains approximately 1000 genes that are still relatively uncharacterized. As the majority of these ORFs have no homologs with characterized sequence or protein structure, traditional sequence-based approaches cannot be applied to deduce their biological function. Here, we characterize YER067W, a conserved gene of unknown function that is strongly induced in response to many stress conditions and repressed in drug resistant yeast strains. Gene expression patterns of YER067W and its paralog YIL057C suggest an involvement in energy metabolism. We show that yeast lacking YER067W display altered levels of reserve carbohydrates and a growth deficiency in media that requires aerobic metabolism. Impaired mitochondrial function and overall reduction of ergosterol content in the YER067W deleted strain explained the observed 2- and 4-fold increase in resistance to the drugs fluconazole and amphotericin B, respectively. Cell fractionation and immunofluorescence microscopy revealed that Yer067w is associated with cellular membranes despite the absence of a transmembrane domain in the protein. Finally, the 1.7 A resolution crystal structure of Yer067w shows an alpha-beta fold with low similarity to known structures and a putative functional site.YER067W's involvement with aerobic energetic metabolism suggests the assignment of the gene name RGI1, standing for respiratory growth induced 1. Altogether, the results shed light on a previously uncharacterized protein family and provide basis for further studies of its apparent role in energy metabolism control and drug resistance.


Assuntos
Resistência Microbiana a Medicamentos , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Carbono/metabolismo , Metabolismo Energético/genética , Fluconazol/farmacologia , Genes Fúngicos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Filogenia , Conformação Proteica , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência de Aminoácidos
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