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1.
Nat Metab ; 6(6): 1108-1127, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38822028

RESUMO

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.


Assuntos
Lisossomos , Macrófagos , Fosfato de Piridoxal , Lisossomos/metabolismo , Macrófagos/metabolismo , Animais , Camundongos , Fosfato de Piridoxal/metabolismo , Hipóxia/metabolismo , Hipóxia Celular , Vitamina B 6/metabolismo , Oxigênio/metabolismo , Inflamação/metabolismo
2.
Redox Biol ; 43: 101966, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857757

RESUMO

Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and ß-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.


Assuntos
Ácidos Graxos , Condicionamento Físico Animal , Animais , Tolerância ao Exercício , Feminino , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Qualidade de Vida
3.
Dev Cell ; 22(1): 79-91, 2012 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-22178499

RESUMO

During development, directional cell division is a major mechanism for establishing the orientation of tissue growth. Drosophila neuroblasts undergo asymmetric divisions perpendicular to the overlying epithelium to produce descendant neurons on the opposite side, thereby orienting initial neural tissue growth. However, the mechanism remains elusive. We provide genetic evidence that extrinsic GPCR signaling determines the orientation of cortical polarity underlying asymmetric divisions of neuroblasts relative to the epithelium. The GPCR Tre1 activates the G protein oα subunit in neuroblasts by interacting with the epithelium to recruit Pins, which regulates spindle orientation. Because Pins associates with the Par-complex via Inscuteable, Tre1 consequently recruits the polarity complex to orthogonally orient the polarity axis to the epithelium. Given the universal role of the Par complex in cellular polarization, we propose that the GPCR-Pins system is a comprehensive mechanism controlling tissue polarity by orienting polarized stem cells and their divisions.


Assuntos
Divisão Celular/fisiologia , Polaridade Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Células Epiteliais/citologia , Neurônios/citologia , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/citologia , Animais , Western Blotting , Células Cultivadas , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Células Epiteliais/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Técnicas Imunoenzimáticas , Imunoprecipitação , Peptidilprolil Isomerase de Interação com NIMA , Neurônios/metabolismo , Peptidilprolil Isomerase/genética , Peptidilprolil Isomerase/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Fuso Acromático , Células-Tronco/metabolismo
4.
J Cell Sci ; 122(Pt 18): 3242-9, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19690050

RESUMO

Drosophila neural stem cells or neuroblasts undergo typical asymmetric cell division. An evolutionally conserved protein complex, comprising atypical protein kinase C (aPKC), Bazooka (Par-3) and Par-6, organizes cell polarity to direct these asymmetric divisions. Aurora-A (AurA) is a key molecule that links the divisions to the cell cycle. Upon its activation in metaphase, AurA phosphorylates Par-6 and activates aPKC signaling, triggering the asymmetric organization of neuroblasts. Little is known, however, about how such a positive regulatory cue is counteracted to coordinate aPKC signaling with other cellular processes. During a mutational screen using the Drosophila compound eye, we identified microtubule star (mts), which encodes a catalytic subunit of protein phosphatase 2A (PP2A), as a negative regulator for aPKC signaling. Impairment of mts function causes defects in neuroblast divisions, as observed in lethal (2) giant larvae (lgl) mutants. mts genetically interacts with par-6 and lgl in a cooperative manner in asymmetric neuroblast division. Furthermore, Mts tightly associates with Par-6 and dephosphorylates AurA-phosphorylated Par-6. Our genetic and biochemical evidence indicates that PP2A suppresses aPKC signaling by promoting Par-6 dephosphorylation in neuroblasts, which uncovers a novel balancing mechanism for aPKC signaling in the regulation of asymmetric cell division.


Assuntos
Divisão Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Neurônios/citologia , Proteína Quinase C/metabolismo , Transdução de Sinais , Animais , Proteínas de Ciclo Celular/metabolismo , Polaridade Celular , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Embrião não Mamífero/citologia , Embrião não Mamífero/enzimologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Genes de Insetos , Modelos Biológicos , Neurônios/enzimologia , Folículo Ovariano/citologia , Fenótipo , Fosforilação , Ligação Proteica , Proteína Fosfatase 2/metabolismo , Transporte Proteico , Proteínas Supressoras de Tumor/metabolismo
5.
Nat Cell Biol ; 8(6): 586-93, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16648846

RESUMO

The orientation of the mitotic spindle relative to the cell axis determines whether polarized cells undergo symmetric or asymmetric divisions. Drosophila epithelial cells and neuroblasts provide an ideal pair of cells to study the regulatory mechanisms involved. Epithelial cells divide symmetrically, perpendicular to the apical-basal axis. In the asymmetric divisions of neuroblasts, by contrast, the spindle reorients parallel to that axis, leading to the unequal distribution of cell-fate determinants to one daughter cell. Receptor-independent G-protein signalling involving the GoLoco protein Pins is essential for spindle orientation in both cell types. Here, we identify Mushroom body defect (Mud) as a downstream effector in this pathway. Mud directly associates and colocalizes with Pins at the cell cortex overlying the spindle pole(s) in both neuroblasts and epithelial cells. The cortical Mud protein is essential for proper spindle orientation in the two different division modes. Moreover, Mud localizes to centrosomes during mitosis independently of Pins to regulate centrosomal organization. We propose that Drosophila Mud, vertebrate NuMA and Caenorhabditis elegans Lin-5 (refs 5, 6) have conserved roles in the mechanism by which G-proteins regulate the mitotic spindle.


Assuntos
Centrossomo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fuso Acromático , Animais , Proteínas de Ciclo Celular , Polaridade Celular , Drosophila , Células Epiteliais/citologia , Proteínas de Ligação ao GTP/fisiologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Ligação Proteica
6.
J Cell Biol ; 164(5): 729-38, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-14981094

RESUMO

Drosophila melanogaster neuroblasts (NBs) undergo asymmetric divisions during which cell-fate determinants localize asymmetrically, mitotic spindles orient along the apical-basal axis, and unequal-sized daughter cells appear. We identified here the first Drosophila mutant in the Ggamma1 subunit of heterotrimeric G protein, which produces Ggamma1 lacking its membrane anchor site and exhibits phenotypes identical to those of Gbeta13F, including abnormal spindle asymmetry and spindle orientation in NB divisions. This mutant fails to bind Gbeta13F to the membrane, indicating an essential role of cortical Ggamma1-Gbeta13F signaling in asymmetric divisions. In Ggamma1 and Gbeta13F mutant NBs, Pins-Galphai, which normally localize in the apical cortex, no longer distribute asymmetrically. However, the other apical components, Bazooka-atypical PKC-Par6-Inscuteable, still remain polarized and responsible for asymmetric Miranda localization, suggesting their dominant role in localizing cell-fate determinants. Further analysis of Gbetagamma and other mutants indicates a predominant role of Partner of Inscuteable-Galphai in spindle orientation. We thus suggest that the two apical signaling pathways have overlapping but different roles in asymmetric NB division.


Assuntos
Proteínas de Transporte/metabolismo , Divisão Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Neurônios/fisiologia , Proteína Quinase C/metabolismo , Sistemas do Segundo Mensageiro/fisiologia , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Proteínas de Ciclo Celular/metabolismo , Polaridade Celular , Tamanho Celular , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Drosophila melanogaster/embriologia , Embrião não Mamífero/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades beta da Proteína de Ligação ao GTP/genética , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Isoenzimas/metabolismo , Substâncias Macromoleculares , Dados de Sequência Molecular , Neurônios/citologia , Neuropeptídeos , Mutação Puntual , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas/genética , Proteínas/metabolismo , Fuso Acromático/metabolismo
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