RESUMEN
N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.
Asunto(s)
Glutamina , Leucemia Mieloide Aguda , Humanos , Glutamina/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Estabilidad del ARN , Pronóstico , Antígenos de Histocompatibilidad Menor , Sistema de Transporte de Aminoácidos ASC/genética , Sistema de Transporte de Aminoácidos ASC/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Mammalian preimplantation embryos follow a stereotypic pattern of development from zygotes to blastocysts. Here, we use labeled nutrient isotopologue analysis of small numbers of embryos to track downstream metabolites. Combined with transcriptomic analysis, we assess the capacity of the embryo to reprogram its metabolism through development. Early embryonic metabolism is rigid in its nutrient requirements, sensitive to reductive stress and has a marked disequilibrium between two halves of the TCA cycle. Later, loss of maternal LDHB and transcription of zygotic products favors increased activity of bioenergetic shuttles, fatty-acid oxidation and equilibration of the TCA cycle. As metabolic plasticity peaks, blastocysts can develop without external nutrients. Normal developmental metabolism of the early embryo is distinct from cancer metabolism. However, similarities emerge upon reductive stress. Increased metabolic plasticity with maturation is due to changes in redox control mechanisms and to transcriptional reprogramming of later-stage embryos during homeostasis or upon adaptation to environmental changes.
Asunto(s)
Adaptación Fisiológica , Blastocisto/metabolismo , Metaboloma , Animales , Células Cultivadas , Ciclo del Ácido Cítrico , Glucosa/metabolismo , Glutamina/metabolismo , Ratones , Ratones Endogámicos C57BL , NAD/metabolismo , Oxidación-Reducción , TranscriptomaRESUMEN
Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of aging. However, the physical characteristics of the extracellular matrix are also altered in cancerous and aging tissues. Here, we demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via solute carrier family 9 member A1-dependent ion exchange and heat shock factor 1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer.
Asunto(s)
Adhesión Celular/fisiología , Mecanotransducción Celular/fisiología , Dinámicas Mitocondriales/fisiología , Adulto , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans , Respiración de la Célula , Células Cultivadas , Matriz Extracelular/metabolismo , Femenino , Células HEK293 , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/patología , Hiperglucemia/fisiopatología , Integrinas/fisiología , Intercambio Iónico , Ratones , Microscopía Confocal , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/fisiología , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Intercambiador 1 de Sodio-Hidrógeno/fisiología , Imagen de Lapso de TiempoRESUMEN
Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2-induced severe systemic toxicity and multiorgan involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery, followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity, and failure to thrive. We demonstrate that there is metabolic suppression of oxidative phosphorylation and the tricarboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia, and splenic atrophy, mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate, and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We performed metabolomic profiling of peripheral blood and identified a panel of TCA cycle metabolites that served as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, which affects expression of immune response genes and could, in part, contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2-induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.
Asunto(s)
COVID-19/complicaciones , Epigénesis Genética/inmunología , Insuficiencia de Crecimiento/etiología , SARS-CoV-2/patogenicidad , Síndrome Debilitante/etiología , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Animales Modificados Genéticamente , COVID-19/metabolismo , COVID-19/fisiopatología , COVID-19/virología , Ciclo del Ácido Cítrico/fisiología , Metilación de ADN/fisiología , Modelos Animales de Enfermedad , Insuficiencia de Crecimiento/fisiopatología , Humanos , Inmunidad/genética , Masculino , Ratones , Fosforilación Oxidativa , Sistema Renina-Angiotensina/fisiología , SARS-CoV-2/metabolismo , Síndrome Debilitante/fisiopatologíaRESUMEN
Constitutive expression of the chemokine Mcp1 in mouse cardiomyocytes creates a model of inflammatory cardiomyopathy, with death from heart failure at age 7-8 months. A critical pathogenic role has previously been proposed for induced oxidative stress, involving NADPH oxidase activation. To test this idea, we exposed the mice to elevated oxygen levels. Against expectation, this prevented, rather than accelerated, the ultrastructural and functional signs of heart failure. This result suggests that the immune signaling initiated by Mcp1 leads instead to the inhibition of cellular oxygen usage, for which mitochondrial respiration is an obvious target. To address this hypothesis, we combined the Mcp1 model with xenotopic expression of the alternative oxidase (AOX), which provides a sink for electrons blocked from passage to oxygen via respiratory complexes III and IV. Ubiquitous AOX expression provided only a minor delay to cardiac functional deterioration and did not prevent the induction of markers of cardiac and metabolic remodeling considered a hallmark of the model. Moreover, cardiomyocyte-specific AOX expression resulted in exacerbation of Mcp1-induced heart failure, and failed to rescue a second cardiomyopathy model directly involving loss of cIV. Our findings imply that mitochondrial involvement in the pathology of inflammatory cardiomyopathy is multifaceted and complex.