RESUMEN
FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Drosophila , Factores de Transcripción Forkhead , Longevidad , Estrés Oxidativo , Animales , Longevidad/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Caenorhabditis elegans/metabolismo , Humanos , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Bombyx/genética , Bombyx/metabolismo , Bombyx/fisiología , Drosophila melanogaster/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Especies Reactivas de Oxígeno/metabolismo , Regulación de la Expresión GénicaRESUMEN
In the field of neurodegenerative diseases, especially sporadic Parkinson's disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial (mt)DNA in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology. To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb-/-/Ifnar-/- mice). We found that the lack of neuronal IFNß/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an "infectious-like" manner. We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNß/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA. These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.
Asunto(s)
ADN Mitocondrial , Enfermedad de Parkinson , Humanos , Ratones , Animales , ADN Mitocondrial/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Proteómica , Mitocondrias/metabolismo , Neuronas/metabolismoRESUMEN
Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-ß is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-ß induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-ß signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria-endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-ß in the Ifnb-/- model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-ß rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-ß activates mitochondrial fission in neurons through the pSTAT5/PGAM5/S622 Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.
Asunto(s)
Interferón beta/metabolismo , Dinámicas Mitocondriales , Enfermedad de Parkinson/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Dinaminas/metabolismo , Forminas/metabolismo , Interferón beta/genética , Ratones , Mitocondrias/metabolismo , Neuronas/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Factor de Transcripción STAT5/metabolismoRESUMEN
Cancer is a multistep process. In the early phases of this disease, mutations in oncogenes and tumor suppressors are thought to promote clonal expansion. These mutations can increase cell competitiveness, allowing tumor cells to grow within the tissue by eliminating wild type host cells. Recent studies have shown that cell competition can also function in later phases of cancer. Here, we examine the existing evidence linking cell competition and tumorigenesis. We focus on the mechanisms underlying cell competition and their contribution to disease pathogenesis.