RESUMO
Stem cells preferentially use glycolysis instead of oxidative phosphorylation and this metabolic rewiring plays an instructive role in their fate; however, the underlying molecular mechanisms remain largely unexplored. PIWI-interacting RNAs (piRNAs) and PIWI proteins have essential functions in a range of adult stem cells across species. Here, we show that piRNAs and the PIWI protein Aubergine (Aub) are instrumental in activating glycolysis in Drosophila female germline stem cells (GSCs). Higher glycolysis is required for GSC self-renewal and aub loss-of-function induces a metabolic switch in GSCs leading to their differentiation. Aub directly binds glycolytic mRNAs and Enolase mRNA regulation by Aub depends on its 5'UTR. Furthermore, mutations of a piRNA target site in Enolase 5'UTR lead to GSC loss. These data reveal an Aub/piRNA function in translational activation of glycolytic mRNAs in GSCs, and pinpoint a mechanism of regulation of metabolic reprogramming in stem cells based on small RNAs.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Glicólise , Fatores de Iniciação de Peptídeos , RNA Interferente Pequeno , Animais , Glicólise/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Feminino , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/genética , Fatores de Iniciação de Peptídeos/metabolismo , Fatores de Iniciação de Peptídeos/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Diferenciação Celular , Reprogramação Celular/genética , Regiões 5' não Traduzidas , Células-Tronco de Oogônios/metabolismo , Células-Tronco de Oogônios/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Reprogramação Metabólica , RNA de Interação com PiwiRESUMO
Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ. Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.