Subject(s)
COVID-19 , Receptors, Chimeric Antigen , Vaccines , Humans , SARS-CoV-2 , COVID-19/prevention & control , Antibodies, ViralABSTRACT
Although typically upregulated upon cellular stress, autophagy can also be utilized under homeostatic conditions as a quality control mechanism or in response to developmental cues. Here, we report that autophagy is required for the maintenance of somatic cyst stem cells (CySCs) in the Drosophila testis. Disruption of autophagy in CySCs and early cyst cells (CCs) by the depletion of autophagy-related (Atg) genes reduced early CC numbers and affected CC function, resembling decreased epidermal growth factor receptor (EGFR) signaling. Indeed, our data indicate that EGFR acts to stimulate autophagy to preserve early CC function, whereas target of rapamycin (TOR) negatively regulates autophagy in the differentiating CCs. Finally, we show that the EGFR-mediated stimulation of autophagy regulates lipid levels in CySCs and CCs. These results demonstrate a key role for autophagy in regulating somatic stem cell behavior and tissue homeostasis by integrating cues from both the EGFR and TOR signaling pathways to control lipid metabolism.
Subject(s)
Autophagy/genetics , Drosophila Proteins/metabolism , Drosophila/metabolism , ErbB Receptors/metabolism , Germ Cells/metabolism , Lipid Metabolism/genetics , Receptors, Invertebrate Peptide/metabolism , Stem Cells/metabolism , Animals , Animals, Genetically Modified , Autophagosomes/metabolism , Cell Differentiation/genetics , Drosophila Proteins/genetics , ErbB Receptors/genetics , Gene Knockdown Techniques , Germ Cells/growth & development , Homeostasis , MAP Kinase Signaling System/genetics , Male , RNA Interference , Receptors, Invertebrate Peptide/genetics , TOR Serine-Threonine Kinases/metabolism , Testis/cytology , Testis/metabolism , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolismABSTRACT
The capacity of stem cells to self-renew or differentiate has been attributed to distinct metabolic states. A genetic screen targeting regulators of mitochondrial dynamics revealed that mitochondrial fusion is required for the maintenance of male germline stem cells (GSCs) in Drosophila melanogaster. Depletion of Mitofusin (dMfn) or Opa1 led to dysfunctional mitochondria, activation of Target of rapamycin (TOR) and a marked accumulation of lipid droplets. Enhancement of lipid utilization by the mitochondria attenuated TOR activation and rescued the loss of GSCs that was caused by inhibition of mitochondrial fusion. Moreover, constitutive activation of the TOR-pathway target and lipogenesis factor Sterol regulatory element binding protein (SREBP) also resulted in GSC loss, whereas inhibition of SREBP rescued GSC loss triggered by depletion of dMfn. Our findings highlight a critical role for mitochondrial fusion and lipid homeostasis in GSC maintenance, providing insight into the potential impact of mitochondrial and metabolic diseases on the function of stem and/or germ cells.
