Mitochondrial fusion regulates lipid homeostasis and stem cell maintenance in the Drosophila testis
Mitochondrial fusion regulates lipid homeostasis and stem cell maintenance in the Drosophila testis
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DOI：
10.1038/s41556-019-0332-3
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发表时间：
2019-06-01
影响因子：
21.3
通讯作者：
Jones, D. Leanne
中科院分区：
文献类型：
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作者：
Demarco, Rafael Senos;Uyemura, Bradley S.;Jones, D. Leanne
干细胞自我更新或分化的能力归因于不同的代谢状态。一项针对线粒体动力学调节因子的基因筛选显示，线粒体融合是维持果蝇雄性生殖系干细胞（GSC）所必需的。线粒体融合蛋白（dMfn）或Opa 1的耗尽导致线粒体功能障碍，雷帕霉素靶蛋白（TOR）的激活和脂滴的显著积累。线粒体对脂质利用的增强减弱了TOR活化，并挽救了由线粒体融合抑制引起的GSC损失。此外，组成性激活的TOR-途径的目标和脂肪生成因子固醇调节元件结合蛋白（SREBP）也导致GSC的损失，而抑制SREBP拯救GSC的损失所引发的dMfn的耗尽。我们的研究结果强调了线粒体融合和脂质稳态在GSC维持中的关键作用，为线粒体和代谢疾病对干细胞和/或生殖细胞功能的潜在影响提供了深入了解。
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.