线粒体融合调控果蝇精巢中的脂质稳态和干细胞维持。

Mitochondrial fusion regulates lipid homeostasis and stem cell maintenance in the Drosophila testis.

机构信息

Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.

Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.

出版信息

Nat Cell Biol. 2019 Jun;21(6):710-720. doi: 10.1038/s41556-019-0332-3. Epub 2019 Jun 3.

DOI:10.1038/s41556-019-0332-3

PMID:31160709

Abstract

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.

摘要

干细胞的自我更新或分化能力归因于其独特的代谢状态。一项针对线粒体动力学调节因子的基因筛选发现，在线虫中，线粒体融合对于维持雄性生殖干细胞（GSCs）至关重要。Mitofusin（dMfn）或 Opa1 的耗竭会导致线粒体功能障碍、雷帕霉素靶蛋白（TOR）的激活以及脂滴的大量积累。增强线粒体对脂质的利用可以减弱 TOR 的激活，并挽救由于抑制线粒体融合而导致的 GSCs 丢失。此外，TOR 通路靶标和脂质生成因子固醇调节元件结合蛋白（SREBP）的组成性激活也会导致 GSC 的丢失，而抑制 SREBP 则可以挽救由于 dMfn 耗竭而触发的 GSC 丢失。我们的研究结果强调了线粒体融合和脂质动态平衡在 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新的见解。