Department of Molecular Genetics, University of Toronto, Ontario, Canada.
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh Pennsylvania, United States of America.
PLoS Genet. 2023 Jan 25;19(1):e1010610. doi: 10.1371/journal.pgen.1010610. eCollection 2023 Jan.
Stem cells often possess immature mitochondria with few inner membrane invaginations, which increase as stem cells differentiate. Despite this being a conserved feature across many stem cell types in numerous organisms, how and why mitochondria undergo such remodelling during stem cell differentiation has remained unclear. Here, using Drosophila germline stem cells (GSCs), we show that Complex V drives mitochondrial remodelling during the early stages of GSC differentiation, prior to terminal differentiation. This endows germline mitochondria with the capacity to generate large amounts of ATP required for later egg growth and development. Interestingly, impairing mitochondrial remodelling prior to terminal differentiation results in endoplasmic reticulum (ER) lipid bilayer stress, Protein kinase R-like ER kinase (PERK)-mediated activation of the Integrated Stress Response (ISR) and germ cell death. Taken together, our data suggest that mitochondrial remodelling is an essential and tightly integrated aspect of stem cell differentiation. This work sheds light on the potential impact of mitochondrial dysfunction on stem and germ cell function, highlighting ER lipid bilayer stress as a potential major driver of phenotypes caused by mitochondrial dysfunction.
干细胞通常具有不成熟的线粒体，其内膜凹陷较少，随着干细胞分化而增加。尽管这是许多生物体中许多干细胞类型的保守特征，但线粒体在干细胞分化过程中如何以及为何会发生这种重塑仍然不清楚。在这里，我们使用果蝇生殖干细胞（GSCs）表明，在 GSC 分化的早期，即终端分化之前，复合物 V 驱动线粒体重塑。这使生殖线粒体具有产生大量 ATP 的能力，ATP 是后期卵子生长和发育所必需的。有趣的是，在终端分化之前损害线粒体重塑会导致内质网（ER）脂双层应激、蛋白激酶 R 样内质网激酶（PERK）介导的整合应激反应（ISR）激活和生殖细胞死亡。总之，我们的数据表明，线粒体重塑是干细胞分化的一个重要且紧密整合的方面。这项工作揭示了线粒体功能障碍对干细胞和生殖细胞功能的潜在影响，强调内质网脂双层应激是由线粒体功能障碍引起的表型的潜在主要驱动因素。
