Mitochondrial remodelling is essential for female germ cell differentiation and survival.
Mitochondrial remodelling is essential for female germ cell differentiation and survival.
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DOI：
10.1371/journal.pgen.1010610
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发表时间：
2023-01
期刊：
影响因子：
4.5
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中科院分区：
文献类型：
--
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干细胞通常具有不成熟的线粒体，其内膜内陷很少，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，但线粒体如何以及为什么在干细胞分化期间经历这种重塑仍然不清楚。在这里，使用果蝇种系干细胞（GSC），我们表明，复合物V驱动线粒体重塑GSC分化的早期阶段，在终端分化之前。这赋予生殖系线粒体产生大量ATP的能力，这些ATP是卵子生长和发育所需的。有趣的是，在终末分化之前损害线粒体重塑导致内质网（ER）脂质双层应激、蛋白激酶R样ER激酶（PERK）介导的综合应激反应（ISR）的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和紧密整合的方面。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，突出了ER脂质双层应激作为线粒体功能障碍引起的表型的潜在主要驱动因素。干细胞是组织发育和再生所必需的。随着干细胞分化成特化细胞，它们的线粒体经常发生变化，包括线粒体内膜的重塑。使用果蝇卵巢中的成年生殖系干细胞群体，我们表明，分化过程中的线粒体重塑赋予生殖系线粒体产生大量ATP的能力，这是后期卵子生长和发育所必需的。有趣的是，我们还发现，损害线粒体重塑诱导内质网应激，这导致过早终止分化和最终的细胞死亡。我们的工作阐明了线粒体功能障碍对干细胞功能和分化的潜在影响，以及线粒体疾病的潜在机制。
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. Stem cells are necessary for both tissue development and regeneration. As stem cells differentiate into specialized cells their mitochondria often undergo changes, including the remodelling of their inner mitochondrial membranes. Using a population of adult germline stem cells in the Drosophila ovary, we show that mitochondrial remodelling during differentiation acts to endow germline mitochondria with the capacity to generate large amounts of ATP, which are required for later egg growth and development. Interestingly, we also find that impairing mitochondrial remodelling induces endoplasmic reticulum stress, which results in premature termination of differentiation and eventual cell death. Our work illuminates the potential impact of mitochondrial dysfunction on stem cell function and differentiation, and potential mechanisms of mitochondrial disease.
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