Asymmetric mitochondrial inheritance: Charting mechanism(s) and function(s) during animal development

线粒体不对称遗传：绘制动物发育过程中的机制和功能

• 批准号: BB/V015648/1
• 负责人: Barbara Conradt
• 金额: $ 74.52万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV015648%2F1
• 关键词: Asymmetric; mitochondrial; inheritance; Charting; mechanism

Mitochondria are organelles that are essential for eukaryotic cells. Most importantly, they provide energy in the form of ATP, which is critical for numerous cellular reactions and, hence, cell viability. However, mitochondria are required for processes other than ATP production and, indeed, novel functions of mitochondria continue to be uncovered. For example, it has recently been suggested that when a stem cell divides, mitochondria play a decisive role in the ability of one of its daughter cells to commit to the stem cell fate. How mitochondria impact on cell fate decisions, such as the commitment to the stem cell fate, is currently an open question in the fields of developmental and stem cell biology.Mitochondria cannot be made de novo and are generated from preexisting organelles. For this reason, it is imperative that during cell division, both daughter cells inherit enough mitochondria to cover their energy demands. It is known that in 'symmetrically' dividing animal cells, mitochondria fragment into numerous distinct organelles before division, and this leads to the partitioning of similar numbers of mitochondrial fragments into both daughter cells. However, it is not known how mitochondria are inherited during the 'asymmetric' divisions that are typical of stem cells, which produce two qualitatively different daughter cells. Our preliminary results, briefly summarized below, indicate that the questions how mitochondria impact on cell fate decisions and how mitochondria are inherited in asymmetrically dividing cells are intimately connected. The overarching hypothesis that we will test in the proposed work is that apart from a 'permissive' i.e. energy-providing role, the process of mitochondrial inheritance can have an 'instructive' role and provide a daughter cell with specific 'information' that influences or dictates its fate. More provocatively, we propose that 'asymmetric mitochondrial inheritance' is a major driver of cell fate divergence and that whether a cell division is functionally 'symmetric' or 'asymmetric' depends at least in part on whether mitochondria are partitioned symmetrically or not. One reason why it has been difficult to study mitochondrial inheritance in animals is the lack of an appropriate model. We have recently discovered asymmetric mitochondrial inheritance in the context of a critical cell fate decision during the development of Caenorhabditis elegans. This animal model captivates researchers by offering unique biology (highly reproducible and fast development, transparency) and powerful methodology (genetic and imaging-based methods) that together make it possible to observe mitochondria in real time as they are being inherited. The cell QL.p, for example, divides to generate an anterior daughter cell, QL.pa, which survives, and a posterior daughter cell, QL.pp, which dies. We discovered that during QL.p division, smaller, fragmented mitochondria are inherited by QL.pp whereas larger mitochondria are inherited by QL.pa. Importantly, we had previously found that 'unwanted' cells (i.e. cells that reproducibly die during C. elegans development, such as QL.pp) have fragmented mitochondria and that preventing mitochondrial fragmentation rescues some of these unwanted cells from the 'cell death fate'. This indicates that asymmetric mitochondrial inheritance is partially required for the ability of a cell to commit to the cell death fate. In the proposed work, we will use the division of QL.p as a paradigm to uncover mechanism(s) involved in asymmetric mitochondrial inheritance (Aim 1) and to address the question of how mitochondria impact on cell fate decisions (Aim 2). To that end we will identify aspect(s) of cell fate that are affected by asymmetric mitochondrial inheritance and uncover critical differences between mitochondria inherited by QL.pp and QL.pa.

线粒体是真核细胞必需的细胞器。最重要的是，它们以 ATP 形式提供能量，这对于许多细胞反应以及细胞活力至关重要。然而，线粒体对于 ATP 生成以外的过程是必需的，并且事实上，线粒体的新功能不断被发现。例如，最近有人提出，当干细胞分裂时，线粒体对其子细胞之一决定干细胞命运的能力起着决定性作用。线粒体如何影响细胞命运决定，例如对干细胞命运的承诺，目前是发育和干细胞生物学领域的一个悬而未决的问题。线粒体不能从头制造，而是由预先存在的细胞器产生。因此，在细胞分裂过程中，两个子细胞必须继承足够的线粒体来满足其能量需求。众所周知，在“对称”分裂的动物细胞中，线粒体在分裂前分裂成许多不同的细胞器，这导致相似数量的线粒体片段分配到两个子细胞中。然而，目前尚不清楚线粒体在干细胞典型的“不对称”分裂过程中是如何遗传的，干细胞会产生两个性质不同的子细胞。我们的初步结果（简要总结如下）表明线粒体如何影响细胞命运决定以及线粒体如何在不对称分裂细胞中遗传的问题密切相关。我们将在拟议的工作中测试的总体假设是，除了“许可”即提供能量的作用之外，线粒体遗传过程还可以具有“指导”作用，并为子细胞提供影响或决定其命运的特定“信息”。更具挑衅性的是，我们提出“不对称线粒体遗传”是细胞命运分歧的主要驱动因素，并且细胞分裂在功能上是“对称”还是“不对称”至少部分取决于线粒体是否对称分配。研究动物线粒体遗传困难的原因之一是缺乏合适的模型。我们最近发现了秀丽隐杆线虫发育过程中关键细胞命运决定背景下的不对称线粒体遗传。这种动物模型通过提供独特的生物学（高度可重复、快速发展、透明）和强大的方法（基于遗传和成像的方法）而吸引了研究人员，这些方法共同使得在线粒体遗传过程中实时观察线粒体成为可能。例如，细胞 QL.p 分裂产生存活的前子细胞 QL.pa 和死亡的后子细胞 QL.pp。我们发现，在 QL.p 分裂期间，较小的、碎片化的线粒体由 QL.pp 遗传，而较大的线粒体由 QL.pa 遗传。重要的是，我们之前发现“不需要的”细胞（即在秀丽隐杆线虫发育过程中可重复死亡的细胞，例如 QL.pp）具有破碎的线粒体，并且防止线粒体破碎可以将其中一些不需要的细胞从“细胞死亡命运”中拯救出来。这表明不对称线粒体遗传是细胞承担细胞死亡命运的能力所必需的。在拟议的工作中，我们将使用 QL.p 的划分作为范例来揭示参与不对称线粒体遗传的机制（目标 1）并解决线粒体如何影响细胞命运决定的问题（目标 2）。为此，我们将确定受不对称线粒体遗传影响的细胞命运的各个方面，并揭示 QL.pp 和 QL.pa 遗传的线粒体之间的关键差异。

项目成果

PUF-8, a C. elegans ortholog of the RNA-binding proteins PUM1 and PUM2, is required for robustness of the cell death fate.

PUF-8是RNA结合蛋白PUM1和PUM2的秀丽隐杆线虫直系同源物，是细胞死亡命运的鲁棒性所必需的。

• DOI: 10.1242/dev.201167
• 发表时间: 2023-10-01
• 期刊: Development (Cambridge, England)