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

线粒体是真核细胞必不可少的细胞器。最重要的是，它们以ATP的形式提供能量，这对许多细胞反应至关重要，因此对细胞的生存能力至关重要。然而，除了ATP的产生外，线粒体还需要其他过程，事实上，线粒体的新功能正在不断被发现。例如，最近有人提出，当干细胞分裂时，线粒体在其中一个子细胞走向干细胞命运的能力中起着决定性的作用。线粒体如何影响细胞命运的决定，如对干细胞命运的承诺，是目前发育和干细胞生物学领域的一个悬而未决的问题。线粒体不能从头产生，而是由先前存在的细胞器产生的。因此，在细胞分裂过程中，两个子细胞都必须继承足够的线粒体来满足它们的能量需求。众所周知，在动物细胞的“对称”分裂中，线粒体在分裂前分裂成许多不同的细胞器，这导致了相似数量的线粒体片段分裂到两个子细胞中。然而，目前尚不清楚线粒体是如何在干细胞典型的“不对称”分裂过程中遗传的，这种分裂会产生两个质量不同的子细胞。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的问题以及线粒体如何在不对称分裂的细胞中遗传是密切相关的。我们将在提议的工作中测试的首要假设是，除了“允许”即提供能量的作用外，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”。更具有挑衅性的是，我们提出“不对称线粒体遗传”是细胞命运分化的主要驱动因素，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裂。动物线粒体遗传研究困难的一个原因是缺乏合适的模型。我们最近发现了在秀丽隐杆线虫发育过程中一个关键的细胞命运决定的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（高度可复制和快速发展，透明度）和强大的方法（遗传和基于成像的方法）吸引了研究人员，这些方法共同使实时观察线粒体遗传成为可能。例如，细胞QL.p分裂产生一个存活的前子细胞QL.pa，和一个死亡的后子细胞QL.pp。我们发现在QL.p分裂过程中，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，我们之前已经发现，“不需要的”细胞（即在秀丽隐杆线虫发育过程中可再生死亡的细胞，如QL.pp）具有碎片化的线粒体，防止线粒体碎片化可以挽救一些不需要的细胞免于“细胞死亡命运”。这表明，不对称线粒体遗传是细胞走向细胞死亡的能力的部分必要条件。在提出的工作中，我们将使用QL.p的分裂作为范式来揭示涉及不对称线粒体遗传的机制（目的1），并解决线粒体如何影响细胞命运决定的问题（目的2）。为此，我们将确定受不对称线粒体遗传影响的细胞命运方面，并揭示QL.pp和QL.pa遗传的线粒体之间的关键差异。

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.