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

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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.