Segos, Ioannis; (2024) Non-random segregation of mitochondria during asymmetric neuroblast division. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Asymmetric cell division is an essential mechanism that generates cells with different identities and fates during animal development. Fate divergence can be driven intrinsically through the asymmetric segregation of macromolecular fate determinants. However, there has been growing evidence that mitochondria can also act as fate determinants, but previous studies were mostly conducted on unicellular and in vitro systems. Here, I used Caenorhabditis elegans to study mitochondrial segregation in vivo during post-embryonic development, focusing on the asymmetric cell division of the neuroblast QL.p. To do so, I developed a method to perform super resolution live imaging of mitochondria. My workflow includes the drug-free mechanical immobilization of animals using polystyrene nanobeads, which has never been used before in C. elegans larvae to achieve super resolution. Developing my image processing methodology, I demonstrate for the first time that the frequency distribution of fluorescence intensities is not affected by photobleaching, and that global thresholding alone allows the quantitative comparison of mitochondria along timeseries. Following my methodological workflow, I found that QL.p mitochondria are asymmetrically segregated in terms of quantity, membrane potential, and morphology. I also observed that mitochondrial fission-fusion dynamics is essential during QL.p division and that such asymmetric segregation is disrupted in absence of mitochondrial dynamics. Next, I pioneered high- and super-resolution tracking of the QL.p lineage monitoring the entire development of the first larval stage of C. elegans. By doing so, I found that mitochondrial density is positively correlated with cell survival in cells fated to undergo apoptosis. In addition to that, disrupting fission-fusion dynamics impacted on the cell life-vs-death decision. I propose that mitochondria dynamics and the asymmetric segregation of mitochondria are concerted to ensure that cells that are fated to die inherit relatively fewer mitochondria, which in turn favours the acquisition of their fate.

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