Stochastic Dynamics of Subcellular Structures

Banerjee, Binayak (2025) Stochastic Dynamics of Subcellular Structures. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Binayak Banerjee (20RS127)) 20RS127.pdf - Submitted Version Restricted to Repository staff only Download (26MB)

Abstract

The regulation of size and number of subcellular structures is fundamental to various cellular processes. For example, polymeric structures within eukaryotic cells, known as cytoskeletal filaments, demonstrate highly dynamic behavior critical for intracellular organization. Similarly, morphologically and functionally distinct subcellular structures called organelles (such as Golgi bodies, mitochondria, vacuoles, etc.) show large variations in their copy numbers. This thesis explores the stochastic dynamics underlying the size and number distributions of cytoskeletal filaments and organelles, emphasizing the interplay between microscopic biochemical processes and macroscopic heterogeneity. Recent experiments have shown that limited monomer resources in cytoplasm play a crucial role in regulating filament size by introducing negative feedback on the assembly rate. Using coarse-grained mathematical models, we show that nucleotide hydrolysis, an inherent nonequilibrium process, induces bimodal length distributions and bistable toggling of individual microtubule lengths in ensembles, emphasizing its role in promoting length diversity. Additionally, cytoskeletal filaments interact with various motors and proteins in vivo that can either promote growth or facilitate disassembly. For instance, Kinesin-Kip2 motors bind to microtubules and enhance their growth, while actin depolymerizing factor (ADF) cofilin binds to actin filaments in a nucleotide state-dependent manner, leading to their severing. We investigate length-dependent positive feedback on microtubule growth, showing that feedback parameters and hydrolysis rates jointly regulate the emergence of diverse length distributions. Interestingly, collective effects among multiple filaments lead to non-unimodal distributions, suggesting that interactions within a shared subunit pool play a pivotal role in length control. In parallel, severing by actin-binding proteins like cofilins generates skewed and bimodal filament length distributions under limited pool conditions. This study connects nucleotide state-dependent severing to filament length heterogeneity and elucidates how local molecular arrangements influence global filament properties. Finally, the thesis addresses the regulation of organelle number by constructing a model of organelle biogenesis incorporating bursty de novo synthesis. Analytical and numerical studies demonstrate that bursty synthesis amplifies noise in organelle number distributions and broadens the parameter regimes for bimodality. These results suggest that stochastic bursts significantly contribute to cell-to-cell variability in organelle abundance. In summary, this thesis provides a comprehensive framework for understanding how stochastic biochemical processes drive heterogeneity in the size and number of subcellular structures.

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