Aims
From embryonic development and tissue regeneration to tumour proliferation, cellular migration is driven by complex interactions between cytoskeletal dynamics and energy metabolism. Among these cellular processes, mitochondrial dynamics – encompassing biogenesis, fission, fusion, mitophagy, and transport of mitochondria – has emerged as a potential regulator of intracellular energy distribution during migration. However, the extent to which mitochondrial dynamics contributes to cell migration, and how biochemical feedback between cytoskeletal mechanics and metabolism regulates this process, remains unclear. This study aims to develop mathematical models to quantify the role of mitochondrial dynamics in supplying energy to drive cytoskeletal dynamics and cell migration.
Methods
Using photo-gentle microscopy and a novel artificial intelligence-powered microscopy image segmentation workflow (MitoMimics), we captured over 3 hours of mitochondrial dynamics during cell migration at 0.5-second intervals. Custom image analysis algorithms were developed to track mitochondrial transport, fission, fusion, and network topology. These quantitative metrics and parameters inform the development of our mathematical models that simulate mitochondrial energy distribution and mechanical force generation during migration. Our computational approach then integrates experimental data and parameter estimates from our imaging pipeline and prior studies to investigate how perturbations in mitochondrial dynamics affect the mechano-metabolic regulation of cell movement.
Results
Preliminary analyses highlight that fission and fusion rates in healthy control cells are balanced, maintaining mitochondrial network integrity. A higher density and proportion of fission and fusion events in the perinuclear region of the cell supports its role as a hub for mitochondrial and cellular homeostasis. Early validation suggests our MitoMimics segmentation of long spatiotemporal mitochondrial dynamics imaging data accurately tracks mitochondrial transport dynamics over long time scales, surpassing existing tools. By interfacing accurate image segmentation with computational frameworks, we have begun to robustly address fundamental questions in the analysis of mitochondrial dynamics events during cell migration.
Conclusions
This study provides a quantitative and modelling framework for exploring how the contributions of energy metabolism regulate intracellular mechanics during cell migration. Our analysis pipeline and modelling framework can be applied to disease-perturbed cells in diverse biological contexts, such as development and cancer metastasis, offering new insights into the impacts of metabolic shifts on disease progression. These biophysical models could inform therapeutic strategies for diseases linked to abnormal cellular migration, such as cancer metastasis, and promote the integration of experimental data into cell biology modelling.