Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data.

Area of Science:

• Cell biology
• Computational biology
• Biophysics

Background:

• Understanding intracellular organelle dynamics is crucial for cell function.
• Existing models often lack the spatial and temporal resolution to capture complex dynamics.
• Digital twin technology offers a novel approach to model biological systems.

Purpose of the Study:

• To introduce a whole-cell digital twin framework for modeling mesoscale intracellular organelle dynamics.
• To integrate four-dimensional (4D) microscopy with particle-based simulations.
• To investigate the effects of perturbations on mitochondrial dynamics.

Main Methods:

• Integration of 4D lattice light-sheet microscopy with ReaDDy particle-based reaction-diffusion simulations.
• Construction of spatially resolved digital twins of Cal27 cells, including organelles and cytoskeletal networks.
• Modeling of mitochondrial dynamics: fusion/fission, diffusion, and motor-driven transport.

Main Results:

• Simulations accurately reproduced experimental trends in mitochondrial dynamics under various conditions.
• The framework predicted emergent perinuclear mitochondrial clustering under simulated stress.
• Microtubule topology was identified as a critical structural gate for mitochondrial reorganization.

Conclusions:

• The digital twin framework provides a predictive and interpretable approach for studying intracellular dynamics.
• Microtubule network structure, not just motor activity, is essential for mitochondrial clustering.
• This approach enables investigation of perturbation effects on cellular organization.