A multimethod computational simulation approach for investigating mitochondrial dynamics and dysfunction in...

Area of Science:

• Biogerontology
• Mitochondrial Biology
• Computational Biology

Background:

• The mitochondrial free radical theory of aging (MFRTA) is widely accepted but challenged by new findings on reactive oxygen species (ROS).
• Recent studies suggest ROS may not be entirely deleterious and can be beneficial under certain conditions.
• Understanding mitochondrial dysfunction in aging requires integrating multiple stress response pathways.

Purpose of the Study:

• To expand the MFRTA by incorporating additional mitochondrial stress response pathways using an in silico approach.
• To develop a hybrid modeling paradigm to simulate aging mitochondrial phenotypes in Caenorhabditis elegans.
• To investigate the molecular determinants of aging and identify potential cytoprotective agents.

Main Methods:

• Developed a multilevel hybrid-modeling paradigm combining agent-based elements with stochastic system-dynamics.
• Integrated key mitochondrial pathways: unfolded protein response (UPRmt), biogenesis, autophagy, DAF-16/SKN-1 axes, and NAD+-dependent deacetylases.
• Simulated aging mitochondrial phenotypes in a population of energetically demanding cells.

Main Results:

• The in silico model accurately predicted physiological aging parameters, including declines in NAD+ and ATP, and increased ROS.
• Virtual perturbations with pharmacological agents (e.g., rapamycin) and genetic modifications (e.g., skn-1, daf-16) were performed.
• Quantified temporal alterations in specific mechanistic targets, providing insights into aging determinants.

Conclusions:

• The expanded in silico model offers a powerful tool for studying aging mechanisms and mitochondrial dysfunction.
• Simulation results support the complex interplay of various pathways in aging.
• Identified potential therapeutic strategies and cytoprotective agents to improve neurological and muscular healthspan.