Stochasticity contributes to explaining minority and majority MOMP during apoptosis.

Area of Science:

• Cell Biology
• Biophysics
• Computational Biology

Background:

• Apoptosis dysfunction is implicated in cancer and neurodegenerative diseases.
• Mitochondrial outer membrane permeabilization (MOMP) is a critical, typically all-or-none, event in apoptosis.
• Heterogeneity in MOMP, such as minority or majority MOMP, can promote cancer progression and cell survival.

Purpose of the Study:

• To investigate whether stochasticity in protein distribution and interactions contributes to heterogeneity in mitochondrial MOMP responsiveness.
• To understand the conditions under which stochasticity influences MOMP susceptibility.

Main Methods:

• Development of a particle-based, cell-sized model incorporating cytosolic and mitochondrial compartments.
• Experimental parameterization of the model with key apoptosis regulators (MCL-1, BAK, tBID).
• High-performance computing for cell-scale simulations of protein dynamics and MOMP events.

Main Results:

• Stochastic effects predispose fragmented mitochondria to MOMP under low apoptotic stress.
• Smaller mitochondria are more likely to escape MOMP than larger ones under higher stress.
• Experimental data confirmed the model's predictions regarding mitochondrial size and MOMP outcomes.

Conclusions:

• Stochasticity in protein distribution significantly contributes to mitochondrial heterogeneity in MOMP.
• This heterogeneity enables small or fragmented mitochondria to undergo MOMP in minority MOMP scenarios.
• It also allows mitochondria to escape MOMP in majority MOMP scenarios, influencing cell fate.