Mitochondrial mechanics nucleates axonal jamming and swelling

TL;DR

This study presents an agent-based model demonstrating how mitochondrial shape, mechanics, and dynamics influence transport efficiency and axonal integrity, revealing mechanisms behind mitochondrial jams and swelling in neurons.

Contribution

The paper introduces a novel physical model linking mitochondrial morphology and dynamics to transport failure and axonal damage, providing insights into neuronal health.

Findings

Elongated mitochondria are transported efficiently, while flexible ones tend to jam.

Fission increases collision-prone mitochondria, disrupting transport.

Jamming causes mechanical stress leading to axonal swelling.

Abstract

Neuronal function requires precise spatial organization of mitochondria to meet localized energetic demand. However, the physical constraints governing mitochondrial transport in axons remain poorly defined. Bidirectional motor-driven trafficking inherently introduces the potential for collisions, but the implications of these interactions for transport failure and structural damage are not understood. Here, we develop an agent-based model that couples mitochondrial motility, morphology, and lifecycle dynamics to a deformable axonal boundary. We show that mitochondrial traffic jams emerge from a force balance between active propulsion and steric interactions, and that their severity is governed by organelle shape and mechanical properties. Elongated, mechanically rigid mitochondria remain aligned and are transported rapidly, whereas flexible, low-aspect-ratio mitochondria are prone to jamming and accumulation. Incorporating fission and fusion dynamics reveals that fission amplifies transport disruption by generating collision-prone populations, while fusion restores transport by producing anisotropic structures that navigate crowded environments more efficiently. Importantly, we find that sustained jamming generates mechanical stress on the axonal membrane, leading to deformation and swelling. Together, these results establish a physical framework linking mitochondrial dynamics to axonal integrity and provide testable predictions for how dysregulated fission-fusion balance can drive transport failure and structural pathology in neurons.