Mitochondrial mechanics nucleates axonal jamming and swelling

Abstract

1Neuronal 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. 2 SignificanceAxonal deformation is implicated in myriad neurodegenerative conditions. Mitochondrial transport disruption is inextricably linked to axonal deformation and disease progression. Mechanistic understanding of the interplay between mitochondrial transport and axon stability remains opaque. Here, we developed an agent-based model of mitochondrial transport through axons. We found that mitochondria, driven to-ward presynapses for energy supply and toward the soma for repositioning or recycling, can collide, jam, and accumulate within axonal segments. The severity of jamming is sensitive to mitochondrial density as well as mechanical and morphological properties. Further, we found a balance between lifecycle dynamics including fission and fusion is paramount to maintaining homeostatic transport. Lastly, we predict that accumulated mitochondria can deform the axonal membrane, thereby elucidating a direct mechanical link between mitochondrial transport disruption and axonal deformation.