BPS2026 – Mechanochemical coupling of axonal morphology and mitochondrial function

Mitochondria supply most of the energy required for neuronal function, particularly synaptic transmission. Neurons therefore need precise spatiotemporal control of mitochondrial positioning. This control is achieved by bidirectional transport along polarized microtubule bundles, powered by molecular motors. Anterograde transport, mediated by kinesin, delivers healthy mitochondria from the soma toward distal axons and presynaptic terminals. This positioning is critical to provide ATP for synaptic vesicle recycling, to sustain ion channel activity, and to fuel local molecular motors. Retrograde transport, mediated by dynein, returns mitochondria from the axon back to the soma. This pathway is essential for recycling metabolic resources and for clearing damaged or fragmented mitochondria via lysosomal degradation. Although bidirectional transport ensures dynamic regulation of mitochondrial distribution, it is highly constrained by the narrow geometry of axons. The small axonal volume, enclosed by the plasma membrane, amplifies the impact of physical interactions between organelles and other cargo. To study this, we developed a coarse-grained agent-based model of motile mitochondria within a deformable axonal segment. This framework allows us to probe the mechanical feedback between organelle dynamics and axonal morphology under defined membrane boundaries. We first examined how changes in interaction energies influenced organelle organization. These conditions gave rise to persistent traffic jams within cylindrical geometries. Such traffic jams in turn produced axonal swellings. We then quantified swelling amplitudes in deformable axons and observed a nonmonotonic dependence of swelling amplitude on mitochondrial size. Finally, we explored how fission and fusion dynamics shape both jamming and swelling behaviors. Future work will incorporate mitochondrial energetics, particularly ATP generation, into these models. By linking mitochondrial dynamics to axonal mechanics, this study provides new insight into how organelle behavior contributes to axonal pathology. These findings are pertinent to understanding neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease.