Transport and Maturation of Interacting Organelles in Axons

Many organelles are transported long distances through the long narrow projections of neurons. The organelles pass by each other, and in some cases fuse permanently or transiently, exchanging internal material. We explore how the distribution of organelles and their contents depends on transport and interaction parameters, particularly in the context of long linear or branched cell geometries.

First, we will discuss the maintenance of axonal mitochondria stationed at distal regions of high metabolic demand. The turnover of mitochondrial content requires replenishment by delivery of new material from the soma, either through exchanging whole organelles between a stationary and motile population or through transient fusion and fission of motile mitochondria with permanently stationary ones. We show that both mechanisms are equivalent in the mean-field sense, with optimal mitochondrial health requiring intermediate fractions of the population in the motile state, and only a few exchange events per every round-trip of a motile mitochondrion. We also use agent-based simulations to show how transient fusion leads to more robust mitochondrial health, particularly in response to autophagic mechanisms for selectively recycling unhealthy mitochondria.

Additionally, we explore the maturation dynamics of neuronal autophagosomes, which are produced in the distal tip of the axon, and fuse with degradatively active endolysosomes en route to the soma. Parameterizing our model against experimental data, we demonstrate that individual autophagosomes must fuse with only a few endolysosomes, primarily in the distal region, enabling relatively uniform distributions of organelles throughout the axon. The mathematical models presented here provide a quantitative picture of how transport behaviors, fusion, and the geometry of neuronal projections couple together to determine the distribution and functional state of organelles in mammalian axons.