Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: A computational study

Abstract

We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson's disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enter the shorter branch and what portion enter the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities.

Mitochondrial Transport in Symmetric and Asymmetric Axons with Multiple Branching Junctions: A Computational Study

“…Kuznetsov and Kuznetsov (2022a, 2022b, 2023) developed an alternative model of mitochondria transport in an axon that is based on simulating mitochondria transport and accumulation in various energy demand sites. The motivation was to apply powerful methods developed for compartmental systems (Metzler et al 2018; Metzler and Sierra 2018) to determine mean age and age density distributions of mitochondria in demand sites located at different distances from the soma.…”

“…The motivation was to apply powerful methods developed for compartmental systems (Metzler et al 2018; Metzler and Sierra 2018) to determine mean age and age density distributions of mitochondria in demand sites located at different distances from the soma. The model developed in our research was obtained by extending the model of mitochondria transport suggested in Kuznetsov and Kuznetsov (2022a, 2022b, 2023) to symmetric and asymmetric axons with multiple branching junctions (Fig. 1).…”

Effect of mitochondrial circulation on mitochondrial age density distribution

“…Each demand site is represented by three compartments containing populations of anterograde, stationary, and retrograde mitochondria. We developed this model in our previous publications and utilized it for determining the mean age of mitochondria along the axon length 28 and for computing the mean age and age density distributions of mitochondria in a branching axon 29 …”

“…We developed this model in our previous publications and utilized it for determining the mean age of mitochondria along the axon length 28 and for computing the mean age and age density distributions of mitochondria in a branching axon. 29 The main question that we ask in this paper is how the mean age and age density distributions of mitochondria in the compartments located at different distances from the soma are affected by mitochondria returning to the circulation. According to our hypothesis, some of the mitochondria that exit the axon change the motors that propel them to kinesin and return to the circulation.…”

Effect of mitochondrial circulation on mitochondrial age density distribution

“…Each demand site is represented by three compartments containing populations of anterograde, stationary, and retrograde mitochondria. We developed this model in our previous publications and utilized it for determining the mean age of mitochondria along the axon length [24] and for computing the mean age and age density distributions of mitochondria in a branching axon [25].…”