Modeling of ATP Transport in an Axon: Effects of Spontaneous Neuron Firing and Mitochondrial Transfer via Tunneling Nanotubes
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
While electrical activity in neurons has been extensively studied, the transport and distribution of adenosine triphosphate (ATP), the primary cellular energy carrier, remain less understood, particularly in relation to metabolic processes in axons. ATP is primarily generated in mitochondria and consumed at synapses, the primary sites of energy demand. Even in healthy axons, approximately half of synaptic boutons lack stationary mitochondria, raising questions about ATP transport between boutons with and without mitochondrial ATP production. This study addresses two key questions: the role of spontaneous neuronal firing in maintaining ATP levels during periods of low energy demand and the ability of a single bouton with a donated mitochondrion to supply ATP to neighboring boutons lacking mitochondria. Using computational simulations, the study examines ATP transport under various firing patterns and mitochondrial distributions, incorporating factors such as quiescent periods, duty cycles, and ATP diffusivity. Spontaneous neuronal firing stabilizes ATP levels during periods of low energy demand, preventing reactive oxygen species (ROS) release from mitochondria. Simulations reveal that in neurons damaged by neurodegeneration, a single bouton containing a donated mitochondrion can support ATP levels in multiple empty boutons. However, as the number of empty boutons increases, ATP concentration declines, potentially falling below the critical threshold required for synaptic transmission.
Nomenclature
a 0 kinetic constant characterizing the rate of ATP consumption in a bouton
A c cross-sectional area of the axon
C ATP concentration per unit length of the axon
C 0 typical value of ATP concentration per unit length of the axon
C min minimum ATP concentration required to sustain synaptic transmission
duty duty cycle
D ATP diffusivity in the cytosol
f frequency at which neuron fires during the active phase
i active number of action potentials that occur during the active phase
i total total number of action potentials that propagate down the axon during the active phase plus the number of action potentials that were missed during the quiescent phase
L distance between boutons
m ATP production rate per unit length of a mitochondrion
ATP production rate per unit mass of tissue
N empty number of boutons in the CV that lack stationary mitochondria
t time
x position along the axon
x m half-length of a mitochondrion
Greek symbols
γ percentage of tissue volume occupied by mitochondria
δ half the width of an axonal varicosity
ϖ mass of an individual mitochondrion
Λ homeostatic portion of energy expended on homeostatic maintenance of a bouton
