Modeling of ATP transport in an axon: Effects of spontaneous neuron firing and mitochondrial transfer via tunneling nanotubes

While electrical activity in neurons has been extensively studied, the transport and distribution of adenosine triphosphate (ATP), the primary cellular energy carrier, remain less studied, 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: (i) What is the role of spontaneous neuronal firing in maintaining ATP levels during periods of low energy demand? and (ii) How many neighboring boutons lacking mitochondria can a bouton with a donated mitochondrion support with ATP? 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.