The bioenergetics of neuronal morphogenesis and regeneration: Frontiers beyond the mitochondrion

Abstract

The formation of axons and dendrites during development, and their regeneration following injury, are energy intensive processes. The underlying assembly and dynamics of the cytoskeleton, axonal transport mechanisms, and extensive signaling networks all rely on ATP and GTP consumption. Cellular ATP is generated through oxidative phosphorylation (OxP) in mitochondria, glycolysis and "regenerative" kinase systems. Recent investigations have focused on the role of the mitochondrion in axonal development and regeneration emphasizing the importance of this organelle and OxP in axon development and regeneration. In contrast, the understanding of alternative sources of ATP in neuronal morphogenesis and regeneration remains largely unexplored. This review focuses on the current state of the field of neuronal bioenergetics underlying morphogenesis and regeneration and considers the literature on the bioenergetics of non-neuronal cell motility to emphasize the potential contributions of non-mitochondrial energy sources.

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

“…As discussed above, lipids are necessary for proper sealing of the plasma membrane, formation of a new growth cone and regeneration after axonal injury. These energy demanding processes require optimal mitochondrial transport and adenosine triphosphate (ATP) production [ 58 , 119 , 120 , 121 , 122 , 123 ]. During glucose metabolism, most ATP is produced by oxidative phosphorylation in mitochondria.…”

Bioenergetic Requirements and Spatiotemporal Profile of Nerve Growth Factor Induced PI3K-Akt Signaling Along Sensory Axons

“…In embryonic neurons both OxP and glycolysis contribute to ATP levels with relative contributions varying between neurons (reviewed in Gallo, 2020). In the population of neurons used in the current study, measurement of the ATP/ADP ratio showed that OxP [inhibited using antimycin-A (AA)] and glycolysis (inhibited by exchanging to medium containing no glucose and supplemented with 2-deoxyglucose to inhibit glycolysis and with pyruvate to maintain mitochondrial respiratory function, Glycolysis Inhibition Medium; GIM) both contribute approximately equally to the ATP/ADP ratio and inhibition of both has additive effects (Ketschek et al, 2021).…”

“…The role of glycolysis in axonal biology has received less attention than oxidative phosphorylation but it has been shown to regulate aspects of synaptic physiology (Ashrafi and Ryan, 2017). In developing central and peripheral nervous system neurons the contribution of glycolysis to net ATP levels is greatest during early embryogenesis and then wanes as oxidative phosphorylation becomes a more prominent source (reviewed in Gallo, 2020). Glycolytic enzymes are found throughout the axons of developing sensory neurons and glycolysis contributes to sensory axon extension and growth cone dynamics (Ketschek et al, 2021).…”

Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients

“…Independent of lobulation, 'transversal zones' have been identified by leveraging the molecular topography defined by the expression of specific genes across the cerebellum. Interestingly, most significant voxels lie within a central zone characterized by Purkinje cells expressing zebrin II 71 , which is analogous to aldolase C 72 , an important player in glycolytic ATP biosynthesis 73 , posing an indirect link to mitochondrial dynamics 74 . Thus, m.3243A>G-related atrophy might be restricted to certain Purkinje subtypes (e.g., zebrin II+).…”

“…Interestingly, most significant voxels lie within a central zone characterized by Purkinje cells expressing zebrin II, 76 which is analogous to aldolase C72, 77 an important player in glycolytic ATP biosynthesis, 78 posing an indirect link to mitochondrial dynamics. 79 While spinocerebellar ataxia seems to involve neurodegeneration of motor-related cerebellar regions, 80 m.3243A>G-related atrophy might be restricted to certain Purkinje subtypes (e.g., zebrin II+). However, the molecular characterization remains a complex issue and out of the scope of this manuscript.…”