Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Abstract

Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD+) homeostasis, an essential molecule for energy metabolism processes, including NAD+ biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD+ homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.

Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure

“…Recent investigations have revealed that mitochondrial dynamics and their structural adaptations can influence neuronal health, synaptic plasticity, and overall cognitive performance 3 – 6 . Proper mitochondrial function is essential for sustaining neural activities, while its dysfunction may lead to neurodegenerative diseases and cognitive impairments 7 – 9 . Mitochondria typically have an elongated shape, delimited by smooth outer and complex inner membranes 10 .…”

Effects of time-dependent ATP consumption caused by neuron firing on ATP concentrations in synaptic boutons containing and lacking a stationary mitochondrion

“…In the brain, synapses represent the main locations where ATP is consumed [10]. The reason why only about half of the presynaptic release sites contain a stationary mitochondrion remains a mystery, while the remaining sites lack one [11][12][13][14]. The question of how a bouton without a stationary mitochondrion obtains its supply of ATP is investigated in this paper.…”

Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure

“…Recent investigations have revealed that mitochondrial dynamics and their structural adaptations can in uence neuronal health, synaptic plasticity, and overall cognitive performance [3][4][5][6] . Proper mitochondrial function is essential for sustaining neural activities, while its dysfunction may lead to neurodegenerative diseases and cognitive impairments [7][8][9] . Mitochondria typically have an elongated shape, delimited by smooth outer and complex inner membranes 10 .…”