Mechanisms for the maintenance and regulation of axonal energy supply

Chamberlain, Kelly A.; Sheng, Zu‐Hang

doi:10.1002/jnr.24411

Cited by 86 publications

(74 citation statements)

References 177 publications

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“…The mitochondria play an important role in meeting the axonal energy demand as they generate ATP through oxidative phosphorylation (Chamberlain and Sheng, 2019). Following their synthesis in the cell body, the mitochondria enter the axon where they undergo robust trafficking and accumulate at the nodes of Ranvier to meet metabolic needs (Zhang et al, 2012).…”

Section: Axonal Energy Supplymentioning

confidence: 99%

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

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Section: Axonal Energy Supplymentioning

confidence: 99%

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

et al. 2020

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“…Mitochondria are termed the "powerhouses" of the cell, and generate the majority of the cell's supply of adenosine triphosphate (ATP) through the oxidative phosphorylation system (OXPHOS) in which electrons produced by the citric acid cycle are transferred down the mitochondrial respiratory complexes. Neurons have particularly high and continuous energy demands so that mitochondrial function is essential for maintaining neuronal integrity and responsiveness [1][2][3][4][5][6][7]. Mitochondrial energy production fuels various critical neuronal functions, especially the ATP-dependent neurotransmission [1,3,8].…”

Section: Introductionmentioning

confidence: 99%

Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cai

Jeong

2020

Cells

164

107

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Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer’s disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders.

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“…Neurons have high and continuous energy demands in order to maintain their proper function. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation (OXPHOS), which is required to fuel critical neuronal functions (Sheng & Cai, ; Cai & Tammineni, , ; Chamberlain & Sheng, ). Mitochondria also enact essential reactions of metabolism and Ca 2+ signaling, as well as regulate cellular life/death decisions.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

et al. 2020

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Synaptic mitochondria are particularly vulnerable to physiological insults, and defects in synaptic mitochondria are linked to early pathophysiology of Alzheimer's disease (AD). Mitophagy, a cargo‐specific autophagy for elimination of dysfunctional mitochondria, constitutes a key quality control mechanism. However, how mitophagy ensures synaptic mitochondrial integrity remains largely unknown. Here, we reveal Rheb and Snapin as key players regulating mitochondrial homeostasis at synapses. Rheb initiates mitophagy to target damaged mitochondria for autophagy, whereas dynein–Snapin‐mediated retrograde transport promotes clearance of mitophagosomes from synaptic terminals. We demonstrate that synaptic accumulation of mitophagosomes is a feature in AD‐related mutant hAPP mouse brains, which is attributed to increased mitophagy initiation coupled with impaired removal of mitophagosomes from AD synapses due to defective retrograde transport. Furthermore, while deficiency in dynein–Snapin‐mediated retrograde transport recapitulates synaptic mitophagy stress and induces synaptic degeneration, elevated Snapin expression attenuates mitochondrial defects and ameliorates synapse loss in AD mouse brains. Taken together, our study provides new insights into mitophagy regulation of synaptic mitochondrial integrity, establishing a foundation for mitigating AD‐associated mitochondria deficits and synaptic damage through mitophagy enhancement.

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Mechanisms for the maintenance and regulation of axonal energy supply

Cited by 86 publications

References 177 publications

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

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