Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury

Han, Qi; Xie, Yong; Ordaz, Josue D.; Huh, Andrew; Huang, Ning; Wu, Wei; Liu, Nai-Kui; Chamberlain, Kelly A.; Sheng, Zu‐Hang; Xu, Xiao–Ming

doi:10.1016/j.cmet.2020.02.002

Cited by 110 publications

(97 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consequently, motor proteins would arrest, given the cellular milieu being deprived of adequate ATP. The successful manipulation of a key pathway involved in mitochondrial energy metabolism adds to the emerging spinal cord injury literature that has shown that restoring cellular energetics and axonal transport promotes axonal outgrowth and regeneration [ 42 ]. Our data suggest that targeting this tractable pathway may thus also be highly relevant to neurodegeneration [ 56 , 75 ], accepting the possibility of there being other competing mechanisms driving the dysfunctional axonal homeostasis observed in C9orf72 MNs.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

et al. 2021

View full text Add to dashboard Cite

Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.

show abstract

Section: Discussionmentioning

confidence: 99%

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Following injury, the bioenergetic balance is highly disrupted, with mitochondrial depolarization and ATP depletion (Zhou et al, 2016). Increasing mitochondrial transport enhances peripheral and central axon regeneration (Cartoni et al, 2016;Zhou et al, 2016;Han et al, 2020). Electrical stimulation of peripheral nerves increases mitochondrial transport in a frequency dependent fashion (Sajic et al, 2013).…”

Section: Neuronal Activity and Molecular Control Over Axon Growthmentioning

confidence: 99%

Functional Electrical Stimulation and the Modulation of the Axon Regeneration Program

Jara

Agger

Hollis

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation.

show abstract

“…Interestingly, syntaphilin knockout did not result in developmental changes in axon growth. Syntaphilin knockouts have been used since to show increased corticospinal tract axon regeneration through a spinal cord lesion, improved regrowth of monoaminergic axons, increased sprouting and functional recovery in three different models of CNS injury [ 134 ]. Administering creatine—an energy facilitator—further exaggerated this effect, suggesting that improving mitochondrial transport and restoring cellular energetics is sufficient to promote regrowth and functional recovery in the injured CNS.…”

Section: Mitochondriamentioning

confidence: 99%

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

Petrova

Nieuwenhuis

Fawcett

et al. 2021

IJMS

View full text Add to dashboard Cite

Investigating the molecular mechanisms governing developmental axon growth has been a useful approach for identifying new strategies for boosting axon regeneration after injury, with the goal of treating debilitating conditions such as spinal cord injury and vision loss. The picture emerging is that various axonal organelles are important centers for organizing the molecular mechanisms and machinery required for growth cone development and axon extension, and these have recently been targeted to stimulate robust regeneration in the injured adult central nervous system (CNS). This review summarizes recent literature highlighting a central role for organelles such as recycling endosomes, the endoplasmic reticulum, mitochondria, lysosomes, autophagosomes and the proteasome in developmental axon growth, and describes how these organelles can be targeted to promote axon regeneration after injury to the adult CNS. This review also examines the connections between these organelles in developing and regenerating axons, and finally discusses the molecular mechanisms within the axon that are required for successful axon growth.

show abstract

Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury

Cited by 110 publications

References 89 publications

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

Functional Electrical Stimulation and the Modulation of the Axon Regeneration Program

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

Contact Info

Product

Resources

About