Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

Abstract

Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration

“…106 While the specific mechanism behind why DGLA and its metabolites, DHED, are more detrimental to dopaminergic neurons remains unknown, Fonseca et al reported a similar vulnerability of different neuron types in response to biomechanical injury and suggested that such observation could be due to different physiological regulatory mechanisms between different neuron types. 107 Such neuron-type-specific effects triggered by DGLA and DHED warrant future investigation to uncover potential new neurodegeneration mechanisms. However, investigating ferroptosis to understand differential ferroptosis mechanisms between tissues requires studies being carried out at the system level, which is challenging owing to the lack of appropriate genetic and imaging tools.…”

“…Our results complement previous studies by Zille et al, which showed that different cell types could have distinct regulatory pathways for ferroptosis . While the specific mechanism behind why DGLA and its metabolites, DHED, are more detrimental to dopaminergic neurons remains unknown, Fonseca et al reported a similar vulnerability of different neuron types in response to biomechanical injury and suggested that such observation could be due to different physiological regulatory mechanisms between different neuron types . Such neuron-type-specific effects triggered by DGLA and DHED warrant future investigation to uncover potential new neurodegeneration mechanisms.…”

Dihydroxy-Metabolites of Dihomo-gamma-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration

“…reported a similar vulnerability of different neuron-types in response to biomechanical injury and suggested that such observation could be due to different physiological regulatory mechanisms between different neuron types. 87 Such neuron type-specific effects triggered by DGLA and DHED warrant future investigation to uncover potential new neurodegeneration mechanisms. Investigating ferroptosis at the systems level to understand differential ferroptosis mechanisms between tissues is challenging, owing to the lack of appropriate genetic and imaging tools.…”

“…et al, which showed that different cell types could have distinct regulatory pathways for ferroptosis 86. While the specific mechanism behind why DGLA and its metabolites, DHED, are more detrimental to dopaminergic neurons remains unknown, Solano Fonseca et alreported a similar vulnerability of different neuron-types in response to biomechanical injury and suggested that such observation could be due to different physiological regulatory mechanisms between different neuron types 87. Such neuron type-specific effects triggered by DGLA and DHED warrant future investigation to uncover potential new neurodegeneration mechanisms.…”

AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease

“…As a member of the major redox shuttle in neurons, the absence of ARALAR leads to an inability to metabolize lactate [ 25 , 26 ] and thus severely compromises the function of the astrocyte-to-neuron lactate shuttle, which has an important protective role under neurodegenerative and physiological conditions [ 65 , 66 , 67 ]. This aspect will be further discussed in Section 4.1 .…”