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Understanding the Mechanisms Regulat...

Singh, Milind,

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Understanding the Mechanisms Regulating Neuronal Metabolic States In Vivo /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Understanding the Mechanisms Regulating Neuronal Metabolic States In Vivo // Milind Singh.
Author:	Singh, Milind,
Description:	1 electronic resource (139 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Cellular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31845328
ISBN:	9798286442447

Understanding the Mechanisms Regulating Neuronal Metabolic States In Vivo /
Singh, Milind,

Understanding the Mechanisms Regulating Neuronal Metabolic States In Vivo /Milind Singh. - 1 electronic resource (139 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Glycolysis, a glucose-consuming pathway required for cellular energy production, is well conserved across species and has been extensively characterized biochemically. Less is understood regarding how it is subcellularly organized, or coordinated across tissues in vivo. Previous work from our lab found that during transient hypoxia or neuronal stimulation, the rate-limiting glycolytic enzyme phosphofructokinase-1 (PFK-1.1) dynamically re-localizes from the cytoplasm to condensates near synapses in C. elegans neurons. My research examined mechanisms by which PFK-1.1 localization is regulated in neurons, and resulted in two main findings: 1) PFK-1.1 condensate formation in neurons is regulated by a non-cell-autonomous signal derived from hypodermal (epidermal) cells and 2) Glycogen (which is also required for PFK-1.1 localization) is used by neurons to sustain metabolic plasticity.To determine regulation of PFK-1.1 condensate formation in neuron I examined the genetic lesions that affect PFK-1.1 localization. Using cell-specific rescues and HY-Light, a glycolytic sensor that detects the product of Phosphofructokinase, Fructose 1,6- bisphosphate (FBP) in vivo, I determined that non-cell autonomous disruption of glycolysis in hypodermal cells affects both PFK-1.1 condensate formation and FBP levels in neurons. Hypodermal cells in C. elegans are rich in metabolic genes and known to regulate metabolic processes. My data suggest that the state of glycolysis in the hypodermis signals, non- cell autonomously, to the neurons to regulate PFK-1.1 clustering, and metabolic state during transient hypoxia, and reveal mechanisms that are involved in cross-tissue metabolic state communication and cell biological organization of glycolytic proteins.Moreover, I identified a role for glycogen biosynthesis pathway in regulating PFK-1.1 localization. I investigated PYGL-1, an ortholog of glycogen phosphorylase. In PYGL-1 mutants, which inhibit glycogen breakdown, PFK-1.1 is incapable of forming condensates. Glycogen is the main form of energy storage in the brain, and is has been implicated in memory formation and as being neuroprotective under conditions of hypoxia. In the nervous system, glycogen is primarily considered to be utilized by glia, and how glycogen is used in vivo in neurons is not well understood. I investigated whether neurons can utilize glycogen to regulate their metabolic state. Using the HYLight biosensor I first determined that neurons can dynamically regulate glycolytic responses in response to activity or transient hypoxia, which I term glycolytic plasticity. I observed that the disruption of glycogen metabolism affected neuronal FBP levels at baseline, indicating decreased glycolytic flux. Furthermore, I show that glycogen is necessary for sustaining glycolytic plasticity during transient hypoxia. In mutant animals, neuron-specific expression of PYGL-1 was sufficient to restore metabolic responses to hypoxic stress. I determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity (GIDP). I uncovered that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mitochondrial mutants. The ability of neurons to plastically regulate glycolysis through cell-autonomous GDGP is important for 'sustaining synaptic function. My work reveals that in vivo, neurons can directly make use of glycogen as a fuel source to sustain context-specific regulation of glycolytic plasticity and synaptic function.

English

ISBN: 9798286442447Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Cross-tissue metabolic

Understanding the Mechanisms Regulating Neuronal Metabolic States In Vivo /
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