Glycolysis: a bioenergetic or a survival pathway?

Area of Science:

• Neurobiology
• Cellular Metabolism
• Biochemistry

Background:

• Neurons and astrocytes exhibit differential metabolic responses to mitochondrial respiration inhibition.
• Astrocytes maintain mitochondrial membrane potential and resist apoptosis using glycolytically-generated ATP.
• Neurons are susceptible to apoptosis due to impaired glycolysis.

Purpose of the Study:

• To investigate the mechanism behind neuronal inability to increase glycolysis.
• To identify the regulatory factors controlling glucose metabolism in neurons.
• To explore the role of specific enzymes and protein degradation pathways in neuronal survival.

Main Methods:

• Analysis of glucose metabolism pathways in neurons and astrocytes.
• Investigation of the activity and regulation of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, isoform 3 (PFKFB3).
• Study of the role of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)-CDH1 in PFKFB3 degradation.

Main Results:

• Neurons cannot enhance glycolysis because PFKFB3 activity is suppressed.
• PFKFB3 undergoes continuous degradation in neurons, mediated by APC/C-CDH1.
• Neuronal glucose metabolism is primarily directed towards the pentose phosphate pathway for glutathione regeneration.
• Astrocytes, in contrast, can upregulate glycolysis to support ATP production and mitochondrial function.

Conclusions:

• The anaphase-promoting complex/cyclosome (APC/C)-CDH1 pathway is crucial for regulating PFKFB3 stability and neuronal glycolysis.
• Impaired glycolysis in neurons contributes to their vulnerability following mitochondrial respiration inhibition.
• APC/C-CDH1 may serve as a link between glycolysis activation and cell proliferation, given its role in cell cycle regulation.