Metabolic Flux Analysis Uncovers Substrate-Specific Reprogramming and ATP Deficit in CORT-Induced Depressive-like...

Area of Science:

• Neuroscience
• Metabolomics
• Cellular Biology

Background:

• Depression is linked to brain energy metabolism issues.
• The precise metabolic alterations and their mechanisms in depression are not well understood.

Purpose of the Study:

• To investigate metabolic changes in astrocytes under depression-like conditions.
• To elucidate the mechanisms of energy dysregulation in astrocytes using stable isotope-resolved metabolomics.

Main Methods:

• Developed an in vitro depression model using corticosterone (CORT)-treated astrocytes.
• Utilized stable isotope-resolved metabolomics (SIRM) to track glucose, lactate, and glutamine metabolism.
• Applied metabolic flux analysis (MFA) to quantify intracellular metabolic pathways.

Main Results:

• CORT exposure altered astrocyte metabolism, impairing glucose and lactate breakdown but increasing glutamine utilization.
• Astrocytes showed increased glucose uptake and glycolysis, with excess carbon diverted to lactate production instead of the TCA cycle.
• Enhanced glutaminolysis partially compensated for decreased oxidative metabolism, leading to reduced ATP production.

Conclusions:

• Astrocytic energy dysfunction in depression involves impaired glucose metabolism and compensatory glutaminolysis.
• This metabolic reprogramming diminishes ATP production, contributing to cerebral energy homeostasis disruption.
• Findings suggest potential metabolic targets for depression therapies.