AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine

Area of Science:

• Metabolic adaptation
• Cellular signaling
• Nutrient utilization

Background:

• Decreased blood glucose levels trigger fundamental metabolic shifts.
• AMP-activated protein kinase (AMPK) is vital for adapting to low glucose but its mechanisms are unclear.
• Understanding nutrient utilization shifts is crucial for metabolic health.

Purpose of the Study:

• To elucidate the molecular mechanism by which AMP-activated protein kinase (AMPK) regulates metabolic adaptation under low glucose conditions.
• To identify novel substrates and pathways involved in the shift from glucose to other nutrient utilization.
• To investigate the role of the identified pathway in inflammatory responses.

Main Methods:

• Identification of PDZ domain containing 8 (PDZD8) as a novel AMP-activated protein kinase (AMPK) substrate.
• Phosphorylation site mapping (Threonine 527) and analysis of protein-protein interactions.
• Assessment of glutaminase 1 (GLS1) activity and glutaminolysis rates in vitro and in vivo (skeletal muscle).
• In vivo studies in macrophages examining cytokine secretion following lipopolysaccharide (LPS) treatment and PDZD8 mutation.

Main Results:

• AMP-activated protein kinase (AMPK) phosphorylates PDZ domain containing 8 (PDZD8) at T527, enhancing its interaction with and activation of glutaminase 1 (GLS1).
• The AMPK-PDZD8-GLS1 axis is essential for increased glutaminolysis in skeletal muscle during fasting, preceding enhanced fatty acid utilization.
• This pathway is also active in macrophages under low glucose or LPS stimulation, where PDZD8-T527 phosphorylation is linked to pro-inflammatory cytokine dampening.

Conclusions:

• A novel AMP-activated protein kinase (AMPK)-PDZ domain containing 8 (PDZD8)-glutaminase 1 (GLS1) signaling axis promotes glutaminolysis during glucose scarcity.
• This pathway represents an early metabolic adaptation, occurring before increased fatty acid utilization.
• The AMPK-PDZD8-GLS1 pathway plays a role in regulating inflammatory responses in macrophages.