mTORC2 Deficiency Alters the Metabolic Profile of Conventional Dendritic Cells

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Mechanistic target of rapamycin complex 2 (TORC2) deletion in myeloid dendritic cells (DCs) leads to increased pro-inflammatory responses and T cell stimulation.
• The precise molecular mechanisms underlying this phenotype remain largely unresolved.

Purpose of the Study:

• To investigate the metabolic reprogramming and underlying mechanisms in TORC2-deficient myeloid DCs.
• To elucidate the role of TORC2 in regulating cellular metabolism and mitochondrial function in DCs.

Main Methods:

• Analysis of metabolic profiles in wild-type (WT) and TORC2-deficient (TORC2-/-) mouse bone marrow-derived DCs.
• Assessment of glycolytic function, ATP production, lipid content, and cell viability.
• Measurement of mitochondrial respiration, mass, and DNA copy number.
• Evaluation of signaling pathways, including mechanistic target of rapamycin complex 1 (TORC1) and its downstream targets.

Main Results:

• TORC2-/- DCs exhibit enhanced baseline glycolysis, increased reliance on glycolytic ATP, elevated lipid content, and higher viability post-LPS stimulation.
• TORC2-/- DCs show increased spare respiratory capacity, mitochondrial mass, and mitochondrial DNA copy number, with impaired mitochondrial depolarization.
• Metabolic alterations correlate with compensatory activation of the TORC1 pathway, evidenced by increased expression of upstream genes and activation of downstream targets like p70S6K and 4EBP1.
• Upregulation of Pparγ and Srebf1, key regulators of lipid metabolism, was observed in TORC2-/- DCs.

Conclusions:

• TORC2 deficiency in myeloid DCs promotes a pro-inflammatory metabolic phenotype characterized by enhanced glycolysis and mitochondrial activity.
• Compensatory activation of the TORC1 pathway appears to drive these metabolic changes.
• TORC2 may act as a negative regulator of TORC1-driven metabolic activity and mitochondrial function in myeloid DCs.