Figure 10.

Model of macrophage lipotoxicity under glutamine sufficient and deficient conditions. When glutamine is available, TLR4 activation stimulates glutamine uptake, mTORC1 activation, enhanced formation of TCA intermediates, such as α-KG, and increased mitochondrial respiration. The presence of excess fatty acids like palmitate leads to suppression of mitochondrial respiration, which in the setting of LPS activation likely promotes accumulation of toxic metabolites, lipids and/or redox stress. Lysosome dysfunction ensues leading to macrophage cell death and inflammasome activation. In the absence of glutamine, mTORC1 activation and mitochondrial respiration are diminished leading to enhanced rates of autophagy. In this scenario palmitate no longer suppresses mitochondrial function, which appears to protect against lysosome dysfunction, perhaps by decreasing the formation of damaging metabolites and lipids.