In a recent paper published in Nature Metabolism mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species, Department of Molecular Metabolism postdoctoral fellow Aaron Hosios and other colleagues in the laboratory of Professor Brendan Manning uncover a new role for mTORC1 – a central regulator of cell growth and metabolism – in controlling the fate of intracellular lipid species.
mTORC1 is a master growth regulator that integrates nutritional and hormonal cues to promote anabolic, biosynthetic processes when nutrients and energy are sufficient, while its inactivation under conditions of nutrient deprivation promote a catabolic state to conserve or restore nutrients and energy.
In this study, Hosios used lipidomics to quantify cell intrinsic changes in lipid species following mTORC1 activation or inhibition. These results, supported by microscopy and radiolabel tracing assays, led to the discovery that cells favor membrane phospholipids when mTORC1 is activated under pro-growth conditions. In contrast, when mTORC1 is inactivated, cells are induced to catabolize phospholipids to produce a pool of fatty acids that are either stored as triglycerides in cytosolic lipid droplets as a future source of energy or burned to immediately produce energy through mitochondrial fatty acid oxidation.
The triggering point in this lipid shift upon mTORC1 inactivation appears to be an increase in membrane phospholipid delivery to the lysosome, where phospholipid catabolism ensues, resulting in cytosolic release and accumulation of fatty acids liberated via lysosomal hydrolysis. Surprisingly, this intracellular fatty acid salvaging mechanism was found to occur independent of autophagy, a recycling process known to be inhibited by mTORC1, whereby cells engulf cellular contents to degrade them in the lysosome to restore intracellular nutrients.
Overall, this study provides exciting new insights into how cells adapt to restrictive growth conditions through a coordinated shift in lipid metabolism. These findings will inform future work on the role of mTORC1-regulated changes in intracellular lipid fate in health and disease. For instance, it will be important to determine whether the induced repurposing of membrane fatty acids promotes the survival of cancer cells treated with a myriad of targeted therapeutics that directly or indirectlyNew Publications inhibit mTORC1 within tumors.Click to Access Publication