Anabolic SIRT4 exerts retrograde control over TORC1 signalling by glutamine sparing in the mitochondria

Anabolic and catabolic signalling mediated via mTOR and AMPK have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although, glutamine is known to activate mTOR, if/how differential mitochondrial utilization of glutamine impinges on mTOR signalling is less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signalling/pathways through AMPK-PGC1a/SIRT1-PPARa axis and negatively regulate glutamine metabolism via TCA cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signalling and regulates lipogenesis, autophagy and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to -ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.