Resveratrol-elicited Sirt1 phosphorylation by LKB1 guides mitochondrial metabolism

The NAD⁺-dependent deacetylase Sirt1 is implicated in the prevention of many age-related diseases such as cancer, type 2 diabetes, and cardiovascular disease. Resveratrol, a plant polyphenol, exhibits anti-aging, anti-tumor and vascular protection effects by activating Sirt1. However, the molecular mechanism of Sirt1 activation induced by resveratrol remains unclear. Here, we identify the tumor suppressor LKB1 as a direct activator of Sirt1 elicited by resveratrol. Resveratrol promotes the binding between LKB1 and Sirt1, which elicits LKB1 phosphorylation of Sirt1 at three different serine residues in the C-terminus. Mechanistically, LKB1-mediated phosphorylation increases the intramolecular interaction of Sirt1, that the binding of C-terminus to deacetylase core domain, thereby eliminating DBC1 inhibition and promoting Sirt1-substrate interaction. Functionally, LKB1-dependent Sirt1 activation increases mitochondrial biogenesis and respiration through deacetylation and activation of co-activator PGC-1a. These results uncover Sirt1 as a context-dependent target of LKB1 and suggest that resveratrol-stimulated LKB1-Sirt1 pathway plays a vital role in mitochondrial metabolism.