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Mitochondria-Targeted Inhibitors of the Human SIRT3 Lysine Deacetylase

revised on 26.11.2020, 13:38 and posted on 27.11.2020, 06:32 by Kathrin Sten Troelsen, Michael Bæk,, Alexander Lund Nielsen, Andreas Stahl Madasen, Nima Rajabi, Christian Adam Olsen

Sirtuin 3 (SIRT3) is the major protein lysine deacetylase in the mitochondria. This hydrolase regulates a wide range of metabolically involved enzymes and has been considered as a potential drug target in certain cancers. Investigation of pharmacological intervention has been challenging due to a lack of potent and selective inhibitors of SIRT3. Here, we developed a strategy for selective inhibition of SIRT3 in cells, over its structurally similar isozymes that localize primarily to nucleus (SIRT1) and cytoplasm (SIRT2). This was achieved by directing the inhibitors straight to the mitochondria through incorporation of sequences inspired by previously described mitochondria-targeting peptides. Our inhibitors exhibited excellent mitochondrial localization in HeLa cells as indicated by fluorophore-conjugated versions and target engagement was demonstrated by a thermal shift assay of SIRT3 using western blotting. The acetylation state of documented SIRT3 target MnSOD was shown to be perturbed in cells with little effect on known targets of SIRT1 and SIRT2, showing that our lead compound exhibits selectivity for SIRT3 in cells. We expect that the developed inhibitor will now enable a more detailed investigation of SIRT3 as a potential drug target and help shed further light on the diverse biology regulated by this enzyme.


Lundbeck Foundation R218-2016-1277

Lundbeck Foundation R289-2018-2074

Danish Independent Research Council–Natural Sciences 6108-00166B

Carlsberg Foundation 2013-01-0333, CF15-011, and CF18-0442

Novo Nordisk Foundation NNF17OC0029464

European Research Council ERC-CoG-725172–SIRFUNCT


Email Address of Submitting Author


University of Copenhagen



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest