Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity

Rommel A. Mathias, Todd M. Greco, Adam Oberstein, Hanna G. Budayeva, Rumela Chakrabarti, Elizabeth A. Rowland, Yibin Kang, Thomas Shenk, Ileana M. Cristea

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177 Scopus citations

Abstract

Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism.

Original languageEnglish (US)
Pages (from-to)1615-1625
Number of pages11
JournalCell
Volume159
Issue number7
DOIs
StatePublished - Dec 18 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mathias, R. A., Greco, T. M., Oberstein, A., Budayeva, H. G., Chakrabarti, R., Rowland, E. A., Kang, Y., Shenk, T., & Cristea, I. M. (2014). Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell, 159(7), 1615-1625. https://doi.org/10.1016/j.cell.2014.11.046