Abstract
Mammalian sirtuins have diverse roles in aging, metabolism and disease. Recently we reported a new function for SIRT5 in urea cycle regulation. Our study uncovered that SIRT5 localized to mitochondria matrix and deacetylates carbamoyl phosphate synthetase 1 (CPS1), an enzyme which is the first and rate-limiting step of urea cycle. Deacetylation of CPS1 by SIRT5 resulted in activation of CPS1 enzymatic activity. Indeed, SIRT5-deficient mice failed to up-regulate CPS1 activity and showed hyper ammonemia during fasting. Similar effects are also observed on high protein diet or calorie restriction. These data indicate SIRT5 also has an emerging role in the metabolic adaptation to fasting, high protein diet and calorie restriction.
Highlights
Mammalian sirtuins have diverse roles in aging, metabolism and disease
These findings show that SIRT3 and SIRT4 directly control the activity of metabolic enzymes in mitochondria and play an important role in energy metabolism
By systemic sub-fractionation of isolated mitochondria from mouse liver, we found SIRT5 was localized in the matrix fraction, as well as SIRT3 and SIRT4
Summary
Mammalian sirtuins have diverse roles in aging, metabolism and disease. Recently we reported a new function for SIRT5 in urea cycle regulation. There are seven Sir2 homologues called sirtuins (SIRT1-7), which regulate various biological functions in aging, metabolism and disease. SIRT3 interacts with acetyl-CoA synthetase 2 (ACS2) and deacetylates Lys-642 in vitro and in vivo. Deacetylation of ACS2 by SIRT3 upregulates the acetyl-CoA synthesis activity [3, 4].
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