Mammalian sirtuins and energy metabolism

Abstract

Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases that can extend the lifespan of several lower model organisms including yeast, worms and flies. The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response. Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals. This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.

Keywords: aging; energy metabolism; nutrients; sirtuins.

Figure 1

Schematic representation of seven mammalian sirtuins.

Figure 2

The diverse functions of SIRT1 in central nutrient sensing and peripheral energy metabolism. The activity of SIRT1 is regulated by the cellular metabolic status, small molecule activators, interacting proteins, as well as post-translational modifications. After activation, SIRT1 modulates a variety of metabolic activities systemically and locally through either direct protein deacetylation or indirect chromatin remodeling.

Figure 3

SIRT6 is a critical regulator in genome stability, metabolism, and inflammatory response. By deacetylation of H3, SIRT6 regulates metabolic homeostasis and inflammatory response in peripheral tissues, while functioning as a central regulator of somatic growth.

Figure 4

Mitochondrial sirtuins in the center of mitochondrial energy metabolism and anti-oxidative stress response. Mitochondria are central metabolic organelles for the production of cellular ATP from various nutrients including glucose, fatty acids, and amino acids. However, ROS, such as superoxide, are also produced during the oxidative phosphorylation. Mitochondria also contain numerous enzymatic complexes involved in intermediary metabolism pathways that function for nutrient adaptation and antioxidant defense. Mitochondrial sirtuins are essential for normal mitochondrial functions through interaction and modification of a number of mitochondrial proteins. SIRT3 deacetylates and maintains the normal functions of various mitochondrial proteins (blue) involved in fatty acid oxidation, ketogenesis, oxidative phosphorylation, antioxidant defense, and amino acid metabolism. GDH (orange) can also be ADP-ribosylated and repressed by SIRT4. SIRT5 deacetylates and activates CPS1 (green). This figure is modified from reference 9.