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Mammalian sirtuins and energy metabolism.

Li X, Kazgan N - Int. J. Biol. Sci. (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. lix3@niehs.nih.gov

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.

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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.
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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.

Mentions: Despite the important localization of SIRT3-5, mice with deletions of these mitochondrial sirtuins lack obvious phenotypes 101, explaining why the biochemical and biological functions of these proteins have just started to be elucidated (Figure 4). SIRT3, the most studied mitochondrial sirtuin, is highly expressed in metabolically active tissues such as brown adipose, muscle, liver, kidney, heart, and brain 102, 103. Consistent with this expression pattern and its mitochondrial localization, deletion of SIRT3 in mice leads to striking mitochondrial protein hyperacetylation 101. These hyperacetylated proteins include subunits of oxidative phosphorylation complexes 104, metabolic enzymes such as acetyl-CoA synthetase 2 105, 106, long-chain acyl CoA dehydrogenase (LCAD) 107 and 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) synthase 2 108, as well as oxidative stress reducing enzymes isocitrate dehydrogenase 2 (IDH2) 36, superoxide dismutase 2 (SOD2) 35, and MnSOD 109. A number of recent studies have reported that hyperacetylation of these mitochondrial proteins in SIRT3 deficient mice results in a variety of metabolic abnormalities including reduced ATP production, decreased rates of fatty acid oxidation and ketone body production, and fatty liver 104, 107, 108, 110. In addition, SIRT3 also regulates mitochondrial translation 111, a process that may indirectly impact all mitochondrial pathways.


Mammalian sirtuins and energy metabolism.

Li X, Kazgan N - Int. J. Biol. Sci. (2011)

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.
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Related In: Results  -  Collection

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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.
Mentions: Despite the important localization of SIRT3-5, mice with deletions of these mitochondrial sirtuins lack obvious phenotypes 101, explaining why the biochemical and biological functions of these proteins have just started to be elucidated (Figure 4). SIRT3, the most studied mitochondrial sirtuin, is highly expressed in metabolically active tissues such as brown adipose, muscle, liver, kidney, heart, and brain 102, 103. Consistent with this expression pattern and its mitochondrial localization, deletion of SIRT3 in mice leads to striking mitochondrial protein hyperacetylation 101. These hyperacetylated proteins include subunits of oxidative phosphorylation complexes 104, metabolic enzymes such as acetyl-CoA synthetase 2 105, 106, long-chain acyl CoA dehydrogenase (LCAD) 107 and 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) synthase 2 108, as well as oxidative stress reducing enzymes isocitrate dehydrogenase 2 (IDH2) 36, superoxide dismutase 2 (SOD2) 35, and MnSOD 109. A number of recent studies have reported that hyperacetylation of these mitochondrial proteins in SIRT3 deficient mice results in a variety of metabolic abnormalities including reduced ATP production, decreased rates of fatty acid oxidation and ketone body production, and fatty liver 104, 107, 108, 110. In addition, SIRT3 also regulates mitochondrial translation 111, a process that may indirectly impact all mitochondrial pathways.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. lix3@niehs.nih.gov

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.

Show MeSH