Mitochondrial sirtuins: Regulators of protein acylation and metabolism

Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, CA 94158, USA.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 08/2012; 23(9):467-76. DOI: 10.1016/j.tem.2012.07.004
Source: PubMed


Sirtuins are NAD(+)-dependent protein deacetylases and have been implicated in the regulation of metabolism, stress responses, and aging. Three sirtuins are located in mitochondria: SIRT3, 4, and 5. SIRT3 deacetylates and regulates the enzymatic activity of many metabolic enzymes in mitochondria, whereas SIRT5 removes two novel post-translational modifications, lysine malonylation and succinylation. Here, we review the current knowledge of how mitochondrial sirtuins function in metabolism and metabolic diseases, and offer a conceptual model how they may regulate mitochondrial function through distinct deacylation activities (deacetylation, demalonylation, or desuccinylation).

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    • "Mitochondrial matrix proteins can also be modified via a widely spread non-enzymatic acylation , dependent on the pH of the mitochondrial matrix and the actual concentration of acyl-CoA inside the mitochondria [18]. The presence of three matrix-located sirtuins (SIRT 3-5) with NAD + -dependent deacetylase activity further suggests an essential role of mitochondrial protein acetylation in metabolism regulation [19] [20]. "
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    ABSTRACT: Seventy years from the formalization of the Krebs cycle as the central metabolic turntable sustaining the cell respiratory process, key functions of several of its intermediates, especially succinate, and fumarate, have been recently uncovered. The presumably immutable organization of the cycle has been challenged by a number of observations, and the variable subcellular location of a number of its constitutive protein components is now well recognized, although yet unexplained. Nonetheless, the most striking observations have been made in the recent period while investigating human diseases, especially a set of specific cancers, revealing the crucial role of Krebs cycle intermediates as factors affecting genes methylation and thus cell remodeling. We review here the recent advances and persisting incognita about the role of Krebs cycle acids in diverse aspects of cellular life and human pathology.
    Biochimica et Biophysica Acta 03/2014; 1837(8). DOI:10.1016/j.bbabio.2014.03.013 · 4.66 Impact Factor
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    • "The sirtuins (SIRT) are a class of Nicotinamide Adenine Dinucleotide (NAD)-dependent deacetylase which regulate cellular metabolism. Among them, SIRT3-5 are localized in mitochondria to deacetylate several crucial enzymes involved in mitochondrial functions [38]. SIRT3 deacetylates various key enzymes, such as long-chain acyl-CoA dehydrogenase , leading to an increase of mitochondrial fatty acid oxidation in liver and its deficiency causes metabolic syndrome [39] [40]. "
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    ABSTRACT: Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.
    The Scientific World Journal 03/2014; 2014:604685. DOI:10.1155/2014/604685 · 1.73 Impact Factor
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    • "This observation indicated that while Sirt3 might play a role in mediating uridine-induced protein deacetylation, participation of deacetylases other than Sirt3 were likely. Indeed, mammals possess 7 sirtuins (Sirt1–7), where 3 sirtuins are associated with the mitochondrial fractions (Sirt3, -4, and -5) [41], [42]. "
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    ABSTRACT: Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+)/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD) and acyl-CoA oxidase 1 (ACOX1), and induces excessive accumulation of long chain fatty acids (LCFA) and very long chain fatty acids (VLCFA). Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+)/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.
    PLoS ONE 01/2014; 9(1):e87179. DOI:10.1371/journal.pone.0087179 · 3.23 Impact Factor
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