Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

Kong, Xingxing; Wang, Rui; Xue, Yan; Liu, Xiaojun; Zhang, Huabing; Chen, Yong; Fang, Fude; Chang, Yongsheng

doi:10.1371/journal.pone.0011707

Cited by 633 publications

(617 citation statements)

References 56 publications

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“…SIRT3 via peroxisome proliferator-activated receptor-γ coactivator-α (PGC-1α) (36,37). Notably, we did not see an effect of SIRT2 on microtubule polymer stability.…”

Section: Nad + Prevents Microtubule Polymer Disassembly Elicited Bymentioning

confidence: 62%

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Harkcom¹,

Ghosh²,

Sung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Nicotinamide adenine dinucleotide (NAD + ) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal degeneration. A major goal is to identify the NAD + -regulated cellular pathways that may mediate these effects. Here we show that the dynamic assembly and disassembly of microtubules is markedly altered by NAD + . Furthermore, we show that the disassembly of microtubule polymers elicited by microtubule depolymerizing agents is blocked by increasing intracellular NAD + levels. We find that these effects of NAD + are mediated by the activation of the mitochondrial sirtuin sirtuin-3 (SIRT3). Overexpression of SIRT3 prevents microtubule disassembly and apoptosis elicited by antimicrotubule agents and knockdown of SIRT3 prevents the protective effects of NAD + on microtubule polymers. Taken together, these data demonstrate that NAD + and SIRT3 regulate microtubule polymerization and the efficacy of antimicrotubule agents.N icotinamide adenine dinucleotide (NAD + ) is an endogenous dinucleotide that is present in the cytosol, nucleus, and mitochondria. Athough it serves an important role as a redox cofactor in metabolism, NAD + is also a substrate for several families of enzymes, including the poly(ADP ribose) polymerases and the sirtuin deacetylase enzymes (reviewed in refs. 1 and 2). The level of intracellular NAD + is regulated by many factors, including diet and energy status (3), axonal injury (4), DNA damage (5), and certain disease states (6), suggesting that NAD + -dependent signaling is dynamically modulated in diverse contexts.NAD + -dependent signaling can be induced by treatment of cells with exogenous NAD + , which increases intracellular NAD + levels and results in diverse effects in cells and animals. These effects include enhanced oxygen consumption and ATP production (7), as well as protection from genotoxic stress and apoptosis (3). Mice treated with nicotinamide riboside, a NAD + precursor that is metabolized into NAD + , have enhanced oxidative metabolism, increased insulin sensitivity, and protection from high-fat diet-induced obesity (8). These results demonstrate that NAD + -dependent pathways can enhance metabolic function and improve a variety of disease phenotypes.An NAD + -regulated pathway also inhibits axonal degeneration elicited by axonal transection (4). Treatment of axons with 5-20 mM NAD + markedly delays the axon degenerative process (9). Additionally, animals that express the Wallerian degeneration slow (Wld S ) protein, a fusion of the NAD + biosynthetic enzyme Nicotinamide mononucleotide adenylyl transferase 1 and Ube4a, exhibit markedly delayed degeneration of the distal axonal fragment after axonal transection (10), and expression of Wld S mitigates disease phenotypes in several neurodegenerative disease models (11)(12)(13)(14). Thus, understanding the intracellular pathways regulated by NAD + may be important for understanding the pa...

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“…SIRT3 via peroxisome proliferator-activated receptor-γ coactivator-α (PGC-1α) (36,37). Notably, we did not see an effect of SIRT2 on microtubule polymer stability.…”

Section: Nad + Prevents Microtubule Polymer Disassembly Elicited Bymentioning

confidence: 62%

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Harkcom¹,

Ghosh²,

Sung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The authors attributed the loss of SIRT3 protein to the reduction in PGC‐1 α , a known regulator of SIRT3 (Kong et al. 2010). A similar reduction in SIRT3 levels has been observed in the heart (Alrob et al.…”

Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

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“…Electromobility shift assay Electromobility shift assay ( E M S A ) w a s p e r f o r m e d u s i n g t h e L i g h t S h i f t Chemiluminescent EMSA kit (Pierce, Appleton, WI, USA) as previously described [26]. Briefly, HEK293A cells were transfected with FOXO1, FOXO1+FOXQ1 and FOXQ1 expression plasmids.…”

Section: Preparation Of Expression Plasmids and Recombinant Adenovirusesmentioning

confidence: 99%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

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Aim/hypothesis Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis. Methods We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production. Results Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wildtype C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes. Conclusions/interpretation FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.

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Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

Cited by 633 publications

References 56 publications

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

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Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

Cited by 633 publications

References 56 publications

NAD + and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

NAD + and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

Contact Info

Product

Resources

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NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents