SIRT3, a human SIR2 homologue, is an NAD- dependent deacetylase localized to mitochondria

Onyango, Patrick; Celic, Ivana; McCaffery, J. Michael; Boeke, Jef D.; Feinberg, Andrew P.

doi:10.1073/pnas.222538099

Cited by 507 publications

(410 citation statements)

References 31 publications

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“…To define the effects of SIRT3 on p53‐dependent neuronal activity, we cotransfected mito‐p53 with WT SIRT3 or ΔSIRT3 in DIV7 primary cortical neurons and determined neuronal DNA damage and mitochondrial function (Onyango et al ., 2002; Shi et al ., 2005). As expected, ectopic expression of mito‐p53 induced significant (around 80%) neuronal DNA damage (indicating DNA fragmentation by DAPI staining) compared to control vector (DsRed)‐transfected neurons (around 20%) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.

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Section: Resultsmentioning

confidence: 99%

“…SIRT3, the most abundant sirtuin in the brain, is localized to the mitochondrial inner membrane and matrix and nucleus of neurons (Onyango et al ., 2002). It regulates mitochondrial activity by ROS in many cell types and modulates CREB phosphorylation and fat metabolism (Shi et al ., 2005; Hirschey et al ., 2010; Kim et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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“…In man, individual sirtuins may provide separate functional components of this process (Shiels and Davies, 2003). This is intriguing, in the light of the observations that SIRT7 localises to the nucleolus and SIRT3 localises to the mitochondrion (Onyango et al, 2002;Michishita et al, 2005). These subcellular locations, along with the telomere nucleoprotein complex, provide the components of a functional trinity, we have termed the MTR, that senses, assesses and signals damage (Shiels and Davies, 2003;Shiels and Jardine, 2003).…”

Section: Discussionmentioning

confidence: 99%

Altered sirtuin expression is associated with node-positive breast cancer

et al. 2006

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Sirtuins are genes implicated in cellular and organismal ageing. Consequently, they are speculated to be involved in diseases of ageing including cancer. Various cancers with widely differing prognosis have been shown to have differing and characteristic expression of these genes; however, the relationship between sirtuin expression and cancer progression is unclear. In order to correlate cancer progression and sirtuin expression, we have assessed sirtuin expression as a function of primary cell ageing and compared sirtuin expression in normal, 'nonmalignant' breast biopsies to breast cancer biopsies using real-time polymerase chain reaction (PCR). Levels of SIRT7 expression were significantly increased in breast cancer (Po0.0001). Increased levels of SIRT3 and SIRT7 transcription were also associated with node-positive breast cancer (Po0.05 and Po0.0001, respectively). This study has demonstrated differential sirtuin expression between nonmalignant and malignant breast tissue, with consequent diagnostic and therapeutic implications.

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“…In contrast to the primarily nuclear SIRT1, SIRT2 is localized to the cytoplasm where it can deacetylate α-tubulin (23), and SIRT3, SIRT4, and SIRT5 are located in the mitochondrial matrix (24)(25)(26), but knowledge of their cellular targets is uncertain. The other human homologs, SIRT6 and SIRT7, are found in the nucleus (24), where SIRT6 is reported to possess ADPribosyltransferase activity (27).…”

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confidence: 99%

Sir2 Protein Deacetylases: Evidence for Chemical Intermediates and Functions of a Conserved Histidine

2005

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Sir2 NAD + -dependent protein deacetylases are implicated in a variety of cellular processes such as apoptosis, gene silencing, life-span regulation, and fatty acid metabolism. In spite of this, there have been relatively few investigations into the detailed chemical mechanism. Sir2 proteins (sirtuins) catalyze the chemical conversion of NAD + and acetylated-lysine to nicotinamide, deacetylatedlysine, and 2'-O-acetyl-ADP-ribose (OAADPr). In this study, Sir2-catalyzed reactions are shown to transfer an 18 O-label from the peptide acetyl group to the ribose 1'-position of OAADPr, providing direct evidence for the formation of a covalent α-1'-O-alkylamidate, whose existence is further supported by the observed methanolysis of the α-1'-O-alkylamidate intermediate to yield β-1'-Omethyl-ADP-ribose in a Sir2 histidine-to-alanine mutant. This conserved histidine (His-135 in HST2) activates the ribose 2'-hydroxyl for attack on the α-1'-O-alkylamidate. The histidine mutant is stalled at the intermediate, allowing water and other alcohols to compete kinetically with the attacking 2'-hydroxyl. Measurement of the pH dependence of k cat and k cat /K m values for both wild-type and histidine-to-alanine mutant enzymes confirms roles of this residue in NAD + -binding and in generalbase activation of the 2'-hydroxyl. Also, transfer of an 18 O-label from water to the carbonyl oxygen of the acetyl group in OAADPr is consistent with water addition to the proposed 1'-2'cyclic intermediate formed after 2'-hydroxyl attack on the α-1'-O-alkylamidate. The effect of pH and of solvent viscosity on the k cat values suggests that final product release is rate-limiting in the wild-type enzyme. Implications of this new evidence on the mechanisms of deacetylation and possible ADPribosylation catalyzed by Sir2 deacetylases are discussed. Keywords SIR2; sirtuin; Deacetylation; NAD; HistoneThe growing interest in the silent information regulator 2 (Sir2 or sirtuin) family of proteins lies in their involvement in a rapidly expanding list of cellular processes including gene silencing (1,2), cell cycle regulation (3), fatty acid metabolism (4), apoptosis (5-7), and lifespan extension (8)(9)(10). Conserved among all forms of life with five homologs in yeast (ySir2 and HST1−4) and seven in humans (SIRT1−7) (11,12), most sirtuins display NAD + -dependent protein deacetylase activity (13-16). SIRT1 has received the most attention and is reported to deacetylate a growing number of substrates including 18), FOXO proteins † This work was supported by National Institutes of Health grant GM065386 (to J.M.D.) and by National Institutes of Health Biotechnology Training Grant NIH 5 T32 GM08349 (to B.C.S.). This study was also supported by the National Science Foundation grant NSF CHE-9629688 for the NMR spectrometer used. [19][20][21], and HIV Tat protein (22) suggesting its involvement in a broad range of biological processes such as glucose homeostasis, cell survival under stress, and HIV transcription. In contrast to the primarily nuclear SIRT1, SI...

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SIRT3, a human SIR2 homologue, is an NAD- dependent deacetylase localized to mitochondria

Cited by 507 publications

References 31 publications

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Altered sirtuin expression is associated with node-positive breast cancer

Sir2 Protein Deacetylases: Evidence for Chemical Intermediates and Functions of a Conserved Histidine

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