CNS SIRT3 Expression Is Altered by Reactive Oxygen Species and in Alzheimer’s Disease

Weir, Heather J.; Murray, Tracey K.; Kehoe, Patrick Gavin; Love, Seth; Verdin, Eric; O’Neill, Michael; Lane, Jon D.; Balthasar, Nina

doi:10.1371/journal.pone.0048225

Cited by 105 publications

(91 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, four different methodologies confirmed that SIRT3 mRNA and protein levels are apparently decreased in AD. As it has been shown that p53 expression was increased in AD brain (Hooper et al ., 2007) and SIRT3 alteration is linked to ROS accumulation in AD (Weir et al ., 2012), we examined the relationship between SIRT3 and p53 protein levels in AD cortex. p53 protein levels were significantly increased in both nuclear and mitochondrial fractions of patients with AD while SIRT3 protein levels were significantly decreased in the mitochondrial fraction ( P < 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The mitochondria‐associated senescence domain of p53 can interact with SIRT3 resulting in growth arrest (Li et al ., 2010). Because p53 is elevated in AD brain and SIRT3 induces mitochondrial ROS accumulation in AD, it has been proposed that impaired molecular interactions between SIRT3 and p53 may lead to mitochondrial dysfunction in AD (Hooper et al ., 2007; Weir et al ., 2012). In this context, we discovered that that SIRT3 deacetylates p53, thereby reducing p53 occupancy of mitochondrial DNA.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…CR, fasting, exercise, and genotoxic and oxidative stress all increase SIRT3 expression. 11,18,29,31,40,41 Collectively, these data suggest that SIRT3 is upregulated as part of a stressresponsive, cell-protective mechanism. SIRT3-mediated deacetylation results in increased activity of the majority of its target proteins.…”

Section: Sirt3: Dispensable Until Times Of Stress?mentioning

confidence: 85%

“…30 In addition, primary hippocampal neurons overexpressing SIRT3 were protected against death induced by inhibition of the ETC, shown to lead to an increase in mitochondrial ROS production. 31 …”

Section: Sirt3-dependent Regulation Of Oxidative Stress and Cell Survmentioning

confidence: 99%

“…26,[30][31][32][33] Cancer is associated with the metabolic reprogramming of cells, orchestrated by various mechanisms including transcriptional changes induced by the transcription factor hypoxia inducible factor-1α (HIF-1α). Ordinarily targeted for degradation under normoxic conditions, HIF-1α is stabilized when levels of ROS are increased.…”

Section: Sirt3 In Diseasementioning

confidence: 99%

See 1 more Smart Citation

SIRT3: A Central Regulator of Mitochondrial Adaptation in Health and Disease

2013

View full text Add to dashboard Cite

SIRT3 is a NAD+ -dependent deacetylase that regulates the function of numerous mitochondrial proteins with roles in metabolism, oxidative stress, and cell survival. It is emerging as an instrumental regulator of the mitochondrial adaptive responses to stress, including metabolic reprogramming and enhancing antioxidant defense mechanisms. Here, we discuss the role that SIRT3 plays at both a cellular and physiological level and consider its involvement in disease. Mitochondrial dysfunction is a key contributing factor in many diseases; however, the mechanisms involved are often not well understood, and few targeted therapies exist. If manipulation of SIRT3 proves to be beneficial in disease states, then it could be a promising target for novel therapies.

show abstract

Insulin signaling pathway protects neuronal cell lines by Sirt3 mediated IRS2 activation

et al. 2018

View full text Add to dashboard Cite

Cellular stress like ER and oxidative stress are the principle causative agents of various proteinopathies. Multifunctional protein PARK7/DJ-1 provides protection against cellular stress. Recently, insulin/IGF also has emerged as a neuro-protective molecule. However, it is not known whether DJ-1 and insulin/IGF complement each other for cellular protection in response to stress. In this study, we show for the first time, that in human and mouse neuronal cell lines, down regulation of DJ-1 for 48 h leads to compensatory upregulation of insulin/IGF signaling (IIS) pathway genes, namely, insulin receptor, insulin receptor substrate, and Akt under normal physiological conditions as well as in cellular stress conditions. Moreover, upon exogenous supply of insulin there is a marked increase in the IIS components both at gene and protein levels leading to down regulation and inactivation of GSK3β. By immunoprecipitation, it was observed that Sirt3 mediated deacetylation and activation of FoxO3a could not occur under DJ-1 downregulation. Transient DJ-1 downregulation also led to Akt mediated increased phosphorylation and nuclear exclusion of FoxO3a. When DJ-1 was downregulated increased interaction of Sirt3 with IRS2 was observed leading to its activation resulting in IIS upregulation. Thus, transient downregulation of DJ-1 leads to stimulation of IIS pathway by Sirt3 mediated IRS2 activation. Consequently, antiapoptotic program is triggered in neuronal cells via Akt-GSK3β-FoxO3a axis. © 2018 BioFactors, 44(3):224-236, 2018.

show abstract

CNS SIRT3 Expression Is Altered by Reactive Oxygen Species and in Alzheimer’s Disease

Cited by 105 publications

References 25 publications

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

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

SIRT3: A Central Regulator of Mitochondrial Adaptation in Health and Disease

Insulin signaling pathway protects neuronal cell lines by Sirt3 mediated IRS2 activation

Contact Info

Product

Resources

About