Sirt3 Deficiency Increased the Vulnerability of Pancreatic Beta Cells to Oxidative Stress-Induced Dysfunction

Zhou, Yu; Chung, Arthur C.K.; Fan, Rongrong; Lee, Heung Man; Xu, Gang; Tomlinson, Brian; Chan, Juliana C.N.; Kong, Alice P.S.

doi:10.1089/ars.2016.6859

Cited by 49 publications

(70 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been well documented that SIRT3 is involved in various oxidative stress-related diseases, where deficiency or functional impairment was crucial for mitochondrial dysfunction and disease progression [19] , [20] , [67] . Considering the important role of oxidative stress and mitochondrial dysfunction in NP cell apoptosis and the unexplored mechanisms, we further investigated SIRT3 function in human NP tissues and its relationships with AGEs-induced oxidative stress and IVD degeneration.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration

et al. 2018

View full text Add to dashboard Cite

Intervertebral disc (IVD) degeneration contributes largely to pathoanatomical and degenerative changes of spinal structure that increase the risk of low back pain. Apoptosis in nucleus pulposus (NP) can aggravate IVD degeneration, and increasing studies have shown that interventions targeting NP cell apoptosis can ameliorate IVD degeneration, exhibiting their potential for use as therapeutic strategies. Recent data have shown that advanced glycation end products (AGEs) accumulate in NP tissues in parallel with the progression of IVD degeneration and form a microenvironment of oxidative stress. This study examined whether AGEs accumulation aggravates NP cell apoptosis and IVD degeneration, and explored the mechanisms underlying these effects. We observed that the viability and proliferation of human NP cells were significantly suppressed by AGEs treatment, mainly due to apoptosis. Furthermore, activation of the mitochondrial apoptosis pathway was detected after AGEs treatment. In addition, the molecular data showed that AGEs could significantly aggravate the generation of mitochondrial reactive oxygen species and prolonged activation of the mitochondrial permeability transition pore, as well as the increased level of Bax protein and decreased level of Bcl-2 protein in mitochondria. These effects could be reduced by antioxidant (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) and Visomitin (SKQ1). Importantly, we identified that impairment of Sirtuin3 (SIRT3) function and the mitochondrial antioxidant network were vital mechanisms in AGEs-induced oxidative stress and secondary human NP cell apoptosis. Finally, based on findings that nicotinamide mononucleotide (NMN) could restore SIRT3 function and rescue human NP cell apoptosis through adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-γ coactivator 1α (AMPK-PGC-1α) pathway in vitro, we confirmed its protective effect on AGEs-induced IVD degeneration in vivo. In conclusion, our data demonstrate that SIRT3 protects against AGEs-induced human NP cell apoptosis and IVD degeneration. Targeting SIRT3 to improve mitochondrial redox homeostasis may represent a potential therapeutic strategy for attenuating AGEs-associated IVD degeneration.

show abstract

Section: Discussionmentioning

confidence: 99%

Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Oxidative stress is the common pathophysiology of diabetic cardiomyopathy and cardiac lipotoxicity [ 107 , 108 ]. SIRT3 protects pancreatic beta cells from lipotoxicity by antagonizing oxidative stress-induced cell damage [ 109 ]. Thus, SIRT3 can inhibit diabetic cardiomyopathy and cardiac lipotoxicity.…”

Section: Sirt3 In Cardiovascular Diseasementioning

confidence: 99%

SIRT3: A New Regulator of Cardiovascular Diseases

Sun

Liu

Chen

et al. 2018

Oxidative Medicine and Cellular Longevity

136

106

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) are the leading causes of death worldwide, and defects in mitochondrial function contribute largely to the occurrence of CVDs. Recent studies suggest that sirtuin 3 (SIRT3), the mitochondrial NAD+-dependent deacetylase, may regulate mitochondrial function and biosynthetic pathways such as glucose and fatty acid metabolism and the tricarboxylic acid (TCA) cycle, oxidative stress, and apoptosis by reversible protein lysine deacetylation. SIRT3 regulates glucose and lipid metabolism and maintains myocardial ATP levels, which protects the heart from metabolic disturbances. SIRT3 can also protect cardiomyocytes from oxidative stress-mediated cell damage and block the development of cardiac hypertrophy. Recent reports show that SIRT3 is involved in the protection of several heart diseases. This review discusses the progress in SIRT3-related research and the role of SIRT3 in the prevention and treatment of CVDs.

show abstract

“…Subsequent studies support a role for SIRT3 in the maintenance of β cell function ( Caton et al, 2013 ; Kim et al, 2015 ; Zhang et al, 2016 ; Zhou et al, 2017 ). Knockdown of SIRT3 in β cell lines promotes both oxidative and endoplasmic reticulum (ER) stress, decreases cell viability, reduces glucose-stimulated ATP content, and, ultimately, impairs glucose- and leucine-stimulated insulin secretion ( Caton et al, 2013 ; Zhang et al, 20616 ; Zhou et al, 2017 ). Pancreatic islets isolated from global SIRT3 KO 129Sv mice display increased markers of oxidative stress and apoptosis as well as impaired GSIS ( Zhou et al, 2017 ).…”

Section: Introductionmentioning

confidence: 95%

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition

et al. 2018

View full text Add to dashboard Cite

SUMMARY SIRT3 is a nicotinamide adenine dinucleotide (NAD+)- dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial metabolism, could be susceptible to SIRT3-mediated effects. We used CRISPR/Cas9 technology to manipulate SIRT3 expression in β cells, resulting in widespread SIRT3-dependent changes in acetylation of key metabolic enzymes but no appreciable changes in glucose- or pyruvate-stimulated insulin secretion or metabolomic profile during glucose stimulation. Moreover, these broad changes in the SIRT3-targeted acetylproteome did not affect responses to nutritional or ER stress. We also studied mice with global SIRT3 knockout fed either standard chow (STD) or high-fat and high-sucrose (HFHS) diets. Only when chronically fed HFHS diet do SIRT3 KO animals exhibit a modest reduction in insulin secretion. We conclude that broad changes in mitochondrial protein acetylation in response to manipulation of SIRT3 are not sufficient to cause changes in islet function or metabolism.

show abstract

Sirt3 Deficiency Increased the Vulnerability of Pancreatic Beta Cells to Oxidative Stress-Induced Dysfunction

Abstract: These results suggest that Sirt3 may be a target for amelioration of beta cell dysfunction due to obesity and T2D. Antioxid. Redox Signal. 27, 962-976.

Cited by 49 publications

References 40 publications

Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration

Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration

SIRT3: A New Regulator of Cardiovascular Diseases

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition

Contact Info

Product

Resources

About