Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmah-null mice affect hearing loss

Kwon, Deug-Nam; Park, Woo-Jin; Choi, Yun-Jung; Gurunathan, Sangiliyandi; Kim, Jin-Hoi

doi:10.18632/aging.100800

Cited by 39 publications

(48 citation statements)

References 50 publications

(49 reference statements)

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“…SIRT3 is considered a crucial protein against oxidative stress, since it deacetylates and activates several proteins related to mitochondrial function and antioxidant enzymes (Alhazzazi, Kamarajan, Verdin, & Kapila, ; Oliver, Roca, & Sastre‐Serra, ). In this regard, we observed an increase in ROS levels and ROS production after SIRT3 knockdown, as has been widely described before (Finley & Haigis, ; Finley et al, ; Kong et al, ; Park, Choi, Gurunathan, & Kim, ; Pons, Sastre‐Serra, Oliver, & Roca, ). This increase has been attributed to the hyperacetylation, and thus inactivation, of SIRT3 targets, mainly MnSOD, which is one of the most important antioxidant enzymes of the cell (Ozden et al, ; Vassilopoulos, Parisiadou, Yan, & Gius, ; Zou et al, ).…”

Section: Discussionsupporting

confidence: 87%

Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Torrens-Mas¹,

Hernández-López²,

Oliver³

et al. 2018

J Cell Physiol

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Sirtuin 3 (SIRT3) is the major mitochondria deacetylase and regulates ROS levels by targeting several key proteins, such as those involved in mitochondrial function and antioxidant defenses. This way, SIRT3 balances ROS production and scavenging and promotes cell survival. The aim of this study was to analyze the effect of SIRT3 silencing on the antioxidant response in SW620 colon cancer cell line, and whether this intervention could improve efficacy of oxaliplatin, a common drug used to treat colon cancer. For this purpose, we obtained stable clones of SW620 with SIRT3 knockdown and determined parameters such as ROS levels and ROS production, levels of several antioxidant enzymes, cell viability, and apoptosis. Results showed that after SIRT3 silencing, both ROS levels and production were increased, and antioxidant enzymes gene expression was significantly reduced. Furthermore, manganese superoxide dismutase levels and enzymatic activity were reduced. Combination of SIRT3 knockdown with oxaliplatin treatment further increased ROS production and apoptosis, reducing cell viability. Finally, survival curves on colon cancer patients suggested that SIRT3 expression is related to a poorer prognosis. In conclusion, SIRT3 could be a target for colon cancer, since it regulates the antioxidant response and its knockdown improves the efficacy of oxaliplatin treatment.

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Section: Discussionsupporting

confidence: 87%

Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Torrens-Mas¹,

Hernández-López²,

Oliver³

et al. 2018

J Cell Physiol

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“…SIRT3 is a mitochondrial NAD + ‐dependent histone deacetylase, which plays an important role in energy production, metabolism, apoptosis, and cell signaling during aging (D'Aquila, Rose, Panno, Passarino, & Bellizzi, ; Kwon, Park, Choi, Gurunathan, & Kim, ). For example, SIRT3 inhibits lipid accumulation in Mϕs through deacetylation of isocitrate dehydrogenase 2 (Sheng et al, ).…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 suppresses the formation of renal calcium oxalate crystals through promoting M2 polarization of macrophages

Xi¹,

Chen

Jing

et al. 2018

Journal Cellular Physiology

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This study aims to verify whether the inhibitory effect of Sirtuin 3 (SIRT3) on the formation of renal calcium oxalate crystals was mediated through promoting macrophages (Mϕs) polarization. Identification and quantification of M1 and M2 monocytes were performed using fluorescence‐activated cell sorting analysis. SIRT3 protein level and forkhead box O1 (FOXO1) acetylation level were measured using western blot analysis. Cell apoptosis of HK‐2 was detected by flow cytometry. Mouse kidney tissues were subjected to Von Kossa staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and immunohistochemical staining for detection of kidney crystals deposition, apoptosis, and expression of crystal‐related molecules, respectively. The results showed that human peripheral blood monocytes from patients with kidney stone (KS) exhibited decreased M2 monocytes percentage and SIRT3 expression, whereas increased FOXO1 acetylation compared with the normal controls. In vitro assay revealed that SIRT3 overexpression in bone marrow‐derived M0/M1/M2 Mϕs induced M2 polarization and decreased FOXO1 acetylation. Furthermore, FOXO1 knockdown reversed SIRT3‐mediated induction of M2 polarization and inhibition of HK‐2 (human proximal tubular cell line) apoptosis. Further in vivo experiments demonstrated that SIRT3‐overexpressing Mϕs transfusion not only induced M2 polarization, but also alleviated inflammation, apoptosis, and crystals deposition in glyoxylate‐induced KS mice. In conclusion, SIRT3 suppresses formation of renal calcium oxalate crystals through promoting M2 polarization via deacetylating FOXO1.

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“…In addition, it has been proven that SIRT3 plays key roles in mitochondrial functions through deacetylation of mitochondrial proteins, such as acetyl‐CoA synthase 2 (AceCS2), glutamate dehydrogenase (GDH), and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit nine (NDUFA9) (Ahn et al, ). A recent study shows that reduction of SIRT3 expression results in oxidative stress and mitochondrial dysfunction due to ROS production in ARHL mice (Kwon, Park, Choi, Gurunathan, & Kim, ). Moreover, SIRT1 activation by pharmacological agents such as resveratrol, increases mitochondrial biogenesis through SIRT1‐dependent deacetylation of the transcriptional coactivator, PGC‐1α (Desquiret‐Dumas et al, ).…”

Section: Introductionmentioning

confidence: 99%

Augmentation of cellular NAD⁺by NQO1 enzymatic action improves age‐related hearing impairment

Kim

Cao

Oh³

et al. 2019

Aging Cell

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Age‐related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD+/NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP‐1, and PGC‐1α. Nonetheless, the beneficial effect of direct modulation of cellular NAD+ levels on aging and age‐related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of β‐lapachone (β‐lap), a known plant‐derived metabolite that modulates cellular NAD+ by conversion of NADH to NAD+ via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD+ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro‐inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF‐κB, p53, and IDH2. However, augmentation of NAD+ by β‐lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD+ levels by pharmacological agents may be a tangible therapeutic option for treating various age‐related diseases, including ARHL.

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Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmah-null mice affect hearing loss

Cited by 39 publications

References 50 publications

Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Sirtuin 3 suppresses the formation of renal calcium oxalate crystals through promoting M2 polarization of macrophages

Augmentation of cellular NAD⁺by NQO1 enzymatic action improves age‐related hearing impairment

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Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmah-null mice affect hearing loss

Cited by 39 publications

References 50 publications

Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Sirtuin 3 suppresses the formation of renal calcium oxalate crystals through promoting M2 polarization of macrophages

Augmentation of cellular NAD+by NQO1 enzymatic action improves age‐related hearing impairment

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Augmentation of cellular NAD⁺by NQO1 enzymatic action improves age‐related hearing impairment