SIRT5 desuccinylates and activates SOD1 to eliminate ROS

Lin, Zhi-Feng; Xu, Huini; Wang, Jianyun; Lin, Qiang; Ruan, Zhen; Liu, Fabing; Wang, Jin; Huang, Haihua; Chen, Xi

doi:10.1016/j.bbrc.2013.10.033

Cited by 225 publications

(179 citation statements)

References 22 publications

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“…These observations highlighted the potential role of SIRT5 in promoting lung cancer growth and drug resistance, by promoting the expression of NRF2 and its downstream targets (94). Another study proposed that SIRT5-mediated SOD1 desuccinylation and activation might be relevant in lung tumor cell growth (88). SOD1 KD lung tumor cells expressing succinylation-resistant SOD1 mutant displayed reduced proliferation (88), potentially indicating that regulation of SOD1 via succinylation is critical for lung tumor cell growth.…”

Section: Figmentioning

confidence: 97%

“…SOD1 is overexpressed in many types of cancer cells (113,152), and its activity may be essential for limiting ROS levels to a level that is consistent with robust cellular proliferation. In this regard, a recent study by Lin et al found that succinylation of SOD1 leads to decreases in its activity (88). SIRT5 binds to, desuccinylates, and activates SOD1.…”

Section: Fig 6 Overview Of Interplay Between Mitochondrialmentioning

confidence: 99%

“…SOD1 is a key cellular antioxidant enzyme, and SOD1-mediated ROS detoxification is significantly increased when SOD1 is co-overexpressed with SIRT5 (88). A number of observations potentially implicate SOD1 in tumorigenesis (114).…”

Section: Metabolic Targets Of Sirt5mentioning

confidence: 99%

“…For example, increased SOD1 expression was found in a panel of breast cancer cell lines (113); overexpression of SOD1 promotes growth of lung cancer cells (152); and inhibition of SOD1 induces cell death in the lung carcinoma cell line A549 (49). Mutation of the SOD1 succinylation site inhibited the growth of lung cancer cells (88), suggesting a role for SIRT5-mediated SOD1 desuccinylation and activation in promoting tumorigenesis.…”

Section: Metabolic Targets Of Sirt5mentioning

confidence: 99%

“…Another study proposed that SIRT5-mediated SOD1 desuccinylation and activation might be relevant in lung tumor cell growth (88). SOD1 KD lung tumor cells expressing succinylation-resistant SOD1 mutant displayed reduced proliferation (88), potentially indicating that regulation of SOD1 via succinylation is critical for lung tumor cell growth. Clearly, further studies are warranted to explore the possible involvement of SIRT5 in tumorigenesis and reprograming of cancer cell metabolism.…”

Section: Figmentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

132

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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Section: Figmentioning

confidence: 97%

Section: Fig 6 Overview Of Interplay Between Mitochondrialmentioning

confidence: 99%

Section: Metabolic Targets Of Sirt5mentioning

confidence: 99%

Section: Metabolic Targets Of Sirt5mentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

132

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SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer

et al. 2018

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Lactate dehydrogenase B (LDHB) is a glycolytic enzyme that catalyses the conversion of lactate and NAD + to pyruvate, NADH and H+. Protons (H+) generated by LDHB promote lysosomal acidification and autophagy in cancer, but how this role is regulated has not been defined. In this study, we identified an important post‐translational mechanism by which LDHB is regulated during autophagy in cancer cells. Mass spectrometry revealed that protein sirtuin 5 (SIRT5) is a binding partner of LDHB that deacetylated LDHB at lysine‐329, thereby promoting its enzymatic activity. Deacetylated LDHB increased autophagy and accelerated the growth of colorectal cancer (CRC) cells. Notably, SIRT5 knockout or inhibition by GW5074 increased LDHB acetylation at K329 and inhibited LDHB activity, which downregulated autophagy and CRC cell growth in vitro and in vivo. Clinically, the LDHB‐Ac‐K329 staining score in CRC tissues was lower than that in corresponding peritumour tissues. Low LDHB‐Ac‐K329 status was associated with malignant progression of human CRC and served as a potential prognostic indicator for patients with CRC. Altogether, we conclude that SIRT5‐induced deacetylation of LDHB triggers hyperactivation of autophagy, a key event in tumorigenesis. Thus, the SIRT5/LDHB pathway may represent a novel target for treating CRC.

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Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells

et al. 2021

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Sunitinib (Sun), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, is the standard first‐line treatment against advanced clear cell renal cell carcinoma (RCC), but resistance to therapy is inevitable. Reactive oxygen species production is associated with sensitivity to chemotherapy, but the underlying mechanisms are not completely understood. Here, we investigated the mechanisms contributing to Sun resistance using the RCC cell lines ACHN and 786‐O. We report that Sun‐resistant cells exhibited reduced apoptosis, increased cell viability, increased reactive oxygen species production and disrupted mitochondrial function. Furthermore, chronic Sun treatment resulted in an up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels. Knockdown of Sirt5/IDH2 impaired mitochondrial function and partially attenuated Sun resistance. Finally, up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promoted protein stability. In conclusion, dysregulation of Sirt5/IDH2 partially contributes to Sun resistance in RCC cells by affecting antioxidant capacity.

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SIRT5 desuccinylates and activates SOD1 to eliminate ROS

Cited by 225 publications

References 22 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer

Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells

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