Neuronal Sirt3 Protects against Excitotoxic Injury in Mouse Cortical Neuron Culture

Kim, Sun Hee; Lu, Hua; Alano, Conrad C.

doi:10.1371/journal.pone.0014731

Cited by 147 publications

(138 citation statements)

References 71 publications

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“…While ROS are required for glucose metabolism and metastasis in triple-negative breast cancers (9), decreased SirT3 levels concomitant with high ROS levels are frequently observed in all breast cancers (8). Based on these findings, SirT3 is considered a tumor suppressor (5,8).SirT3 regulates the activity of magnesium superoxide dismutase (MnSOD), which detoxifies superoxide to hydrogen peroxide (5,7,(10)(11)(12)(13)(14). Moreover, SirT3 has been linked to augmented transcription of MnSOD and catalase, both known targets of the transcription factor FOXO3A (15).…”

mentioning

confidence: 99%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

236

213

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The mitochondria of cancer cells are characterized by elevated oxidative stress caused by reactive oxygen species (ROS). Such an elevation in ROS levels contributes to mitochondrial reprogramming and malignant transformation. However, high levels of ROS can cause irreversible damage to proteins, leading to their misfolding, mitochondrial stress, and ultimately cell death. Therefore, mechanisms to overcome mitochondrial stress are needed. The unfolded protein response (UPR) triggered by accumulation of misfolded proteins in the mitochondria (UPR mt ) has been reported recently. So far, the UPR mt has been reported to involve the activation of CHOP and estrogen receptor alpha (ER␣). The current study describes a novel role of the mitochondrial deacetylase SirT3 in the UPR mt . Our data reveal that SirT3 acts to orchestrate two pathways, the antioxidant machinery and mitophagy. Inhibition of SirT3 in cells undergoing proteotoxic stress severely impairs the mitochondrial network and results in cellular death. These observations suggest that SirT3 acts to sort moderately stressed from irreversibly damaged organelles. Since SirT3 is reported to act as a tumor suppressor during transformation, our findings reveal a dual role of SirT3. This novel role of SirT3 in established tumors represents an essential mechanism of adaptation of cancer cells to proteotoxic and mitochondrial stress. Mitochondrial reprogramming associated with elevated reactive oxygen species (ROS) levels is a hallmark of cancers. Altered mitochondrial metabolism and ROS, both required during oncogenic transformation (1-4), are regulated by the mitochondrial deacetylase SirT3 (5-7). Reduction in SirT3 levels and the resulting elevated ROS levels have been directly linked to the switch to glycolysis, known as the Warburg effect (8). While ROS are required for glucose metabolism and metastasis in triple-negative breast cancers (9), decreased SirT3 levels concomitant with high ROS levels are frequently observed in all breast cancers (8). Based on these findings, SirT3 is considered a tumor suppressor (5,8).SirT3 regulates the activity of magnesium superoxide dismutase (MnSOD), which detoxifies superoxide to hydrogen peroxide (5,7,(10)(11)(12)(13)(14). Moreover, SirT3 has been linked to augmented transcription of MnSOD and catalase, both known targets of the transcription factor FOXO3A (15). The SirT3-dependent deacetylation of FOXO3A promotes both its nuclear translocation and its transcriptional activity (16,17). Therefore, mechanistically, the reduction of SirT3 levels leads to an elevation in ROS levels by compromising the mitochondrial antioxidant machinery.Mitochondria are the main source of ROS production (18). However, they are also the main targets of oxidative stress. Excessive ROS induce oxidative damage to DNA, lipids, and proteins, leading to their misfolding and aggregation in the mitochondria. Upon accumulation of misfolded and aggregated proteins in the mitochondria, cells mount the unfolded protein response (UPR mt ), a mitochondrial-to nu...

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confidence: 99%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

236

213

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“…Recent studies have indicated that neuronal SIRT3 protects cells against excitotoxicity (44). Notably, we found that mutant Htt depleted SIRT3 protein levels.…”

Section: Discussionmentioning

confidence: 47%

trans-(−)-ε-Viniferin Increases Mitochondrial Sirtuin 3 (SIRT3), Activates AMP-activated Protein Kinase (AMPK), and Protects Cells in Models of Huntington Disease

Jin

Cichewicz

et al. 2012

Journal of Biological Chemistry

187

140

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“…SIRT3 was important for neuron viability in a primary cell model that used NMDA to deplete NAD and induce excitotoxic injury (105). Mice with a neuron-specific deletion of Sirt6 did not die of hypoglycemia like full-body knock-outs (79).…”

Section: Brainmentioning

confidence: 99%

From Sirtuin Biology to Human Diseases: An Update

Sebastián

Satterstrom

Haigis

et al. 2012

Journal of Biological Chemistry

208

159

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Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD ؉ -dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.Over three-quarters of a century ago, Clive McCay and colleagues first noted that rats kept on a calorie-restricted diet lived longer than freely fed controls (1). Despite the length of time that has elapsed since this discovery, the molecular mechanism that drives this life span extension has remained elusive. Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (2). Moreover, Sir2 was required for the life span of yeast to be extended by calorie restriction (3). These discoveries launched a new field in biology: the study of Sir2 and its homologs in mammals, called sirtuins.Mammals have seven sirtuins (SIRT1-7) that possess NAD ϩ -dependent deacetylase, deacylase, and ADP-ribosyltransferase activities (4). Sirtuins are found in different subcellular locations, including the nucleus (SIRT1, SIRT6, and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3-5), although in some studies, SIRT1 has been found to possess cytosolic activities, and SIRT2 has been found to associate with nuclear proteins. Sirtuins have important functions in a diverse yet interrelated set of physiological processes. In this minireview, we discuss research done in the past four years featuring their roles in aging, metabolism, cancer biology, cardiovascular disease, inflammation, and brain pathology. AgingFollowing the first publication describing a role for yeast Sir2 in promoting longevity (2), many laboratories focused on elucidating whether sirtuins might play similar roles in other organisms. Sirtuins have been shown to regulate life span in lower organisms, including yeast, nematodes, and fruit flies (5), although their role in worm and fly life span has recently been debated (6, 7). Most of these studies have described a key role for SIRT1 in regulating the metabolic response to calorie restriction (CR) 5 (8), a dietary intervention that robustly extends life span across numerous species. However, wholebody overexpression of SIRT1 in mice does not affect life span (9). Nevertheless, SIRT1 does appear to promote healthy aging by protecting against several age-related pathologies (10).The strongest link between mammalian sirtuins and the antiaging effects of CR comes from SIRT3, which mediates the prevention of age-related hearing loss by CR (11). Hearing loss is a hallmark of mammalian aging and is characterized by a gradual loss of spiral...

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Neuronal Sirt3 Protects against Excitotoxic Injury in Mouse Cortical Neuron Culture

Cited by 147 publications

References 71 publications

SirT3 Regulates the Mitochondrial Unfolded Protein Response

SirT3 Regulates the Mitochondrial Unfolded Protein Response

trans-(−)-ε-Viniferin Increases Mitochondrial Sirtuin 3 (SIRT3), Activates AMP-activated Protein Kinase (AMPK), and Protects Cells in Models of Huntington Disease

From Sirtuin Biology to Human Diseases: An Update

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