The Experts below are selected from a list of 12312 Experts worldwide ranked by ideXlab platform

Michael Way - One of the best experts on this subject based on the ideXlab platform.

John G. Pastorino - One of the best experts on this subject based on the ideXlab platform.

  • Sirtuin-3 modulates Bak- and Bax-dependent apoptosis.
    Journal of cell science, 2012
    Co-Authors: Manish Verma, Nataly Shulga, John G. Pastorino
    Abstract:

    Sirtuin-3 exhibits properties of a tumor suppressor partly emanating from its ability to control the state of mitochondrial metabolism, with depletion of sirt-3 increasing tumor cell survival. In the present study we demonstrate that depletion of Sirtuin-3 brings about an anti-apoptotic phenotype via stimulating cyclophilin-D activity, which promotes the binding of hexokinase II to the mitochondria, thereby preventing Bak/Bax dependent mitochondrial injury and cell death. By contrast, increased expression of Sirtuin-3 decreases cyclophilin-D activity, resulting in detachment of hexokinase II from the mitochondria and potentiation of Bak- and Bax-induced mitochondrial injury and loss of cell viability.

  • Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by Sirtuin-3.
    Journal of cell science, 2010
    Co-Authors: Nataly Shulga, John G. Pastorino
    Abstract:

    Ethanol increases the vulnerability of mitochondria to induction of the mitochondrial permeability transition (MPT). Cyclophilin-D activity enhances the potential for the permeability transition pore (PTP) to open. In the present study, we demonstrate that ethanol and its metabolism sensitize the PTP to opening, in part by increasing the acetylation and activity of cyclophilin-D. This effect of ethanol is mediated by inhibiting the activity of Sirtuin-3, an NAD(+) dependent deacetylase that is localized to the mitochondrial matrix. The ethanol-enhanced acetylation of cyclophilin-D also increases the interaction of cyclophilin-D with the adenine nucleotide translocator-1 (ANT-1) and is dependent on ethanol metabolism. Moreover, activation of AMPK, a known positive modulator of Sirtuin activity, prevented the ethanol-induced suppression of Sirtuin-3 activity and the attendant increase of cyclophilin-D acetylation, activity and association with ANT-1. Additionally, AMPK reactivation of Sirtuin-3 prevented the sensitization to the MPT and the enhancement of cell killing by TNF in cells exposed to ethanol.

  • Sirtuin 3 deacetylation of cyclophilin d induces dissociation of hexokinase ii from the mitochondria
    Journal of Cell Science, 2010
    Co-Authors: Nataly Shulga, Robin Wilsonsmith, John G. Pastorino
    Abstract:

    We demonstrate that the transition from a reliance on glycolysis to oxidative phosphorylation in a transformed cell line is dependent on an increase in the levels and activity of Sirtuin-3. Sirtuin-3 deacetylates cyclophilin D, diminishing its peptidyl-prolyl cis-trans isomerase activity and inducing its dissociation from the adenine nucleotide translocator. Moreover, the Sirtuin-3-induced inactivation of cyclophilin D causes a detachment of hexokinase II from the mitochondria that is necessary for stimulation of oxidative phosphorylation. These results might have important implications for the role of Sirtuin-3 in the metabolism of some cancer cells and their susceptibility to mitochondrial injury and cytotoxicity.

Jiong Shi - One of the best experts on this subject based on the ideXlab platform.

  • Ketones improves Apolipoprotein E4-related memory deficiency via Sirtuin 3.
    Aging, 2019
    Co-Authors: Junxiang Yin, Megan Nielsen, Jiong Shi
    Abstract:

    Background Apolipoprotein E4 (ApoE4) is the major genetic risk factor of Alzheimer's disease (AD). ApoE4 carriers have cerebral hypometabolism which is thought as a harbinger of AD. Our previous studies indicated ketones improved mitochondria energy metabolism via Sirtuin 3 (Sirt3). However, it is unclear whether ketones upregulate Sirt3 and improve ApoE4-related learning and memory deficits. Results Ketones improved learning and memory abilities of ApoE4 mice but not ApoE3 mice. Sirt3, synaptic proteins, the NAD+/ NADH ratio, and ATP production were significantly increased in the hippocampus and the cortex from ketone treatment. Methods Human ApoE3 and ApoE4 transgenic mice (9-month-old) were treated with either ketones or normal saline by daily subcutaneous injections for 3 months (ketones, beta-hydroxybutyrate (BHB): 600 mg/kg/day; acetoacetate (ACA): 150 mg/kg/day). Learning and memory ability of these mice were assessed. Sirt3 protein, synaptic proteins (PSD95, Synaptophysin), the NAD+/ NADH ratio, and ATP levels were measured in the hippocampus and the cortex. Conclusion Our current studies suggest that ketones improve learning and memory abilities of ApoE4 transgenic mice. Sirt3 may mediate the neuroprotection of ketones by increasing neuronal energy metabolism in ApoE4 transgenic mice. This provides the foundation for Sirt3's potential role in the prevention and treatment of AD.

  • Sirtuin 3 Mediates Tau Deacetylation
    Journal of Alzheimer's Disease, 2019
    Co-Authors: Junxiang Yin, Megan Nielsen, Thomas G. Beach, Li Guo, Jiong Shi
    Abstract:

    Background Emerging evidence shows tau acetylation has been observed in Alzheimer's disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear. Objective We studied the effects of Sirt3 on tau acetylation and its aggregations. Methods We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown or overexpression. Results The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells. Conclusions Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation.

  • Sirtuin 3 promotes microglia migration by upregulating CX3CR1.
    Cell Adhesion & Migration, 2019
    Co-Authors: Runjing Cao, Junxiang Yin, Li Guo, Jiong Shi
    Abstract:

    We studied the role of Sirtuin 3 (SIRT3) in microglial cell migration in ischemic stroke. We used a middle cerebral artery occlusion (MCAO) model of focal ischemia. We then applied lentivirus-packaged SIRT3 overexpression and knock down in microglial N9 cells to investigate the underlying mechanism driving microglial cell migration. More microglial cells appeared in the ischemic lesion side after MCAO. The levels of SIRT3 were increased in macrophages, the main source of microglia, after ischemia. CX3CR1 levels were increased with SIRT3 overexpression. SIRT3 promoted microglial N9 cells migration by upregulating CX3CR1 in both normal and glucose deprived culture media. These effects were G protein-dependent. Our study for the first time shows that SIRT3 promotes microglia migration by upregulating CX3CR1.

  • Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism
    Aging, 2018
    Co-Authors: Junxiang Yin, Megan Nielsen, Tanner Carcione, Winnie S. Liang, Jiong Shi
    Abstract:

    Alzheimer's disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.

  • Amyloid-β Increases Tau by Mediating Sirtuin 3 in Alzheimer’s Disease
    Molecular Neurobiology, 2018
    Co-Authors: Junxiang Yin, Megan Nielsen, Thomas G. Beach, Pengcheng Han, Winnie S. Liang, Melissa Song, Geidy E. Serrano, Richard J. Caselli, Jiong Shi
    Abstract:

    Increasing evidence indicates that Sirtuin 3 (Sirt3) has neuroprotective effects in regulating oxidative stress and energy metabolism, both of which are involved in the pathogenesis of Alzheimer’s disease (AD). However, it is unclear whether Sirt3 is associated with cognitive performance and pathological changes in AD. We conducted a case-control study of the postmortem brains of AD (n = 16), mild cognitive impairment (n = 13), and age- and education-matched cognitively normal (CN, n = 11) subjects. We measured the mRNA and protein levels of Sirt3 and assessed their association with cognitive performance and AD pathology. In an ex vivo model of cortical neurons from transgenic mice that carry human tau protein, we modified Sirt3 expression by genetic knockdown and knock-in to investigate the cause-effect relationship between Sirt3 and tau. Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN. This reduction was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. Further study with genetic manipulation of Sirt3 revealed that amyloid-β increased levels of total tau acetylated tau through its modulation of Sirt3. These data suggest that reduction of Sirt3 is critically involved in pathogenesis of AD.

Nataly Shulga - One of the best experts on this subject based on the ideXlab platform.

  • Sirtuin-3 modulates Bak- and Bax-dependent apoptosis.
    Journal of cell science, 2012
    Co-Authors: Manish Verma, Nataly Shulga, John G. Pastorino
    Abstract:

    Sirtuin-3 exhibits properties of a tumor suppressor partly emanating from its ability to control the state of mitochondrial metabolism, with depletion of sirt-3 increasing tumor cell survival. In the present study we demonstrate that depletion of Sirtuin-3 brings about an anti-apoptotic phenotype via stimulating cyclophilin-D activity, which promotes the binding of hexokinase II to the mitochondria, thereby preventing Bak/Bax dependent mitochondrial injury and cell death. By contrast, increased expression of Sirtuin-3 decreases cyclophilin-D activity, resulting in detachment of hexokinase II from the mitochondria and potentiation of Bak- and Bax-induced mitochondrial injury and loss of cell viability.

  • Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by Sirtuin-3.
    Journal of cell science, 2010
    Co-Authors: Nataly Shulga, John G. Pastorino
    Abstract:

    Ethanol increases the vulnerability of mitochondria to induction of the mitochondrial permeability transition (MPT). Cyclophilin-D activity enhances the potential for the permeability transition pore (PTP) to open. In the present study, we demonstrate that ethanol and its metabolism sensitize the PTP to opening, in part by increasing the acetylation and activity of cyclophilin-D. This effect of ethanol is mediated by inhibiting the activity of Sirtuin-3, an NAD(+) dependent deacetylase that is localized to the mitochondrial matrix. The ethanol-enhanced acetylation of cyclophilin-D also increases the interaction of cyclophilin-D with the adenine nucleotide translocator-1 (ANT-1) and is dependent on ethanol metabolism. Moreover, activation of AMPK, a known positive modulator of Sirtuin activity, prevented the ethanol-induced suppression of Sirtuin-3 activity and the attendant increase of cyclophilin-D acetylation, activity and association with ANT-1. Additionally, AMPK reactivation of Sirtuin-3 prevented the sensitization to the MPT and the enhancement of cell killing by TNF in cells exposed to ethanol.

  • Sirtuin 3 deacetylation of cyclophilin d induces dissociation of hexokinase ii from the mitochondria
    Journal of Cell Science, 2010
    Co-Authors: Nataly Shulga, Robin Wilsonsmith, John G. Pastorino
    Abstract:

    We demonstrate that the transition from a reliance on glycolysis to oxidative phosphorylation in a transformed cell line is dependent on an increase in the levels and activity of Sirtuin-3. Sirtuin-3 deacetylates cyclophilin D, diminishing its peptidyl-prolyl cis-trans isomerase activity and inducing its dissociation from the adenine nucleotide translocator. Moreover, the Sirtuin-3-induced inactivation of cyclophilin D causes a detachment of hexokinase II from the mitochondria that is necessary for stimulation of oxidative phosphorylation. These results might have important implications for the role of Sirtuin-3 in the metabolism of some cancer cells and their susceptibility to mitochondrial injury and cytotoxicity.

Ramin Homayouni - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of Sirtuin-3 probe quality and co-expressed genes using literature cohesion
    BMC Bioinformatics, 2019
    Co-Authors: Kazi I. Zaman, Robert W. Williams, Ramin Homayouni
    Abstract:

    Background Gene co-expression studies can provide important insights into molecular and cellular signaling pathways. The GeneNetwork database is a unique resource for co-expression analysis using data from a variety of tissues across genetically distinct inbred mice. However, extraction of biologically meaningful co-expressed gene sets is challenging due to variability in microarray platforms, probe quality, normalization methods, and confounding biological factors. In this study, we tested whether literature derived functional cohesion could be used as an objective metric in lieu of ‘ground truth’ to evaluate the quality of probes and microarray datasets. Results We examined Sirtuin-3 (Sirt3) co-expressed gene sets extracted from either liver or brain tissues of BXD recombinant inbred mice in the GeneNetwork database. Depending on the microarray platform, there were as many as 26 probes that targeted different regions of Sirt3 primary transcript. Co-expressed gene sets (ranging from 100–1000 genes) associated with each Sirt3 probe were evaluated using the previously developed literature-derived cohesion p -value (LPv) and benchmarked against ‘gold standards’ derived from proteomic studies or Gene Ontology classifications. We found that the maximal F-measure was obtained at an average window size of 535 genes. Using set size of 500 genes, the Pearson correlations between LPv and F-measure as well as between LPv and mitochondrial gene enrichment p -values were 0.90 and 0.93, respectively. Importantly, we found that the LPv approach can distinguish high quality Sirt3 probes. Analysis of the most functionally cohesive Sirt3 co-expressed gene set revealed core metabolic pathways that were shared between hippocampus and liver as well as distinct pathways which were unique to each tissue. These results are consistent with other studies that suggest Sirt3 is a key metabolic regulator and has distinct functions in energy-producing vs. energy-demanding tissues. Conclusions Our results provide proof-of-concept that literature cohesion analysis is useful for evaluating the quality of probes and microarray datasets, particularly when experimentally derived gold standards are unavailable. Our approach would enable researchers to rapidly identify biologically meaningful co-expressed gene sets and facilitate discovery from high throughput genomic data.

  • Evaluation of Sirtuin-3 probe quality and co-expressed genes using literature cohesion.
    BMC bioinformatics, 2019
    Co-Authors: Sujoy Roy, Kazi I. Zaman, Robert W. Williams, Ramin Homayouni
    Abstract:

    Gene co-expression studies can provide important insights into molecular and cellular signaling pathways. The GeneNetwork database is a unique resource for co-expression analysis using data from a variety of tissues across genetically distinct inbred mice. However, extraction of biologically meaningful co-expressed gene sets is challenging due to variability in microarray platforms, probe quality, normalization methods, and confounding biological factors. In this study, we tested whether literature derived functional cohesion could be used as an objective metric in lieu of 'ground truth' to evaluate the quality of probes and microarray datasets. We examined Sirtuin-3 (Sirt3) co-expressed gene sets extracted from either liver or brain tissues of BXD recombinant inbred mice in the GeneNetwork database. Depending on the microarray platform, there were as many as 26 probes that targeted different regions of Sirt3 primary transcript. Co-expressed gene sets (ranging from 100-1000 genes) associated with each Sirt3 probe were evaluated using the previously developed literature-derived cohesion p-value (LPv) and benchmarked against 'gold standards' derived from proteomic studies or Gene Ontology classifications. We found that the maximal F-measure was obtained at an average window size of 535 genes. Using set size of 500 genes, the Pearson correlations between LPv and F-measure as well as between LPv and mitochondrial gene enrichment p-values were 0.90 and 0.93, respectively. Importantly, we found that the LPv approach can distinguish high quality Sirt3 probes. Analysis of the most functionally cohesive Sirt3 co-expressed gene set revealed core metabolic pathways that were shared between hippocampus and liver as well as distinct pathways which were unique to each tissue. These results are consistent with other studies that suggest Sirt3 is a key metabolic regulator and has distinct functions in energy-producing vs. energy-demanding tissues. Our results provide proof-of-concept that literature cohesion analysis is useful for evaluating the quality of probes and microarray datasets, particularly when experimentally derived gold standards are unavailable. Our approach would enable researchers to rapidly identify biologically meaningful co-expressed gene sets and facilitate discovery from high throughput genomic data.