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SIRT2 knockout exacerbates insulin resistance in high fat-fed mice.
Lantier L, Williams AS, Hughey CC, Bracy DP, James FD, Ansari MA, Gius D, Wasserman DH
(2018) PLoS One 13: e0208634
MeSH Terms: Acetylation, Animals, Diet, High-Fat, Energy Metabolism, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle, Skeletal, Phosphorylation, Proto-Oncogene Proteins c-akt, Sirtuin 2
Show Abstract · Added January 8, 2019
The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.
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16 MeSH Terms
Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection.
Hulgan T, Kallianpur AR, Guo Y, Barnholtz-Sloan JS, Gittleman H, Brown TT, Ellis R, Letendre S, Heaton RK, Samuels DC, CHARTER Study
(2019) J Acquir Immune Defic Syndr 80: e95-e102
MeSH Terms: AIDS Dementia Complex, Adult, Anti-Retroviral Agents, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genome-Wide Association Study, Genotype, HIV Infections, Humans, Male, Middle Aged, Mitochondria, Neurocognitive Disorders, Neuropsychological Tests
Show Abstract · Added December 11, 2019
BACKGROUND - Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.
METHODS - In the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.
RESULTS - Among 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.
CONCLUSIONS - Higher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.
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Relationships Between Adipose Mitochondrial Function, Serum Adiponectin, and Insulin Resistance in Persons With HIV After 96 Weeks of Antiretroviral Therapy.
Hulgan T, Ramsey BS, Koethe JR, Samuels DC, Gerschenson M, Libutti DE, Sax PE, Daar ES, McComsey GA, Brown TT
(2019) J Acquir Immune Defic Syndr 80: 358-366
MeSH Terms: Adiponectin, Adipose Tissue, Adult, DNA, Female, HIV Infections, HIV-1, Homeostasis, Humans, Insulin Resistance, Male, Middle Aged, Mitochondria, Obesity, RNA, Viral, Retrospective Studies, Viral Load
Show Abstract · Added December 11, 2019
OBJECTIVE - Some antiretroviral therapy (ART) and HIV itself confer metabolic risk, perhaps through altered mitochondrial function and adipokines. In AIDS Clinical Trials Group study A5224s, adipose mitochondrial DNA (mtDNA) levels decreased on ART, and electron transport chain complex I (CI) and complex IV (CIV) activity decreased. Another study found decreased serum adiponectin on ART with mtDNA mutation m.10398A>G. We hypothesized that decreased adipose tissue mitochondrial function would be associated with lower adiponectin and insulin sensitivity on ART, and m.10398G would influence these changes.
DESIGN - Retrospective analysis of an ART-naive substudy population from A5224s.
METHODS - Analyses included adipose mtDNA levels, CI and CIV activity by immunoassay, visceral adipose tissue by computed tomography, and fasting serum glucose at week 0 and week 96 of ART. Fasting insulin and adiponectin were measured from cryopreserved serum using multiplex bead array. Homeostasis model assessment-2 (HOMA2)-IR and HOMA2-%B estimated insulin resistance and β-cell function, respectively. The m.10398A>G mtDNA variant was available from existing genetic data.
RESULTS - Thirty-seven participants had adipose biopsies at week 0 and week 96. Percent decreases in CIV activity and adiponectin were correlated (Spearman rho 0.41; P = 0.01); this association persisted after controlling for age, sex, body mass index, or visceral adipose tissue in single-covariate regression. HOMA2-IR correlated with decreased CIV (-0.44; P = 0.01) and CI (-0.34; P = 0.05) activity. Among 12 non-Hispanic white persons, m.10398G was associated with decreased adiponectin (P = 0.04).
CONCLUSIONS - Decreased adipose mitochondrial activity correlated with changes in adiponectin and glucose homeostasis on ART. Previous findings that a mtDNA mutation modulates adiponectin levels in persons with HIV were replicated.
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Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS
(2018) Elife 7:
MeSH Terms: Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Beclin-1, Cell Respiration, Fibrosis, Gene Expression Regulation, Genome-Wide Association Study, Genomics, Heart Diseases, Heart Ventricles, Humans, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proton-Translocating ATPases, Mutation, Myeloid Progenitor Cells, Myocardial Infarction, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Reactive Oxygen Species, Reproducibility of Results, Up-Regulation
Show Abstract · Added December 11, 2018
Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
© 2018, Salisbury-Ruf et al.
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26 MeSH Terms
Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment.
Smieszek S, Jia P, Samuels DC, Zhao Z, Barnholtz-Sloan J, Kaur H, Letendre S, Ellis R, Franklin DR, Hulgan T, Kallianpur A, Bush WS, CHARTER Study Group
(2019) Mitochondrion 46: 247-255
MeSH Terms: AIDS Dementia Complex, Cell Nucleus, Continental Population Groups, Genetic Association Studies, HIV Infections, Haplotypes, Humans, Mitochondria, Mitochondrial Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Prospective Studies
Show Abstract · Added December 11, 2019
HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.
Kallianpur AR, Gerschenson M, Hulgan T, Kaur H, Clifford DB, Haas DW, Murdock DG, McArthur JC, Samuels DC, Simpson DM
(2018) AIDS Res Hum Retroviruses 34: 942-949
MeSH Terms: Adult, Alleles, Anti-HIV Agents, CD4 Lymphocyte Count, Case-Control Studies, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genotype, HIV Infections, HIV-1, Hemochromatosis Protein, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Mitochondria, RNA, Viral
Show Abstract · Added December 11, 2019
Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.
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Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.
Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino-Rosano M, Sure VN, Yu S, Zhang R, Münzberg H, Jacobson DA, Katakam PV, Hodson DJ, Bernal-Mizrachi E, Zsombok A, Mauvais-Jarvis F
(2018) JCI Insight 3:
MeSH Terms: Androgens, Animals, Diabetes Mellitus, Type 2, Diet, Western, Dihydrotestosterone, Female, Glucose, Humans, Hyperinsulinism, Hypothalamus, Insulin Resistance, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Neurons, Receptors, Androgen, Streptozocin
Show Abstract · Added June 28, 2018
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic β cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in β cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in β cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic β cells, promoting insulin hypersecretion, oxidative injury, and secondary β cell failure.
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Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update.
Hulgan T
(2018) Curr HIV/AIDS Rep 15: 223-232
MeSH Terms: Adult, Anti-HIV Agents, HIV, HIV Infections, HIV Integrase Inhibitors, HIV Protease Inhibitors, Humans, Hyperglycemia, Inflammation, Insulin Resistance, Mitochondria, Obesity
Show Abstract · Added December 11, 2019
PURPOSE OF REVIEW - This narrative review summarizes recent data on factors associated with insulin resistance (IR) in adults with HIV, including contemporary antiretroviral therapy (ART).
RECENT FINDINGS - IR remains common in persons with HIV, even those receiving contemporary ART. Generalized and abdominal obesity and ectopic fat are correlates of IR, and emerging data have identified associations with biomarkers of inflammation and immune activation. Small studies suggest associations between mitochondria and IR. In ART-naïve individuals, IR increased within 4 weeks of starting ART in persons receiving contemporary boosted protease inhibitors or an integrase inhibitor. The importance of IR in non-diabetic persons with HIV will continue to grow as the population ages and obesity increases. Non-invasive estimates of IR appear to perform well in persons with HIV, but clinically relevant cutoffs are uncertain. Unexpected metabolic effects of newer HIV integrase inhibitors have been reported; thus, careful observation for and studies of IR are still warranted.
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Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling.
Ng VH, Hang BI, Sawyer LM, Neitzel LR, Crispi EE, Rose KL, Popay TM, Zhong A, Lee LA, Tansey WP, Huppert S, Lee E
(2018) J Cell Sci 131:
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis Regulatory Proteins, Cell Line, Glycogen Synthase Kinase 3, Humans, Intracellular Signaling Peptides and Proteins, Mitochondrial Proteins, Phosphorylation, Protein Binding, Threonine, Wnt Signaling Pathway, Wnt3A Protein, X-Linked Inhibitor of Apoptosis Protein, Xenopus
Show Abstract · Added July 6, 2018
X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in embryos. Although XIAP ubiquitylates TLE3 at wild-type levels , it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.
© 2018. Published by The Company of Biologists Ltd.
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Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase.
Chitambar CR, Al-Gizawiy MM, Alhajala HS, Pechman KR, Wereley JP, Wujek R, Clark PA, Kuo JS, Antholine WE, Schmainda KM
(2018) Mol Cancer Ther 17: 1240-1250
MeSH Terms: Animals, Antineoplastic Agents, Brain, Cell Line, Tumor, Disease Models, Animal, Glioblastoma, Heterografts, Humans, Immunohistochemistry, Iron, Male, Mitochondria, Organometallic Compounds, Pyrones, Rats, Receptors, Transferrin, Ribonucleoside Diphosphate Reductase, Ribonucleotide Reductases
Show Abstract · Added March 6, 2020
Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMEC) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSC) lines express TfRs, and that their growth is inhibited by gallium maltolate (GaM) After 24 hours of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). IHC staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2, and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control ( = 0.0159) and reduced tumor mitotic figures ( = 0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals, thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted. .
©2018 American Association for Cancer Research.
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