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Mitochondrial DNA Haplogroups and Delirium During Sepsis.
Samuels DC, Hulgan T, Fessel JP, Billings FT, Thompson JL, Chandrasekhar R, Girard TD
(2019) Crit Care Med 47: 1065-1071
MeSH Terms: Adult, African Americans, Critical Illness, DNA, Mitochondrial, European Continental Ancestry Group, Female, Haplotypes, Humans, Male, Middle Aged, Polymerase Chain Reaction, Retrospective Studies, Sepsis-Associated Encephalopathy, Sequence Analysis, DNA
Show Abstract · Added December 11, 2019
OBJECTIVES - Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.
DESIGN - Retrospective cohort study.
SETTING - Medical and surgical ICUs at a large tertiary care center.
PATIENTS - Caucasian and African American adults with sepsis.
MEASUREMENTS AND MAIN RESULTS - We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).
CONCLUSIONS - Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
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14 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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15 MeSH Terms
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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The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living With Human Immunodeficiency Virus.
Sun J, Brown TT, Samuels DC, Hulgan T, D'Souza G, Jamieson BD, Erlandson KM, Martinson J, Palella FJ, Margolick JB, Kirk GD, Schrack JA
(2018) Clin Infect Dis 67: 778-784
MeSH Terms: Age Factors, Aging, Body Composition, Cohort Studies, DNA, Mitochondrial, Genetic Variation, HIV Infections, Haplotypes, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Risk Factors, Sexual and Gender Minorities, Walking Speed
Show Abstract · Added March 21, 2018
Background - Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV.
Methods - Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models.
Results - A total of 455 HIV-positive white men aged ≥50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups.
Conclusions - Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.
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16 MeSH Terms
Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA.
Wauchope OR, Mitchener MM, Beavers WN, Galligan JJ, Camarillo JM, Sanders WD, Kingsley PJ, Shim HN, Blackwell T, Luong T, deCaestecker M, Fessel JP, Marnett LJ
(2018) Nucleic Acids Res 46: 3458-3467
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, DNA Adducts, DNA, Mitochondrial, Electron Transport, Endothelial Cells, Gene Expression Regulation, Humans, Hypertension, Pulmonary, Lipid Peroxidation, Mice, Mice, Transgenic, Mitochondria, Mutagenesis, Oxidants, Oxidative Stress, Purine Nucleosides, Reactive Oxygen Species, Superoxides
Show Abstract · Added March 14, 2018
Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.
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19 MeSH Terms
Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes.
Mitchell SL, Neininger AC, Bruce CN, Chocron IM, Bregman JA, Estopinal CB, Muhammad A, Umfress AC, Jarrell KL, Warden C, Harlow PA, Wellons M, Samuels DC, Brantley MA
(2017) Invest Ophthalmol Vis Sci 58: 6481-6488
MeSH Terms: Aged, Blood Glucose, Case-Control Studies, DNA, Mitochondrial, Diabetes Mellitus, Type 2, Diabetic Retinopathy, European Continental Ancestry Group, Female, Glycated Hemoglobin A, Haplotypes, Humans, Male, Mitochondria, Polymorphism, Single Nucleotide, Risk Factors, United States
Show Abstract · Added March 21, 2018
Purpose - We previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence.
Methods - Our population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal-Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups.
Results - Neither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK.
Conclusions - European mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control.
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16 MeSH Terms
Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.
Warren EB, Aicher AE, Fessel JP, Konradi C
(2017) PLoS One 12: e0190456
MeSH Terms: Animals, Cells, Cultured, Corpus Striatum, Creatine Kinase, DNA, Mitochondrial, Energy Metabolism, Ethidium, Glycolysis, Humans, Mitochondria, Oxygen Consumption, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 14, 2018
Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.
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13 MeSH Terms
Polymerase gamma in bipolar disorder: It's complicated.
Konradi C
(2017) Psychiatry Clin Neurosci 71: 507
MeSH Terms: Bipolar Disorder, DNA Polymerase gamma, DNA, Mitochondrial, Humans
Added March 14, 2018
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4 MeSH Terms
Estimating relative mitochondrial DNA copy number using high throughput sequencing data.
Zhang P, Lehmann BD, Samuels DC, Zhao S, Zhao YY, Shyr Y, Guo Y
(2017) Genomics 109: 457-462
MeSH Terms: Breast Neoplasms, Cell Line, Tumor, Computational Biology, DNA Copy Number Variations, DNA, Mitochondrial, Data Mining, Databases, Genetic, Female, Genes, Essential, High-Throughput Nucleotide Sequencing, Humans, Mitochondria, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA, Sequence Analysis, RNA, Whole Exome Sequencing
Show Abstract · Added March 21, 2018
We hypothesize that the relative mitochondria copy number (MTCN) can be estimated by comparing the abundance of mitochondrial DNA to nuclear DNA reads using high throughput sequencing data. To test this hypothesis, we examined relative MTCN across 13 breast cancer cell lines using the RT-PCR based NovaQUANT Human Mitochondrial to Nuclear DNA Ratio Kit as the gold standard. Six distinct computational approaches were used to estimate the relative MTCN in order to compare to the RT-PCR measurements. The results demonstrate that relative MTCN correlates well with the RT-PCR measurements using exome sequencing data, but not RNA-seq data. Through analysis of copy number variants (CNVs) in The Cancer Genome Atlas, we show that the two nuclear genes used in the NovaQUANT assay to represent the nuclear genome often experience CNVs in tumor cells, questioning the accuracy of this gold-standard method when it is applied to tumor cells.
Copyright © 2017 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment.
Mehta SR, Pérez-Santiago J, Hulgan T, Day TR, Barnholtz-Sloan J, Gittleman H, Letendre S, Ellis R, Heaton R, Patton S, Suben JD, Franklin D, Rosario D, Clifford DB, Collier AC, Marra CM, Gelman BB, McArthur J, McCutchan A, Morgello S, Simpson D, Connor J, Grant I, Kallianpur A
(2017) J Neuroinflammation 14: 72
MeSH Terms: AIDS Dementia Complex, Adult, Biomarkers, Cell-Free Nucleic Acids, Cohort Studies, Cross-Sectional Studies, DNA, Mitochondrial, Female, HIV, Humans, Iron, Male, Middle Aged, Viral Load, Virus Replication
Show Abstract · Added December 11, 2019
BACKGROUND - Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort.
METHODS - We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression.
RESULTS - CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment.
CONCLUSIONS - CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.
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