scholarly journals Health Outcomes at School Age among Children Who Are HIV-Exposed but Uninfected with Detected Mitochondrial DNA Depletion at One Year

2020 ◽  
Vol 9 (11) ◽  
pp. 3680
Author(s):  
Audrey Monnin ◽  
Nicolas Nagot ◽  
Sabrina Eymard-Duvernay ◽  
Nicolas Meda ◽  
James K. Tumwine ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Hiv Transmission ◽  
Mtdna Depletion ◽  
Prophylactic Drugs ◽  
Mitochondrial Dna Depletion ◽  
Immunodeficiency Virus ◽  
Short And Long Term ◽  
Neuropsychological Outcomes ◽  
Hiv Exposed ◽  
One Year

Infant antiretroviral (ARV) prophylaxis given to children who are human immunodeficiency virus (HIV)-exposed but uninfected (CHEU) to prevent HIV transmission through breastfeeding previously proved its efficacy in the fight against the pediatric epidemic. However, few studies have investigated the short- and long-term safety of prophylactic regimens. We previously reported a decrease of mitochondrial DNA (mtDNA) content among CHEU who received one year of lamivudine (3TC) or lopinavir-boosted ritonavir (LPV/r) as infant prophylaxis. We aimed to describe mtDNA content at six years of age among these CHEU, including those for whom we identified mtDNA depletion at week 50 (decrease superior or equal to 50% from baseline), and to compare the two prophylactic drugs. We also addressed the association between mtDNA depletion at week 50 with growth, clinical, and neuropsychological outcomes at year 6. Quantitative PCR was used to measure mtDNA content in whole blood of CHEU seven days after birth, at week 50, and at year 6. Among CHEU with identified mtDNA depletion at week 50 (n = 17), only one had a persistent mtDNA content decrease at year 6. No difference between prophylactic drugs was observed. mtDNA depletion was not associated with growth, clinical, or neuropsychological outcomes at year 6. This study brought reassuring data concerning the safety of infant 3TC or LPV/r prophylaxis.

scholarly journals Mitochondrial DNA Parameters in Blood of Infants Receiving Lopinavir/Ritonavir or Lamivudine Prophylaxis to Prevent Breastfeeding Transmission of HIV-1

2020 ◽  
Vol 9 (9) ◽  
pp. 2972 ◽  
Author(s):  
Audrey Monnin ◽  
Nicolas Nagot ◽  
Marianne Periès ◽  
Roselyne Vallo ◽  
Nicolas Meda ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Control Group ◽  
First Year ◽  
Mtdna Depletion ◽  
Immunodeficiency Virus ◽  
Maternal Hiv ◽  
Lamivudine Prophylaxis ◽  
Hiv Exposed ◽  
Exposure Prophylaxis ◽  
First Year Of Life

Children who are human immunodeficiency virus (HIV)-exposed but uninfected (CHEU) accumulate maternal HIV and antiretroviral exposures through pregnancy, postnatal prophylaxis, and breastfeeding. Here, we compared the dynamics of mitochondrial DNA (mtDNA) parameters in African breastfed CHEU receiving lopinavir/ritonavir (LPV/r) or lamivudine (3TC) pre-exposure prophylaxis during the first year of life. The number of mtDNA copies per cell (MCN) and the proportion of deleted mtDNA (MDD) were assessed at day 7 and at week 50 post-delivery (PrEP group). mtDNA depletion was defined as a 50% or more decrease from the initial value, and mtDNA deletions was the detection of mtDNA molecules with large DNA fragment loss. We also performed a sub-analysis with CHEU who did not receive a prophylactic treatment in South Africa (control group). From day seven to week 50, MCN decreased with a median of 41.7% (interquartile range, IQR: 12.1; 64.4) in the PrEP group. The proportion of children with mtDNA depletion was not significantly different between the two prophylactic regimens. Poisson regressions showed that LPV/r and 3TC were associated with mtDNA depletion (reference: control group; LPV/r: PR = 1.75 (CI95%: 1.15–2.68), p < 0.01; 3TC: PR = 1.54 (CI95%: 1.00–2.37), p = 0.05). Moreover, the proportion of children with MDD was unexpectedly high before randomisation in both groups. Long-term health impacts of these mitochondrial DNA parameters should be investigated further for both CHEU and HIV-infected children receiving LPV/r- or 3TC- based regimens.

scholarly journals Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Liya Wang ◽  
Ren Sun ◽  
Staffan Eriksson
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Biochemical Characterization ◽  
Basic Knowledge ◽  
Rat Tissues ◽  
Nucleotide Synthesis ◽  
Tissue Specific ◽  
Mtdna Depletion ◽  
Adult Rat ◽  
Mitochondrial Dna Depletion

Abstract Background Deficiency in thymidine kinase 2 (TK2) or p53 inducible ribonucleotide reductase small subunit (p53R2) is associated with tissue specific mitochondrial DNA (mtDNA) depletion. To understand the mechanisms of the tissue specific mtDNA depletion we systematically studied key enzymes in dTMP synthesis in mitochondrial and cytosolic extracts prepared from adult rat tissues. Results In addition to mitochondrial TK2 a cytosolic isoform of TK2 was characterized, which showed similar substrate specificity to the mitochondrial TK2. Total TK activity was highest in spleen and lowest in skeletal muscle. Thymidylate synthase (TS) was detected in cytosols and its activity was high in spleen but low in other tissues. TS protein levels were high in heart, brain and skeletal muscle, which deviated from TS activity levels. The p53R2 proteins were at similar levels in all tissues except liver where it was ~ 6-fold lower. Our results strongly indicate that mitochondria in most tissues are capable of producing enough dTTP for mtDNA replication via mitochondrial TK2, but skeletal muscle mitochondria do not and are most likely dependent on both the salvage and de novo synthesis pathways. Conclusion These results provide important information concerning mechanisms for the tissue dependent variation of dTTP synthesis and explained why deficiency in TK2 or p53R2 leads to skeletal muscle dysfunctions. Furthermore, the presence of a putative cytosolic TK2-like enzyme may provide basic knowledge for the understanding of deoxynucleoside-based therapy for mitochondrial disorders.

scholarly journals Quantitative Evaluation of the Mitochondrial DNA Depletion Syndrome

2010 ◽  
Vol 56 (7) ◽  
pp. 1119-1127 ◽  
Author(s):  
David Dimmock ◽  
Lin-Ya Tang ◽  
Eric S Schmitt ◽  
Lee-Jun C Wong
Keyword(s):  
Mitochondrial Dna ◽  
Real Time ◽  
Muscle Tissue ◽  
Skin Fibroblasts ◽  
Rapid Screening ◽  
Simple Method ◽  
Blood Samples ◽  
Mtdna Depletion ◽  
Coa Ligase ◽  
Mitochondrial Dna Depletion

Abstract Background: The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a reduction in cellular mtDNA content. Mutations in at least 9 genes [POLG, polymerase (DNA directed), gamma; DGUOK, deoxyguanosine kinase; TK2, thymidine kinase, mitochondrial; TYMP, thymidine phosphorylase; MPV17, MpV17 mitochondrial inner membrane protein; SUCLA2, succinate-CoA ligase, ADP-forming, beta subunit; SUCLG1, succinate-CoA ligase, alpha subunit; RRM2B, RRM2B, ribonucleotide reductase M2 B (TP53 inducible); and C10orf2, chromosome 10 open reading frame 2 (also known as TWINKLE)] have been reported to cause mtDNA depletion. In the clinical setting, a simple method to quantify mtDNA depletion would be useful before undertaking gene sequence analysis. Methods: Real-time quantitative PCR (qPCR) was used to measure the mtDNA content in blood, muscle, and liver samples and in skin fibroblast cultures from individuals suspected of mitochondrial disorders, with or without deleterious mutations in genes responsible for MDDS. Results: The mtDNA content was quantified in 776 tissue samples (blood, n = 341; muscle, n = 325; liver, n = 63; skin fibroblasts, n = 47) from control individuals. mtDNA content increased with age in muscle tissue, decreased with age in blood samples, and appeared to be unaffected by age in liver samples. In 165 samples (blood, n = 122; muscle, n = 21; liver, n = 15; skin fibroblasts, n = 7) from patients with molecularly proven MDDSs, severe mtDNA depletion was detected in liver and muscle tissue with high specificity and sensitivity. Blood samples were specific but not sensitive for detecting mtDNA depletion, and skin fibroblasts were not valuable for evaluating mtDNA depletion. Mutations in the POLG, RRM2B, and MPV17 genes were prospectively identified in 1 blood, 1 liver, and 3 muscle samples. Conclusions: Muscle and liver tissues, but not blood or skin fibroblasts, are potentially useful for rapid screening for mtDNA depletion with real-time qPCR.

scholarly journals Mitochondrial DNA Depletion Reduces PARP-1 Levels and Promotes Progression of the Neoplastic Phenotype in Prostate Carcinoma

2008 ◽  
Vol 30 (4) ◽  
pp. 307-322
Author(s):  
Loredana Moro ◽  
Arnaldo A. Arbini ◽  
Ersilia Marra ◽  
Margherita Greco
Keyword(s):  
Mitochondrial Dna ◽  
Cancer Progression ◽  
Prostate Carcinoma ◽  
Lncap Cells ◽  
Mtdna Depletion ◽  
Mtdna Mutations ◽  
Mitochondrial Dna Depletion ◽  
Parp 1 ◽  
Laminin 1 ◽  
Androgen Independent

Mitochondrial dysfunction resulting from mitochondrial DNA (mtDNA) mutations and/or depletion has been correlated with cancer progression and drug resistance. To investigate the role of mtDNA in prostate cancer progression, we used LNCaP and PC-3 prostate carcinoma cells as experimental model. Compared to minimally invasive androgen-dependent LNCaP cells, highly invasive androgen-independent PC-3 cells, as well as androgen-independent DU145 and C4-2 cells, exhibited significantly reduced mtDNA content. In PC-3 cells, reduction of mtDNA was accompanied by decreased mitochondrial membrane potential (Δ&Psi;m), increased migration onto the basement membrane protein laminin-1, reduced chemosensitivity to paclitaxel (IC50=110 nM vs. 22 nM) and decreased expression of poly(ADP-ribose) polymerase (PARP)-1. To investigate the relationship between mtDNA depletion and these phenotypic characteristics, we established mtDNA-depleted LNCaP cells [Rho(−)] by long-term exposure to ethidium bromide or treated wild-type LNCaP cells with a mitochondrial ionophore, carbonyl cyanide m-chlorophenylhydrazone. Both manipulations resulted in Δ&Psi;m loss, acquisition of invasive cytology, increased motility onto laminin-1, reduced sensitivity to paclitaxel (IC50=~100 nM) and ~75% reduction in PARP-1 protein levels, resembling PC-3 cells. Overall, these results provide novel evidence demonstrating that mtDNA depletion in early prostate carcinoma may contribute to the acquisition of a more invasive phenotype that is less sensitive to paclitaxel-induced apoptosis.

scholarly journals Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants

2019 ◽  
Vol 222 (4) ◽  
pp. 628-636 ◽  
Author(s):  
Coleen K Cunningham ◽  
Elizabeth J McFarland ◽  
R Leavitt Morrison ◽  
Edmund V Capparelli ◽  
Jeffrey T Safrit ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Dose Group ◽  
Hiv Transmission ◽  
The United States ◽  
Young Infants ◽  
Immunodeficiency Virus ◽  
Group 3 ◽  
Local Reactions ◽  
Hiv Exposed

Abstract Background Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission. Methods A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis. Results Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1–6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding. Conclusions Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.

scholarly journals Mortality, Human Immunodeficiency Virus (HIV) Transmission, and Growth in Children Exposed to HIV in Rural Zimbabwe

2020 ◽  
Author(s):  
Ceri Evans ◽  
Bernard Chasekwa ◽  
Robert Ntozini ◽  
Florence D Majo ◽  
Kuda Mutasa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Transmission ◽  
Infant Nutrition ◽  
Sub Saharan Africa ◽  
Absolute Difference ◽  
Child Feeding ◽  
Young Child Feeding ◽  
Immunodeficiency Virus ◽  
Sub Saharan ◽  
Hiv Exposed

Abstract Background Clinical outcomes of children who are human immunodeficiency virus (HIV)–exposed in sub-Saharan Africa remain uncertain. Methods The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial evaluated improved infant and young child feeding (IYCF) and/or improved water, sanitation, and hygiene in 2 rural Zimbabwean districts with 15% antenatal HIV prevalence and &gt; 80% prevention of mother-to-child transmission (PMTCT) coverage. Children born between February 2013 and December 2015 had longitudinal HIV testing and anthropometry. We compared mortality and growth between children who were HIV-exposed and HIV-unexposed through 18 months. Children receiving IYCF were excluded from growth analyses. Results Fifty-one of 738 (7%) children who were HIV-exposed and 198 of 3989 (5%) children who were HIV-unexposed (CHU) died (hazard ratio, 1.41 [95% confidence interval {CI}, 1.02–1.93]). Twenty-five (3%) children who were HIV-exposed tested HIV positive, 596 (81%) were HIV-exposed uninfected (CHEU), and 117 (16%) had unknown HIV status by 18 months; overall transmission estimates were 4.3%–7.7%. Mean length-for-age z score at 18 months was 0.38 (95% CI, .24–.51) standard deviations lower among CHEU compared to CHU. Among 367 children exposed to HIV in non-IYCF arms, 147 (40%) were alive, HIV-free, and nonstunted at 18 months, compared to 1169 of 1956 (60%) CHU (absolute difference, 20% [95% CI, 15%–26%]). Conclusions In rural Zimbabwe, mortality remains 40% higher among children exposed to HIV, vertical transmission exceeds elimination targets, and half of CHEU are stunted. We propose the composite outcome of “alive, HIV free, and thriving” as the long-term goal of PMTCT programs. Clinical Trials Registration NCT01824940.

scholarly journals Mitochondrial DNA Depletion in Granulosa Cell Derived Nuclear Transfer Tissues

2021 ◽  
Vol 9 ◽  
Author(s):  
Daniela Bebbere ◽  
Susanne E. Ulbrich ◽  
Katrin Giller ◽  
Valeri Zakhartchenko ◽  
Horst-Dieter Reichenbach ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Transfer ◽  
Bos Taurus ◽  
Donor Cell ◽  
Farm Animals ◽  
Nuclear Reprogramming ◽  
Mtdna Depletion ◽  
Mitochondrial Dna Depletion

Somatic cell nuclear transfer (SCNT) is a key technology with broad applications that range from production of cloned farm animals to derivation of patient-matched stem cells or production of humanized animal organs for xenotransplantation. However, effects of aberrant epigenetic reprogramming on gene expression compromise cell and organ phenotype, resulting in low success rate of SCNT. Standard SCNT procedures include enucleation of recipient oocytes before the nuclear donor cell is introduced. Enucleation removes not only the spindle apparatus and chromosomes of the oocyte but also the perinuclear, mitochondria rich, ooplasm. Here, we use a Bos taurus SCNT model with in vitro fertilized (IVF) and in vivo conceived controls to demonstrate a ∼50% reduction in mitochondrial DNA (mtDNA) in the liver and skeletal muscle, but not the brain, of SCNT fetuses at day 80 of gestation. In the muscle, we also observed significantly reduced transcript abundances of mtDNA-encoded subunits of the respiratory chain. Importantly, mtDNA content and mtDNA transcript abundances correlate with hepatomegaly and muscle hypertrophy of SCNT fetuses. Expression of selected nuclear-encoded genes pivotal for mtDNA replication was similar to controls, arguing against an indirect epigenetic nuclear reprogramming effect on mtDNA amount. We conclude that mtDNA depletion is a major signature of perturbations after SCNT. We further propose that mitochondrial perturbation in interaction with incomplete nuclear reprogramming drives abnormal epigenetic features and correlated phenotypes, a concept supported by previously reported effects of mtDNA depletion on the epigenome and the pleiotropic phenotypic effects of mtDNA depletion in humans. This provides a novel perspective on the reprogramming process and opens new avenues to improve SCNT protocols for healthy embryo and tissue development.

scholarly journals Mitochondrial DNA Content, an Inaccurate Biomarker of Mitochondrial Alteration in Human Immunodeficiency Virus-Related Lipodystrophy

2008 ◽  
Vol 52 (5) ◽  
pp. 1670-1676 ◽  
Author(s):  
Min Ji Kim ◽  
Claude Jardel ◽  
Cyrille Barthélémy ◽  
Véronique Jan ◽  
Jean Philippe Bastard ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Immunodeficiency Virus ◽  
Mitochondrial Dna ◽  
Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Nuclear Dna ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mtdna Depletion ◽  
Immunodeficiency Virus ◽  
Mitochondrial Alteration

ABSTRACT Lipoatrophy is a prevalent side effect of antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its mechanisms are still disputed but include mitochondrial toxicity and, in particular, mitochondrial DNA (mtDNA) depletion induced by nucleoside reverse transcriptase inhibitors. To obtain an integrated evaluation of the mitochondrial alteration in lipoatrophy, we investigated the DNA, RNA, and protein levels in 15 samples of abdominal subcutaneous adipose tissue from HIV-infected patients with peripheral lipoatrophy and compared the results with those for 15 samples from age- and body mass index-matched controls. The DNA and RNA analyses used PCR-based techniques, while proteins were quantified with enzyme-linked immunosorbent assay and measurement of activities with spectrophotometric assays. Depletion of mtDNA and mtDNA-encoded MT-CO2 mRNA was present, but normal levels of mtDNA-dependent activity (cytochrome c oxidase) and protein (MT-CO2p) showed that it was compensated for. An increase in nuclear-DNA-dependent mitochondrial activities (citrate synthase and malate dehydrogenase) and protein (COX4I1p), as well as transcriptional up-regulation of nuclear-DNA-encoded mitochondrial genes (COX4I1 and UCP2), demonstrated increased mitochondrial biogenesis. However, the expression of the known transcription factors of mitochondrial biogenesis (TFAM, NRF1, GABPA, PPARGC1A, PPARGC1B, and PPRC1) was normal or decreased. Increased amounts of activated caspase 3 and of DDIT3 mRNA showed the induction of apoptosis and oxidative stress, respectively. The mtDNA content did not correlate with any other mitochondrial parameter. In conclusion, mtDNA content does not appear to be an accurate biomarker of mitochondrial alteration in lipoatrophic adipose tissue. The preservation of mtDNA-dependent mitochondrial functions occurred despite severe mtDNA depletion. The presence of significant oxidative stress and apoptosis did not correlate with the mtDNA content.

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