O-184 Maternally inherited differences in mitochondrial DNA genotype between ART and spontaneously conceived individuals associate with low birthweight

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Mertens ◽  
F Belva ◽  
A Van Montfoort ◽  
F Zambelli ◽  
S Seneca ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Low Birthweight ◽  
De Novo ◽  
Complex Data ◽  
Maternal Transmission ◽  
Menstrual Cycles ◽  
Increased Risk ◽  
Mtdna Variants ◽  
Lower Birthweight

Abstract Study question Can mitochondrial DNA (mtDNA) variants explain the differences in birthweight between ART and spontaneously conceived (SC) individuals and how do they originate? Summary answer Children born after ART carry more frequently a different mtDNA variant composition, both maternally inherited and de novo, which are predictive of their birthweight percentile. What is known already Children born after ART show an increased risk of lower birthweight and of developing a mild abnormal cardio-metabolic profile later in life. Variation in the mtDNA associates with overall health in the general population, including cardio-metabolic fitness, and can result in changes in mitochondrial function. We hypothesized that mitochondrial DNA variants could explain the differences in birthweight between ART and SC individuals and that these differences may result from maternal transmission and/or from the ovarian stimulation (OS) used in ART. Study design, size, duration We deep-sequenced the mtDNA of 472 individuals of who 283 ART and 189 SC, 182 mother-child pairs and 113 single oocytes from both natural menstrual cycles and OS cycles. The mtDNA was compared between groups and Fisher linear discriminant analysis was used as predictive model for the birthweight percentile. Participants/materials, setting, methods Mitochondrial DNA was enriched by long-range PCR and subsequently sequenced on an Illumina platform. mtDNA server and MuTect were used for variant calling for variants with a load higher than 1.5%, versus the reference NC_012920.1. An orthogonally rotated factor analysis was used to reduce the dimensionality of the studied dependent variables in the complex data of the heteroplasmic variants. Main results and the role of chance ART individuals carried more frequently haplogroup U4 (p = 0.004) and component analysis indicated that they carry a different mtDNA heteroplasmic variant composition than SC individuals (p = 0.01), driven by non-synonymous protein-coding and rRNA-coding variants. These differences were also predictive of the risk of a lower birthweight percentile, especially for the SC children, together with the absence of haplogroup T, the presence of homoplasmic tRNA-variants, pregnancy-induced hypertension and the embryo culture medium used. The differences in heteroplasmic variation observed in the ART children resulted from both maternal transmission (p = 0.03) and de novo mutagenesis (p = 0.02). Mothers of ART children showed a similar mtDNA genotype as their children and differed in the same variant composition when compared to the mothers of SC children (p = 0.03). Furthermore, the comparison of oocytes from the same donors retrieved in natural menstrual cycles and after one OS cycle showed that OS does not increase de novo mutagenesis. Additionally, clinical parameters such as the total dosage of FSH units, the number of oocytes retrieved, and maternal age did not show any correlation with the differences observed in ART individuals. Limitations, reasons for caution This study is observational with no functional tests being performed. Wider implications of the findings We demonstrate an association between a lower birthweight percentile and a mtDNA variant composition which is more frequently carried by ART children. These non-disease associated mtDNA variants could cause a suboptimal mitochondrial function affecting the birthweight. Long-term health consequences of these differences remain to be further elucidated. Trial registration number Not applicable

scholarly journals De Novo Mutation of m.3243A>G together with m.16093T>C Associated with Atypical Clinical Features in a Pedigree with MIDD Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Zhixin Jiang ◽  
Yinan Zhang ◽  
Jingbin Yan ◽  
Fengwen Li ◽  
Xinqian Geng ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Clinical Features ◽  
Mitochondrial Function ◽  
Peripheral Blood ◽  
De Novo ◽  
Brain Mri ◽  
De Novo Mutation ◽  
Function Evaluation ◽  
Ros Generation ◽  
Spontaneous Mutant

Background. The syndrome of maternally inherited diabetes and deafness (MIDD) is typically caused by the m.3243A>G mutation and widely considered maternally inherited. In our study, we aimed to investigate the heredity way of the m.3243A>G among pedigrees with MIDD and discover novel mitochondrial DNA mutations related to atypical clinical phenotypes.Methods. Heteroplasmy levels of the m.3243A>G mutation in peripheral blood, saliva, and urine sediment of 31 individuals from 10 unrelated pedigrees were measured by pyrosequencing. Clinical evaluations including endocrinological, audiological, and magnetic resonance imaging (MRI) examinations, mitochondrial function evaluation in peripheral blood mononuclear cells (PBMCs), and whole mitochondrial DNA (mtDNA) sequencing were performed among the spontaneous mutant pedigrees.Results. Among the 10 unrelated MIDD pedigrees, we found that the de novo m.3243A>G mutation occurred in the family 1957 (F1957). The proband (F1957-II-1) and her son (F1957-III-1) both manifested diabetes with mild bilateral sensorineural hearing loss (SNHL) and abnormal brain MRI, and F1957-III-1 also complained of severe nausea and vomiting. Mitochondrial function evaluation in PBMCs revealed an increased level of ROS generation and decreased levels of ATP and mitochondrial membrane potential (ΔΨm) in the two m.3243A>G carriers. Whole mtDNA sequencing also revealed a de novo heteroplasmic substitution at m.16093T>C in both the proband and her son.Conclusions. Our study showed that de novo m.3243A>G mutation accompanied by other point mutations may occur in the very early embryonic or germ cell stage without maternal inheritance, bringing about both typical and atypical clinical features.

scholarly journals EPID-10. MITOCHONDRIAL DNA SEQUENCE VARIATION AND RISK OF GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii80-ii80
Author(s):  
Claudine Samanic ◽  
Jamie Teer ◽  
Zachary Thompson ◽  
Jordan Creed ◽  
Louis Nabors ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Adult Brain ◽  
European Ancestry ◽  
Inverse Association ◽  
Increased Risk ◽  
Mtdna Sequence ◽  
The Us ◽  
Glioma Risk ◽  
The Uk ◽  
Mtdna Variants

Abstract Malignant gliomas are the most common primary adult brain tumors, with poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, but research on glioma is lacking. We examined the association of germline mtDNA variants and haplogroups with glioma risk in 1,654 glioma cases and 1,065 controls from a US case-control study, and 427 glioma cases and 1,541 controls from the UK Biobank, all genotyped using the UKBiobank array with 276 tiled mtDNA variants. The analysis was restricted to participants of European ancestry, and risk of glioblastoma (GBM) and lower grade glioma (LGG) was examined separately. Distribution of mitochondrial haplogroups (H/HV,I,J,K,R,T,U,V,W,X) were similar in both study populations, with 46.4% and 48.1% of controls in the US and UK studies respectively, identified as H/HV, the most common haplogroup. In the US study there was an inverse association between haplogroup W and glioma (OR=0.43, 95%CI: 0.23–0.79) when compared with the H/HV haplogroup, which was not seen in the UK study (OR=1.10, 95%CI: 0.49–2.49). In the US study, a significant inverse association was observed with the previously reported mtDNA variant m.14798T > C (PMID: 31323957), resulting in the amino acid substitution F18L, for LGG (OR=0.73; 95%CI: 0.53–0.99) though not for GBM (OR=0.86; 95%CI: 0.66–1.11). In the UK study, the F18L substitution was associated with an increased risk of GBM (OR=1.48; 95%CI: 1.07–2.04), and no association was observed for LGG (OR=0.95; 95%CI: 0.53–1.68). Among cases in the US study with isocitrate dehydrogenase 1 (IDH1) status available (747 gliomas), a nonsignificant inverse association of the F18L substitution was observed in glioma cases with wild type (OR=0.72; 95%CI: 0.52–1.01) but not mutant (OR=1.08; 95%CI: 0.70–1.69) IDH1. No other common mtDNA variant (minor allele > 5%) was associated with glioma risk in either study. These associations merit further study.

scholarly journals Chasing a moving target: Detection of mitochondrial heteroplasmy for clinical diagnostics

2017 ◽  
Author(s):  
Eric J. White ◽  
Tristen Ross ◽  
Edgardo Lopez ◽  
Anastasia Nikiforov ◽  
Christopher Gault ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
De Novo ◽  
Clinical Diagnostics ◽  
The Body ◽  
Sequencing Data ◽  
Simple Method ◽  
Large Deletions ◽  
Mucosal Cells ◽  
Mtdna Variants

AbstractClinical interpretation of human mitochondrial DNA (mtDNA) variants has been challenging for technical and biological reasons but the involvement of dysfunctional mitochondria in many diseases makes it imperative to have a validated assay for detecting pathogenic variants. We have tested several methods to identify those best suited to detect and confirm mtDNA variants. The choice of methods is dependent on the amount of DNA available for testing and the sensitivity required for detecting low-level heteroplasmies. There is a tradeoff between a polymerase’s ability to amplify small amounts of DNA and its ability to generate accurate sequence. We report a simple method to measure heteroplasmy levels of large deletions from NGS data alone without need for qPCR or other methods. Use of HapMap samples for standardization needs to be done with caution as most have novel heteroplasmic sites that have arisen during immortalization/cell culture processes. Different batches of DNA can have variable sequence. In contrast, we observed no de novo heteroplasmies in healthy mother-child pairs studied using blood or saliva though the frequency of pre-existing heteroplasmies often changed dramatically across generations. Long-read nanopore sequencing of individuals with two heteroplasmies suggested a random distribution of variants on single molecules but technical artifacts prevent certainty on this finding. Urine provides an additional readily accessible source of mtDNA that can be used for bone marrow transplant recipients whose saliva/blood mtDNA may be contaminated by the BMT donor’s mtDNA. We have characterized cells suspended in urine via expression profiling and shown them to be primarily mucosal cells that are independent of blood. Understanding the pitfalls of the various mtDNA sequencing methods allows development of reliable and accurate tests suitable for clinical diagnostics.Author SummaryMitochondrial DNA is important for many diseases but it is present at many copies per cell so is harder to check for mutations compared to nuclear DNA. We have studied mitochondrial DNA in different ways to see how it changes across generations and in different locations in the body. The tests need to be much more sensitive than nuclear DNA tests so that we can detect mutations down to 1%. We have shown that mitochondrial DNA changes when cell lines are used but saliva, blood and cells in the urine can all be used for testing. Cells in the urine originate as mucosal cells and are independent of blood. We developed a new method for analyzing large deletions that means sequencing data alone can be used for measuring the frequency of deletions. We also followed a family with two variable sites to better understand how mitochondrial DNA changes from mother to child. In some children, the variants stayed the same while, in others, variants disappeared.

Leber Hereditary Optic Neuropathy - Idebenone, Hope of Treatment

2020 ◽  
Vol 70 (12) ◽  
pp. 4244-4247
Keyword(s):  
Mitochondrial Dna ◽  
Visual Field ◽  
Optic Neuropathy ◽  
Mitochondrial Function ◽  
Dna Analysis ◽  
Central Vision ◽  
Leber Hereditary Optic Neuropathy ◽  
Mitochondrial Dna Analysis ◽  
Hereditary Optic Neuropathy

Leber hereditary optical neuropathy (LHON) is part of the class of optic neuropathies in which the mitochondrial function is impaired and is characterized by a painless, subacute, bilateral decrease of the central vision. We shall present the case of two brothers AM aged 31 and AT aged 40 who were diagnosed with LHON and whom we initiated treatment with idebenone 900 mg / day with monitoring at one month and 6 months. The mitochondrial DNA analysis demonstrated the existence of mutations 11778G>A for the mtND4 gene in both patients. Idebenone is a synthetic benzoquinone, analogue of ubiquinone. We found a slight but significant improvement in the visual field in patient AM at one month of treatment. We have not found another case in the literature with an improvement in vision so fast after this treatment, and this has led us to write this article. Keywords: Leber hereditary optical neuropathy (LHON), idebenone, mutations 11778G>A, mtND4 gene

scholarly journals Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity

2021 ◽  
Author(s):  
Hans-Georg Sprenger ◽  
Thomas MacVicar ◽  
Amir Bahat ◽  
Kai Uwe Fiedler ◽  
Steffen Hermans ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cultured Cells ◽  
De Novo ◽  
Metabolic Response ◽  
Interferon Response ◽  
Type I ◽  
Nucleotide Synthesis ◽  
Pyrimidine Synthesis ◽  
Pyrimidine Nucleotide ◽  
De Novo Pyrimidine Synthesis

AbstractCytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

scholarly journals Adolescent, Pregnant, and HIV-Infected: Risk of Adverse Pregnancy and Perinatal Outcomes in Young Women from Southern Mozambique

2021 ◽  
Vol 10 (8) ◽  
pp. 1564
Author(s):  
Clara Pons-Duran ◽  
Aina Casellas ◽  
Azucena Bardají ◽  
Anifa Valá ◽  
Esperança Sevene ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Maternal Morbidity ◽  
Low Birthweight ◽  
Negative Binomial ◽  
Perinatal Outcomes ◽  
Sub Saharan Africa ◽  
P Value ◽  
Increased Risk ◽  
Adverse Pregnancy ◽  
The Impact

Sub-Saharan Africa concentrates the burden of HIV and the highest adolescent fertility rates. However, there is limited information about the impact of the interaction between adolescence and HIV infection on maternal health in the region. Data collected prospectively from three clinical trials conducted between 2003 and 2014 were analysed to evaluate the association between age, HIV infection, and their interaction, with the risk of maternal morbidity and adverse pregnancy and perinatal outcomes in women from southern Mozambique. Logistic regression and negative binomial models were used. A total of 2352 women were included in the analyses; 31% were adolescents (≤19 years) and 29% HIV-infected women. The effect of age on maternal morbidity and pregnancy and perinatal adverse outcomes was not modified by HIV status. Adolescence was associated with an increased incidence of hospital admissions (IRR 0.55, 95%CI 0.37–0.80 for women 20–24 years; IRR 0.60, 95%CI 0.42–0.85 for women >25 years compared to adolescents; p-value < 0.01) and outpatient visits (IRR 0.86, 95%CI 0.71–1.04; IRR 0.76, 95%CI 0.63–0.92; p-value = 0.02), and an increased likelihood of having a small-for-gestational age newborn (OR 0.50, 95%CI 0.38–0.65; OR 0.43, 95%CI 0.34–0.56; p-value < 0.001), a low birthweight (OR 0.40, 95%CI 0.27–0.59; OR 0.37, 95%CI 0.26–0.53; p-value <0.001) and a premature birth (OR 0.42, 95%CI 0.24–0.72; OR 0.51, 95%CI 0.32–0.82; p-value < 0.01). Adolescence was associated with an increased risk of poor morbidity, pregnancy and perinatal outcomes, irrespective of HIV infection. In addition to provision of a specific maternity care package for this vulnerable group interventions are imperative to prevent adolescent pregnancy.

scholarly journals Inhibition of Kynurenine Metabolism and Its Effect in Mitochondrial Function in Hepatocellular Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 124-125
Author(s):  
Raul Castro-Portuguez ◽  
Samuel Freitas ◽  
George Sutphin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitochondrial Function ◽  
De Novo ◽  
Principal Component ◽  
Kynurenine Pathway ◽  
The Cancer Genome Atlas ◽  
Wilcoxon Test ◽  
Nad Synthesis ◽  
Significant Difference ◽  
Kynurenine Metabolism

Abstract Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingested tryptophan is processed in the liver through the kynurenine pathway, the endpoint of which is de novo NAD+ biosynthesis. Dysregulation of tryptophan-kynurenine metabolism and NAD+ synthesis may promote mitochondrial malfunction, tumor reprogramming, and carcinogenesis. Using a publicly available gene expression dataset from liver hepatocellular carcinoma (LIHC) samples available through The Cancer Genome Atlas (TCGA; n = 371), we employed Principal Component Analysis (PCA), hierarchical clustering, gene-pattern expression profiling, and survival analysis to cluster patients and determine overall survival. Our analysis of genes encoding kynurenine pathway enzymes determined that patients with high QPRT expression had a poor prognosis with decreased median survival, with no effect on the maximum survival. There is a significant difference in the survival between patients with high QPRT expression relative to patients with high HAAO/AFMID expression (HR = 1.2, [95% CI 0.5-1.8] P = 0.0181, Gehan-Breslow-Wilcoxon Test). Patients with high QPRT expression have higher survival rates compared with low QPRT expression (HR = 1.4, [95% CI 0.9-2.2] P = 0.0344, Gehan-Breslow-Wilcoxon Test). To test the consequences of kynurenine-pathway inhibition in mitochondrial function and morphology we use 4-Cl-3HAA, an irreversible HAAO inhibitor, and observed a small increase in mitochondrial fragmentation in HepG2 cells after 24 hours of treatment. We conclude that kynurenine metabolism may be useful as a biomarker to predict patient prognosis among HCC patients. In ongoing work, we are testing QPRT inhibitors in cell culture as a potential adjuvant for chemotherapies.

scholarly journals Ultra-Small Iron Nanoparticles Target Mitochondria Inducing Autophagy, Acting on Mitochondrial DNA and Reducing Respiration

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 90
Author(s):  
Lorenzo Rivas-García ◽  
José Luis Quiles ◽  
Alfonso Varela-López ◽  
Francesca Giampieri ◽  
Maurizio Battino ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Metallic Nanoparticles ◽  
Iron Nanoparticles ◽  
Therapeutic Tool ◽  
Mitochondrial Dysfunctions ◽  
Colorectal Cell ◽  
Autophagic Process ◽  
Ht 29 ◽  
Potential Use

The application of metallic nanoparticles (materials with size at least in one dimension ranging from 1 to 100 nm) as a new therapeutic tool will improve the diagnosis and treatment of diseases. The mitochondria could be a therapeutic target to treat pathologies whose origin lies in mitochondrial dysfunctions or whose progression is dependent on mitochondrial function. We aimed to study the subcellular distribution of 2–4 nm iron nanoparticles and its effect on mitochondrial DNA (mtDNA), mitochondrial function, and autophagy in colorectal cell lines (HT-29). Results showed that when cells were exposed to ultra-small iron nanoparticles, their subcellular fate was mainly mitochondria, affecting its respiratory and glycolytic parameters, inducing the migration of the cellular state towards quiescence, and promoting and triggering the autophagic process. These effects support the potential use of nanoparticles as therapeutic agents using mitochondria as a target for cancer and other treatments for mitochondria-dependent pathologies.

Sign in / Sign up

Export Citation Format

Share Document