Ontology highlight
ABSTRACT:
PROVIDER: PRJNA639707 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12021200_1.fastq.gz | Fastqsanger.gz | |||
| SRR12021200_2.fastq.gz | Fastqsanger.gz | |||
| SRR12021201_1.fastq.gz | Fastqsanger.gz | |||
| SRR12021201_2.fastq.gz | Fastqsanger.gz | |||
| SRR12021202_1.fastq.gz | Fastqsanger.gz |
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Project description:Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant
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Project description:Maternal inheritance of mitochondrial DNA (mtDNA) is highly conserved in metazoans. While many species eliminate paternal mtDNA during late sperm development to foster maternal inheritance, the regulatory mechanisms governing this process remain elusive. Through a large-scale genetic screen in Drosophila, we identified 47 mutant lines exhibiting substantial retention of mtDNA in mature sperm. We mapped one line to Poldip2, a gene predominantly expressed in the testis. Disruption of Poldip2 led to pronounced mtDNA retention in mature sperm and subsequent paternal transmission to progeny. Further investigation via imaging, biochemical analyses and ChIP assays revealed that POLDIP2 is a mitochondrial matrix protein capable of binding to mtDNA. Moreover, we uncovered that CLPX, a key component of the major mitochondrial protease, binds to POLDIP2 to co-regulate mtDNA elimination in Drosophila spermatids. This study shed light on the mechanisms underlying mtDNA removal during spermatogenesis, underscoring the pivotal role of this process in safeguarding maternal inheritance.
2024-06-04 | E-MTAB-14100 | biostudies-arrayexpress
Project description:This study aimed to evaluate single nucleotide substitutions in mtDNA and analyze their correlation with inflammatory biomarkers in elderly COVID-19 patients. A total of 30 COVID-19 patients and 33 older adult controls (aged over 65 years) were enrolled. mtDNA was extracted from buffy coat samples and sequenced using a chip-based resequencing system (Affymetrix MitoChip v2.0) which detects both homoplasmic and heteroplasmic mtDNA mutations, and allows the assessment of low-level heteroplasmy. Serum concentration of IL-6, IFN-α, TNF-α and IL-10 were determined in patients by a high-sensitivity immunoassay. We found a higher burden of total heteroplasmic mutation in COVID-19 patients compared to controls with a selective increment in ND1 and COIII genes. Low-level heteroplasmy was significantly elevated in COVID-19 patients, especially in genes of the respiratory complex I. Both heteroplasmic mutation burden and low-level heteroplasmy were associated with increased levels of IL-6, TNF-α, and IFN-α.
2024-01-23 | GSE235626 | GEO
Project description:We performed the CHIP-SEQ assay for LONP1 in C.elegans. Our findings suggest an evolutionary conserved mechanism where mtDNA-bound LONP1 serves as an internal sensor of organelle function that promotes mtDNA replication in dysfunctional compartments. We propose that if LONP1 activity declines, ATFS-1 avoids degradation and binds mtDNA to promote replication in an effort to recover the dysfunctional compartment, which inadvertently promotes ∆mtDNA replication in heteroplasmic cells.
2019-11-19 | GSE140527 | GEO
Project description:Maternal inheritance of mitochondrial DNA (mtDNA) is highly conserved in metazoans. While many species eliminate paternal mtDNA during late sperm development to foster maternal inheritance, the regulatory mechanisms governing this process remain elusive. Through a large-scale genetic screen in Drosophila, we identified 47 mutant lines exhibiting substantial retention of mtDNA in mature sperm. We mapped one line to Poldip2, a gene predominantly expressed in the testis. Disruption of Poldip2 led to pronounced mtDNA retention in mature sperm and subsequent paternal transmission to progeny. Further investigation via imaging, biochemical analyses and ChIP assays revealed that POLDIP2 is a mitochondrial matrix protein capable of binding to mtDNA. Moreover, we uncovered that CLPX, a key component of the major mitochondrial protease, binds to POLDIP2 to co-regulate mtDNA elimination in Drosophila spermatids. This study shed light on the mechanisms underlying mtDNA removal during spermatogenesis, underscoring the pivotal role of this process in safeguarding maternal inheritance.
2024-06-10 | E-MTAB-14104 | biostudies-arrayexpress
Project description:Mitochondrial DNA (mtDNA) 3243A>G tRNALeu(UUR) heteroplasmic mutation (m.3243A>G) exhibits clinically heterogeneous phenotypes. While the high mtDNA heteroplasmy exceeding a critical threshold causes mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome, the low mtDNA heteroplasmy causes maternally inherited diabetes with or without deafness (MIDD) syndrome. How quantitative differences in mtDNA heteroplasmy produces distinct pathological states has remained elusive. Here we show that despite striking similarities in the energy metabolic gene expression signature, the mitochondrial bioenergetics, biogenesis and fuel catabolic functions are distinct in cells harboring low or high levels of the m.3243A>G mutation compared to wild type cells. We further demonstrate that the low heteroplasmic mutant cells exhibit a coordinate induction of transcriptional regulators of the mitochondrial biogenesis, glucose and fatty acid metabolism pathways that lack in near homoplasmic mutant cells compared to wild type cells. Altogether, these results shed new biological insights on the potential mechanisms by which low mtDNA heteroplasmy may progressively cause diabetes mellitus.
2019-04-09 | GSE129091 | GEO
Project description:Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but it is not clear how they arise and propagate in the humans. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Close scrutiny revealed the signature of selection against non-synonymous variants in the protein-coding region, tRNA gene variants, and variants in specific regions of the non-coding D-loop. In isolated single PGCs we saw a profound reduction in the cellular mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules during early germline development. Single cell deep mtDNA sequencing showed rare variants reaching higher heteroplasmy levels in later PGCs, consistent with the observed genetic bottleneck, and predicting >80% levels within isolated organelles. Genome-wide RNA-seq showed a progressive upregulation of genes involving mtDNA replication and transcription, linked to a transition from glycolytic to oxidative metabolism. The metabolic shift exposes deleterious mutations to selection at the organellar level during early germ cell development. In this way, the genetic bottleneck prevents the relentless accumulation of mtDNA mutations in the human population predicted by Muller’s ratchet. Mutations escaping this mechanism will, however, show massive shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
2018-02-02 | GSE77882 | GEO
Project description:We evaluated here the physiological consequences of the generation of heteroplasmic embryos by mix of two wild type mtDNAs in the same zygote. In this animal model, mtDNA heteroplasmy is actively combated during germ-line transmission, embryonic development and somatic life of most differentiated cells. mtDNA heteroplasmy alone, even when both mtDNA types are individually non-pathogenic, causes a disease affecting mainly those tissues that are not able to reduce their heteroplasmy: heart, lung and skeletal muscle.
2020-01-01 | GSE93920 | GEO
Project description:Mitochondria are vital due to their principal role in energy production via oxidative phosphorylation (OXPHOS)1. Mitochondria carry their own genome (mtDNA) encoding critical genes involved in OXPHOS, therefore, mtDNA mutations cause fatal or severely debilitating disorders with limited treatment options. 2. Clinical manifestations of mtDNA disease vary based on mutation type and heteroplasmy levels i.e. presence of mutant and normal mtDNA within each cell. 3,4. We evaluated therapeutic concepts of generating genetically corrected pluripotent stem cells for patients with mtDNA mutations. We initially generated multiple iPS cell lines from a patient with mitochondrial encephalomyopathy and stroke-like episodes (MELAS) caused by a heteroplasmic 3243A>G mutation and a patient with Leigh disease carrying a homoplasmic 8993T>G mutation (Leigh-iPS). Due to spontaneous mtDNA segregation in proliferating fibroblasts, isogenic MELAS iPS cell lines were recovered containing exclusively wild type (wt) mtDNA with normal metabolic function. As expected, all iPS cells from the patient with Leigh disease were affected. Using somatic cell nuclear transfer (SCNT; Leigh-NT1), we then simultaneously replaced mutated mtDNA and generated pluripotent stem cells from the Leigh patient fibroblasts. In addition to reversing to a normal 8993G>T, oocyte derived donor mtDNA (human haplotype D4a) in Leigh-NT1 differed from the original haplotype (F1a) at a additional 47 nucleotide sites. Leigh-NT1 cells displayed normal metabolic function compared to impaired oxygen consumption and ATP production in Leigh-iPS cells or parental fibroblasts (Leigh-fib). We conclude that natural segregation of heteroplasmic mtDNA allows the generation of iPS cells with exclusively wild type mtDNA. Moreover, SCNT offers mitochondrial gene replacement strategy for patients with homoplasmic mtDNA disease.
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Project description:To address the question of whether mtDNA mutations might play a role in familiar ALS (fALS), mtDNA was isolated from whole blood (WB), white blood cells (WBC) and platelets (PLT) from fALS patients and the mitochondrial genome was analyzed using a mtDNA resequencing array (Affymetrix MitoChip v2.0) that allows detection of low-level heteroplasmy in addition to the conventional homoplasmic or heteroplasmic mutations. We distinguished between fALS cases with a prominent maternal (mat) inheritance pattern and fALS cases that do not point to a maternal inheritance pattern (non-mat). As additional controls we compared our results to healthy age and sex matched individuals without any known neurodegenerative background. With this we are aiming to get a deeper insight into a possible role of mtDNA alterations acting as a disease modifier in a subgroup of ALS patients presenting with a maternal transmission of the disease.
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