Mitochondrial DNA Research Articles

Phylogeny of two accacoeliid species (Digenea: Hemiuroidea) ex Mola mola (Linnaeus, 1758) (Tetraodontiformes: Molidae) from Northwest Pacific, with first molecular data on Odhnerium Yamaguti, 1934.

Accacoeliid digeneans associated with fish of the family Molidae exhibit enigmatically high taxonomic diversity. However, the phylogenetic relationships between species within this digenean taxon are poorly understood. In the present study, the first nuclear 28S rRNA gene, ITS2 region of nuclear DNA, and mitochondrial cox1 gene sequence datasets were obtained for two members of the Accacoeliidae, a type and only species of the genus Odhnerium Yamaguti 1934 and an unidentified Accacladocoelium sp. collected from Mola mola (Linnaeus, 1758) off Iturup Island. Analyses of molecular differentiation and phylogenetic relationships indicate that Accacladocoelium sp. is a sister species to Accacladocoelium nigroflavum (Rudolphi, 1819). The genus Odhnerium is closely related to Tetrochetus Looss, 1912, on the 28S rRNA gene-based phylogenetic tree. Results of phylogenetic analysis based on both the mitochondrial cox1 gene and the concatenated ribosomal ITS2 region and cox1 gene of mtDNA show that the genus Odhnerium is close to the A. nigroflavum + Accacladocoelium sp. clade. In turn, the genus Accacladocoelium does not have monophyletic status in the trees reconstructed from these data.

Endothelial cell-released mitochondrial DNA promotes B cell differentiation and virus replication during severe fever with thrombocytopenia syndrome virus infection.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease acquired through tick bites. We have previously demonstrated the correlation between SFTSV-induced mitochondrial dysfunction and inflammation induction, disease progression, and fatal outcome. In the current study, our clinical observation study establishes a strong correlation between elevated levels of circulating cell-free mtDNA and poor prognosis. In vivo studies further reveal endothelial cells as an important source responsible for releasing mtDNA into circulation, which promotes B cell activation, migration, and differentiation via Toll-like receptor 9 (TLR9). Notably, TLR9 activation enhances B-cell susceptibility to SFTSV infection. These findings suggest that mtDNA released by injured endothelial cells facilitates B cell differentiation and virus replication, emphasizing the significant role of mitochondrial damage within endothelial cells in contributing to the severity of SFTS outcomes.IMPORTANCESevere fever with thrombocytopenia syndrome (SFTS) is a new acute tick-borne infectious disease with a high fatality rate of 10%-50%. There is a strong correlation between SFTSV-induced mitochondrial dysfunction and inflammation induction, disease progression, and fatal outcome. Our research has revealed the crucial role of mtDNA in predicting the prognosis of SFTS and its impact on vascular endothelial injuries as well as B cell differentiation, two previously unexplored features of SFTSV infection. Moreover, mtDNA could activate the TLR9 signal to induce plasmablast differentiation in B cells and promote SFTSV infection. This study provides valuable mechanistic and clinical insights into the adverse outcomes associated with SFTSV infection.

Mitochondrial DNA copy number assessment is a potent predictor for prostate cancer in White but not Black Individuals.

Black individuals are disproportionately burdened by prostate cancer compared to White individuals. The mitochondrion is an untapped source for prostate cancer (PCa) biomarkers, and previous work has shown altered mitochondrial DNA (mtDNA) copy number is linked to mitochondrial dysfunction and tumorigenesis. We assess whether mtDNA copy number is altered in patients with and without PCa in a racially specific manner. Circulating cell-free mtDNA copy number from plasma and mtDNA copy number from white blood cells (WBCs) were measured in 199 patients undergoing biopsy (50/50 White cases/controls and 50/49 Black cases/controls). MtDNA copy number was determined via ddPCR. Logistic regressions tested associations between mtDNA and PCa by race. The area under the curve (AUC) was compared between covariate-only models and models with mtDNA. In both plasma and WBCs, mtDNA copy number was significantly increased in cases compared to controls in White patients, but not in Black patients. Interestingly, Black controls had higher mtDNA copy number levels than White controls. Multivariable analysis revealed significant associations of Plasma mtDNA and WBC mtDNA with PCa for White patients only. Elevated mtDNA copy number was more accurate in predicting PCa in White patients than in Black patients. Higher mtDNA copy number levels were associated with PCa in both Black and White patients. Plasma mtDNA may be more accurate than WBC mtDNA in predicting PCa incidence in Black men. Overall, Black controls had higher mtDNA copy number levels than White controls, suggesting mtDNA copy number may be implicated in PCa health disparities.

Guanine quadruplexes mediate mitochondrial RNA polymerase pausing

BackgroundThe information content within nucleic acids extends beyond the primary sequence to include secondary structures with functional roles in transcription regulation. Guanine-rich sequences form structures called guanine quadruplexes that result from non-canonical base pairing between guanine residues. These stable guanine quadruplex structures are prevalent in gene promoters in nuclear DNA and are known to be associated with promoter proximal pausing of some genes. However, the transcriptional impact of guanine quadruplexes that form in nascent RNA is poorly understood.ResultsWe examined mitochondrial RNA polymerase (POLRMT) pausing patterns in primary human skin fibroblast cells using the precision nuclear run-on assay and uncovered over 400 pause sites on the mitochondrial genome. We identified that these pauses frequently occur following guanine-rich sequences where quadruplexes form. Using an in vitro primer extension assay, we show that quadruplexes formed in nascent RNA act as mediators of POLRMT pausing, and in cell-based assays their stabilization disrupts POLRMT transcription. Cells exposed to a guanine-quadruplex stabilizing agent (RHPS4) had diminished mitochondrial gene expression and significantly lowered cellular respiration within 24 h. The resulting ATP stress was sufficient to reduce active transport in renal epithelia.ConclusionsOur findings connect RNA guanine quadruplex-mediated pausing with the regulation of POLRMT transcription and mitochondrial function. We demonstrate that tuning of quadruplex dynamics in nascent RNA, rather than template DNA upstream of the polymerase, is sufficient to regulate mitochondrial gene expression.

Genomic map of the functionally extinct northern white rhinoceros (Ceratotherium simum cottoni)

The northern white rhinoceros (NWR; Ceratotherium simum cottoni) is functionally extinct, with only two nonreproductive females alive. Efforts to rescue the NWR from its inevitable demise have inspired the exploration of unconventional conservation methods, including the development of induced pluripotent stem cells (iPSCs) for the in vitro generation of artificial gametes. The integrity of iPSC genomes is critical for in vitro gametogenesis to be used for assisted reproductive technologies using NWR iPSCs. We generated a chromosome-level NWR reference genome that meets or exceeds the metrics proposed by the Vertebrate Genome Project, using complementary sequencing and mapping methods. The genome represents 40 autosomes, an X and a partially resolved Y chromosome, and the mitochondrial genome. Using comparative FISH mapping, we confirmed a general gene order conservation between the NWR and horse genomes. We aligned the NWR genome with that of the southern white rhinoceros (SWR; Ceratotherium simum simum), a population that has been physically separated from the NWR for tens of thousands of years, and we found that the two subspecies are very similar on the chromosome level. Comparing long-read data from NWR iPSC lines and the fibroblast cultures used for reprogramming, we identified copy number variations that were likely to have been introduced during in vitro iPSC expansion. The NWR reference genome allows for efficient, rapid, and accurate assessment of the genomic integrity of iPSC lines to direct their differentiation. This will assist in strategies to rescue the NWR through extraordinary measures like cloning and the generation of embryos from iPSC-derived gametes.

Repeatome diversity in sea anemone genomics (Cnidaria: Actiniaria) based on the Actiniaria-REPlib library

BackgroundGenomic repetitive DNA sequences (Repeatomes, REPs) are widespread in eukaryotes, influencing biological form and function. In Cnidaria, an early-diverging animal lineage, these sequences remain largely uncharacterized. This study investigates sea anemone REPs (Cnidaria: Actiniaria) in a phylogenetic context. We sequenced and assembled de novo the genome of Actinostella flosculifera and analyzed a total of 38 nuclear genomes to create the first ActiniariaREP library (Actiniaria-REPlib). We compared Actiniaria-REPlib with Repbase and RepeatModeler2 libraries, and used dnaPipeTE to annotate REPs from genomic short-read datasets of 36 species for divergence landscapes.ResultsOur study assembled and annotated the mitochondrial genomes, including 27 newly assembled ones. We re-annotated ~92% of the unknown sequences from the initial nuclear genome library, finding that 6.4–30.6% were DNA transposons, 2.1–11.6% retrotransposons, 1–28.4% tandem repeat sequences, and 1.2–7% unclassifiable sequences. Actiniaria-REPlib recovered 9.4x more REP sequences from actiniarian genomes than Dfam and 10.4x more than Repbase. It yielded 79,903 annotated TE consensus sequences (74,643 known, 5,260 unknown), compared to Dfam with 7,697 (3,742 known, 3,944 unknown) and Repbae (763 known).ConclusionsOur study significantly enhances the characterization of sea anemone repetitive DNA, assembling mitochondrial genomes, re-annotating nuclear sequences, and identifying diverse repeat elements. Actiniaria-REPlib vastly outperforms existing databases, recovering significantly more REP sequences and providing a comprehensive resource for future genomic and evolutionary studies in Actiniaria.

Testing for age- and sex- specific mitonuclear epistasis in Drosophila.

The need for efficient ATP production is predicted to result in the evolution of cooperation between the mitochondrial and nuclear encoded components of the electron transport system. Genotypes where mitochondrial and nuclear genomes from different geographic populations are combined (mismatched), are therefore predicted to result in negative fitness consequences. Such negative fitness effects are expected to be prominent in males, since maternal inheritance of mitochondria can lead to accumulation of male-harming mutations (the mother's curse hypothesis), and they may become more prevalent with ageing. To test these predictions, we measured fertility traits of females and males at different ages using a genetically diverse panel of 27 mitonuclear populations of Drosophila melanogaster with matched or experimentally mismatched mitonuclear genomes. We found no evidence that novel mitonuclear combinations had reduced fitness in females. In males, we found limited evidence of mitonuclear interactions affecting fitness in old age, however, not in the direction predicted. Novel mitonuclear combinations were associated with males that sired more offspring. Sex-specific advantages of mismatched males might arise if novel nuclear alleles compensate for deleterious mitochondrial alleles that have accumulated. If such compensatory effects of novel mitonuclear combinations increasing fitness occur in nature, they could represent a possible counterforce to the mother's curse.

Squat lobsters of the genus Munidopsis Whiteaves, 1874 (Decapoda: Anomura: Munidopsidae) from seamounts on the Nishi-Shichito and Mariana ridges, north-west Pacific off Japan, with descriptions of two new species

We studied material of squat lobsters of the genus Munidopsis Whiteaves, 1874 (Munidopsidae) from the recent cruise of R/V Kaimei (KM20-10C) of the Japan Agency for Marine-Earth Science and Technology carried out on the Nishi-Shichito and Mariana ridges in the Japanese marine protected areas (MPAs). Two species new to science were identified: Munidopsis juxtapallida sp. nov. and M. lignicola sp. nov. The third species, M. spinifrons Dong, Xu, Li & Wang, 2019, heretofore known only from the Weijia Guyot, Northwest Pacific, was also identified. Differentiation of the three species is based on morphological comparison and molecular phylogenetic analysis using the mitochondrial cytochrome c oxidase subunit 1 (COI) gene sequences. For future studies, the sequence data of the mitochondrial 16S rRNA gene of these three species are also provided.

Parallel gene expression changes in ventral midbrain dopamine and GABA neurons during normal aging.

The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific Translating Ribosome Affinity Purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young adult (7-10 month) and old (21-24 month) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in synaptic connectivity and plasticity. Intriguingly, genes involved in serotonergic synthesis were upregulated with age in GABA neurons and not dopamine-releasing cells. In contrast, dopaminergic neurons showed alterations in genes connected with mitochondrial function and calcium signaling, which were markedly downregulated in male mice. Sex differences were detected in both neuron types, but in general were more prominent in dopamine neurons. Multiple sex effects correlated with the differential prevalence for neurodegenerative diseases such as Parkinson's and Alzheimer's seen in humans. In summary, these results provide insight into the connection between non-pathological aging and susceptibility to neurodegenerative diseases involving the ventral midbrain, and identify molecular phenotypes that could underlie homeostatic maintenance during normal aging.Significance statement This work describes altered gene expression profiles in ventral midbrain dopamine and GABA neurons with aging. Experiments used two novel cell type-specific reporter models to enable translatome analysis. Common age-driven alterations included increased inflammatory and pro-survival cell signaling, and downregulation of synaptic transmission and plasticity genes. In individual cell types, we observed upregulation of serotonergic synthesis in GABA neurons and downregulation of mitochondrial function genes in dopamine neurons. Sex differences were detected in both neuronal types, but were more prominent in dopamine neurons. These results reinforce aging as a risk factor for neurodegeneration in these neuronal populations while providing insight into potential mechanisms of homeostatic regulation during healthy aging and into genetic adaptations that are sex or neuron type specific.

Molecular characterization and phylogenetic analyses of the mitogenome of Wan-Xi white goose, a native goose breed in China

BackgroundThe Wan-Xi white goose (WXG), an indigenous Chinese waterfowl (Anserini: Anserinae), is crucial for goose germplasm conservation. This study aimed to sequence and analyze the complete mitochondrial DNA (mtDNA) of WXG using the BGISEQ-500 platform. The mtDNA's structure and function were investigated to gain insights into its genetic diversity and population structure.ResultsThe mtDNA was found to be 16,743 bp long and comprised 22 transfer RNA (tRNA) genes, 2 ribosomal RNA genes, a complement of 13 protein-coding genes (PCGs), as well as a single noncoding control region known as the D-loop. Notably, all tRNA genes, except for trnS1-tRNA which lacked the dihydrouridine stem, were predicted to adopt the typical cloverleaf structure. Given the genetic variability across the mtDNA of Anser spp. and the intergenic gaps identified by codon analysis, the codon usage patterns were comprehensively examined via comparative analysis of the mtDNAs of WXG and 24 other Anser spp. The relative synonymous codon usage (RSCU) values of the 13 mitochondrial PCGs of WXG were consistent with those of the mitochondrial PCGs of the 24 other Anser spp. Analysis of the neutrality (GC3-GC12), the effective number of codons (ENCs)-GC3, and parity rule 2-bias plots further revealed that natural selection emerged as the primary factor influencing codon bias in Anser sp. High nucleotide diversity (Pi > 0.02) was observed in several regions, including the D-loop, ATP6, 12S rRNA, ND1, 16S rRNA_ND1, COX2, and ND5. Furthermore, the results of nonsynonymous (Ka)/synonymous (Ks) analysis of the 13 mitochondrial PCGs of the 25 species under Anser revealed that the genes were subject to strong purifying selection. The findings of phylogenetic analysis further revealed that WXG and 10 other members of Anser cygnoides clustered into a single branch to form a monophyletic group.ConclusionThis research provides valuable insights into the mtDNA of WXG, highlighting its genetic diversity and population structure. The identified mutation hotspots and purifying selection on mitochondrial PCGs suggest potential areas for future research on Anser cygnoides. The findings contribute to our understanding of this rare species and its conservation efforts.

Cardiomyopathy caused by mitochondrial DNA 4300A > G variant.

Cardiomyopathy caused by mitochondrial DNA 4300A > G variant.

Substantial mitochondrial gene order rearrangements and differential evolution rates within the family Capitellidae (Annelida)

Substantial mitochondrial gene order rearrangements and differential evolution rates within the family Capitellidae (Annelida)

Simultaneous Quantification of Mitochondrial DNA Copy Number and Large-Scale Deletion Using Real-Time PCR Method

Alterations in mitochondrial DNA (mtDNA) copy number and the level of large-scale deletions have been shown to affect the function of the oxidative phosphorylation system (OXPHOS) and are associated with carcinogenesis when they exceed a critical threshold. Most studies quantify either mtDNA copy number alteration or large-scale deletions individually, without assessing both parameters simultaneously. In this study, we aim to develop a real-time PCR-based method capable of simultaneously quantifying mtDNA copy number and the extent of large-scale deletions. The detection limit was established at as low as 20 copies per reaction, with high repeatability. Standard curves demonstrated high linearity (R2 > 0.993) and amplification efficiency (> 93.08%). Application of the method to 20 tissue and blood samples from patients with benign breast tumors revealed that mtDNA copy number was generally higher in tissue samples compared to blood. Conversely, the level of large-scale deletions was significantly lower in tissue than in blood samples (p < 0.05). These findings suggest the successful development of a quantitative method based on real-time PCR with high sensitivity and accuracy, which enables the simultaneous quantification of mtDNA copy number and large-scale deletions, providing a valuable tool for mitochondrial gene analysis in biomedical research.

Redescription and Revised Classification Status of Abbreviata phrynocephali comb. nov. (Spirurida: Physalopteridae) from the Yarkand Toad-Headed Agama Phrynocephalus axillaris (Lacertilia: Agamidae)

The genus Abbreviata (Travassos 1920) is distributed worldwide, with lizards serving as the primary hosts. Although Pentadentoptera phrynocephali was previously classified within Pentadentoptera, its original description lacked conclusive morphological and molecular evidence. Notably, key diagnostic features (such as oral dentition structure and spicule ratio) conform to the taxonomic criteria of Abbreviata. These ambiguous characteristics necessitate taxonomic reassessment to resolve systematic uncertainties. In this study, specimens of P. phrynocephali were collected from the stomachs of Phrynocephalus axillaris. Based on an integrated taxonomic approach, we provide detailed morphological redescriptions. We also conducted comparative morphological analyses with congeneric species of Pentadentoptera and Abbreviata. Molecular phylogenetic reconstruction was performed using Bayesian inference based on mitochondrial COI gene sequences. Diagnostic characteristics of this nematode include densely arranged denticles flanking the apical tooth base on the pseudolabial inner margin, a right spicule approximately half the length of the left spicule in males, a caudal region with four pairs of pedunculated papillae, six pairs of sessile papillae, one large unpaired papilla, and a hexadidymous uterus in females. These features distinctly differentiate the species from Pentadentoptera and align it with Abbreviata. Combined morphological and molecular evidence supports the reclassification of P. phrynocephali as Abbreviata phrynocephali (Tao 1985) comb. nov. (Spirurida: Physalopteridae).

Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions

Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.

Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity

Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), including comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity and nuclear DNA methylation levels in adipose and muscle tissue, to identify one CpG at SH3BP4 significantly associated with mitochondrial DNA quantity in adipose tissue (FDR < 0.05). We also show that SH3BP4 methylation correlates with its gene expression. Additionally, we find that 14 out of the 35 obesity-related traits display significant associations with both SH3BP4 methylation and mitochondrial DNA quantity in adipose tissue. We use data from TwinsUK and the Scandinavian T2D-discordant monozygotic twin cohort, to validate the observed associations. Further analysis using ICE FALCON suggests that mitochondrial DNA quantity, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. Examining mitochondrial DNA quantity and obesity-related traits suggests causation from mitochondrial DNA quantity to obesity, but unmeasured within-individual confounding cannot be ruled out. Our findings underscore the impact of mitochondrial DNA quantity on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity.

Origin of Polyploidy, Phylogenetic Relationships, and Biogeography of Botiid Fishes (Teleostei: Cypriniformes)

Botiidae is a small family of freshwater fishes distributed across Southeast Asia, South Asia, and East Asia. It comprises two subfamilies: the diploid Leptobotiinae and the tetraploid Botiinae. Whether species in the Botiinae are autotetraploids or allotetraploids and how many polyploidization events occurred during the evolution of this subfamily remain open questions. The phylogenetic relationships and biogeography of the Botiidae also require further investigation. In the current study, we compared phylogenetic trees constructed using DNA sequences from the mitochondrial genome and five phased nuclear genes. We also performed whole genome sequencing for two tetraploid species: Chromobotia macracanthus and Yasuhikotakia modesta. Genome profiling of five botiine species suggests that they are likely of allotetraploid origin. Nuclear gene tree topologies indicate that the tetraploidization of the Botiinae occurred only once in the common ancestor of this subfamily. Although the possible maternal progenitor and paternal progenitor of the Botiinae cannot be determined, the subfamily Leptobotiinae can be excluded as a progenitor. The gene trees built in this study generally agree on the following sister group relationships: Leptobotiinae/Botiinae, Leptobotia/Parabotia, Chromobotia/Botia, Yasuhikotakia/Syncrossus, and Sinibotia/Ambastaia. Clades formed by the last two generic pairs are also sisters to each other. Timetree analyses and ancestral range reconstruction suggest that the family Botiidae might have originated in East Asia and Mainland Southeast Asia approximately 51 million years ago and later dispersed to South Asia and the islands of Southeast Asia.

The complete mitochondrial genome of Urocitellus undulatus and its phylogenetic analysis

The long-tailed ground squirrel (Urocitellus undulatus) is primarily distributed in various regions, including Xinjiang and Heilongjiang in China, as well as in Siberia, Mongolia, the Russian Federation, and Kazakhstan. In this study, we report the complete mitochondrial genomes of U. undulatus. The genome consists of 16,456 base pairs, including 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region. The phylogenetic relationship indicates a closer evolutionary relationship between U. undulatus and U. richardsonii. These findings provide a foundation for the taxonomic identification, phylogenetic evolution, and mitochondrial genome research of U. undulatus.

Biological Models of Oxidative Purine DNA Damage in Neurodegenerative Disorders

Most DNA damage caused by oxidative metabolism consists of single lesions that can accumulate in tissues. This review focuses on two classes of lesions: the two 8-oxopurine (8-oxo-Pu) lesions that are repaired by the base excision repair (BER) enzyme and the four 5′,8-cyclopurine (cPu) lesions that are repaired exclusively by the nucleotide excision repair (NER) enzyme. The aim is to correlate the simultaneous quantification of these two classes of lesions in the context of neurological disorders. The first half is a summary of reactive oxygen species (ROS) with particular attention to the pathways of hydroxyl radical (HO•) formation, followed by a summary of protocols for the quantification of six lesions and the biomimetic chemistry of the HO• radical with double-stranded oligonucleotides (ds-ODN) and calf thymus DNA (ct-DNA). The second half addresses two neurodegenerative diseases: xeroderma pigmentosum (XP) and Cockayne syndrome (CS). The quantitative data on the six lesions obtained from genomic and/or mitochondrial DNA extracts across several XP and CS cell lines are discussed. Oxidative stress contributes to oxidative DNA damage by resulting in the accumulation of cPu and 8-oxo-Pu in DNA. The formation of cPu is the postulated culprit inducing neurological symptoms associated with XP and CS.

Investigation of the effect of tannic acid on doxorubicin-ınduced testicular damage and functions in a rat model.

Reproductive and testicular toxicity is one of the most important side effects of doxorubicin (DOX), a chemotherapy drug. In our study, we investigated the ameliorative effect of tannic acid (TA), a polyphenol, against DOX-induced testicular and reproductive toxicity in rats. For this purpose, rats divided into four groups (n = 5 each). Rats were treated with DOX cumulatively 30mg/kg (5mg/kg by six equal injections) for 2weeks to induce testicular toxicity. Rats were then treated daily with TA (50mg/kg) and DOX + TA combination. After treatments, animals were decapitated and testicular tissues were removed. Then, to examine the effect of DOX and TA treatments on oxidative stress, changes in Sod, Cat, Gpx, Gst, and Gr specific activities and mRNA levels were determined. To determine the effects on inflammation, changes in the expression levels of Tnf-α, IL6, Foxo1, Foxo3, Cox2, and Inos genes were examined. In order to examine the therapeutic effect of TA on the spermatogenesis process, mRNA levels of Dazl, Amh, and Ddx4, which regulate reproductive functions, were determined. Additionally, changes in oxidative damage markers GSH, MDA, 8-OHdG, iNOS, and TNF-a and changes in mitochondrial DNA copy number were also investigated. The results showed that DOX treatment caused a decrease in the levels of oxidative stress and reproductive parameters and an increase in inflammation and DNA damage parameters. However, it was determined that oxidative stress, inflammation, and tissue damage decreased in testicular tissue after TA treatment. In addition, it was observed that TA also improved the expression levels of reproductive genes. When all the data were evaluated together, it was determined that TA administration has a therapeutic effect against the damage and toxicity caused by DOX.