Search Results (67)

Purpose: Neuroendocrine carcinomas (NECs) are aggressive tumors treated with cisplatin-based chemotherapy, though responses vary. As DNA damage response (DDR) pathways influence cisplatin sensitivity, this single-center retrospective study evaluates the efficacy of first-line cisplatin in recurrent or metastatic NEC based on DDR mutation status. Materials and Methods: This study analyzed patients with grade 3 recurrent or metastatic NEC treated with first-line etoposide plus cisplatin at Samsung Medical Center between January 2019 and September 2023. All patients underwent next-generation sequencing to determine DDR mutation status, defined by pathogenic alterations in major DNA repair pathways. Clinical outcomes were assessed per RECIST v1.1. Survival analyses were conducted using Kaplan–Meier methods and Cox regression models, with significance set at p ≤ 0.05. Results: A total of 40 patients with NEC were included in this study. There were 16 patients with DDR wild-type (WT) and 24 patients with DDR mutant type (MT). The most common primary tumor sites were the pancreas (25.0%), stomach (20.0%), and gallbladder/duct (12.5%). Among 40 patients, those with DDR mutations (n = 24) showed significantly higher objective response (58.3% vs. 12.5%) and disease control rates (91.7% vs. 50.0%) compared to patients with DDR WT (n = 16). The median progression-free survival (PFS) showed the favorable trend in the DDR mutant group (8.0 vs. 4.3 months; p = 0.15), with similar trends observed across homologous recombination repair (HRR), Fanconi anemia (FA), and mismatch repair (MMR) subgroups. Conclusions: This study revealed that patients with DDR mutations had significantly higher response to first-line etoposide–cisplatin, suggesting DDR mutation status as a potential predictive marker to guide treatment and improve outcomes in recurrent or metastatic NEC. Full article

Patients with chronic kidney disease (CKD) face an increased risk of early vascular aging, progressive vascular calcification, and premature death. With increasing age, mitochondrial function and mitochondrial DNA copy number (mtDNA-cn) decline. This has been identified as an independent predictor of frailty and mortality in cardiovascular diseases (CVDs) and cancer. However, the relationship between mtDNA-cn and vascular calcification in the context of a uremic milieu remains ambiguous. We hypothesize that a lower mtDNA-cn is associated with medial calcification, as both are linked to impaired vascular health and accelerated aging. mtDNA-cn was analyzed in 211 CKD5 patients undergoing renal transplantation (RTx) and 196 healthy controls using quantitative PCR (qPCR) for three mtDNA genes (mtND1, mtND4, and mtCOX1) and single-locus nuclear gene hemoglobin beta (HbB). In 32 patients, mtDNA-cn was also quantified one year after RTx. The association between mtDNA-cn and vascular calcification scores, circulatory cell-free (ccf) mtDNA in plasma, and the surrogate marker of biological aging (skin autofluorescence) and CVD risk was assessed. mtDNA-cn was significantly lower in CKD5 patients than in controls and correlated with biological age, vascular calcification, and CVD risk. One year after RTx there was a significant recovery of mtDNA-cn in male patients compared to baseline levels. mtDNA-cn and ccf-mtDNA were inversely correlated. This prospective study provides novel insights into the link between low mtDNA-cn and vascular aging. It demonstrates that RTx restores mtDNA levels and may improve oxidative phosphorylation capacity in CKD. Further investigation is warranted to evaluate mtDNA as a biologically relevant biomarker and a potential therapeutic target for early vascular aging in the uremic environment. Full article

Introduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the ‘common’ 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria. Full article

Hydrogen sulfide (H₂S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H₂S exert cytoprotective effects, excessive concentrations can lead to toxicity, oxidative stress, and inflammation. The aim of this study was to investigate the dose-dependent effects of exogenous H₂S on mitochondrial functions and biogenesis in intestinal epithelial cells under non-stressed conditions. Using a Caco-2 monolayer model, we evaluated the impact of sodium hydrosulfide (NaHS) at concentrations ranging from 1 × 10⁻⁷ M to 5 × 10⁻³ M on mitochondrial metabolism, redox balance, antioxidant defense, inflammatory responses, autophagy/mitophagy, and apoptosis. Our results demonstrated a biphasic response: low-to-moderate H₂S concentrations (1 × 10⁻⁷ M–1.5 × 10⁻³ M) enhance mitochondrial biogenesis through PGC-1α activation, upregulating TFAM and COX-4 expression, and increasing the mtDNA copy number. In contrast, higher concentrations (2 × 10⁻³–5 × 10⁻³ M) impair mitochondrial function, induce oxidative stress, and promote apoptosis. These effects are associated with elevated reactive oxygen species (ROS) production, dysregulation of antioxidant enzymes, and COX-2-mediated inflammation. H₂S-induced autophagy/mitophagy is a protective mechanism at intermediate concentrations but fails to mitigate mitochondrial damage at toxic levels. This study underscores the delicate balance between the cytoprotective and cytotoxic effects of exogenous H₂S in intestinal cells, helping to develop new therapeutic approaches for gastrointestinal disorders. Full article

Crossing Oreochromis niloticus (On) females with O. aureus (Oa) males results in all-male progeny that are essential for effective tilapia aquaculture. However, a reproductive barrier between these species prevents commercial-scale yield. To achieve all-male progeny, the currently used practice is crossing admixed stocks and feeding fry with synthetic androgens. Hybrid tilapias escaping to the wild might impact natural populations. Hybrids competing with wild populations undergo selection for different stressors, e.g., oxygen levels, salinity, and low-temperature tolerance. Forming mitochondrial oxidative phosphorylation (OXPHOS) complexes, mitochondrial (mtDNA) and nuclear DNA (nDNA)-encoded proteins control energy production. Crossbred tilapia have been recorded over 60 years, providing an excellent model for assessing incompatibility between OXPHOS proteins, which are critical for the adaptation of these hybrids. Here, by comparing nonconserved amino acid substitutions, across 116 OXPHOS proteins, between On and Oa, we developed a panel of 13 species-specific probes. Screening 162 SRA experiments, we noted that 39.5% had a hybrid origin with mtDNA-nDNA allele mismatches. Observing that the frequency of interspecific mtDNA-nDNA allele combinations was significantly (p < 10⁻⁴) lower than expected for three factors, UQCRC2, ATP5C1, and COX4B, we concluded that these findings likely indicated negative selection, cytonuclear incompatibility, and a reproductive barrier. Full article

Mitophagy plays a critical role in maintaining mitochondrial quality and cellular homeostasis. But the specific contribution of mitophagy-related E3 ubiquitin ligases to prognoses remains largely unexplored. In this study, we identified a novel mitophagy-related E3 ubiquitin ligase prognostic signature using least absolute shrinkage and selector operator (LASSO) and multivariate Cox regression analyses in breast cancer. Based on median risk scores, patients were divided into high-risk and low-risk groups. Functional enrichment analyses were conducted to explore the biological differences between the two groups. Immune infiltration, drug sensitivity, and mitochondrial-related phenotypes were also analyzed to evaluate the clinical implications of the model. A four-gene signature (ARIH1, SIAH2, UBR5, and WWP2) was identified, and Kaplan–Meier analysis demonstrated that the high-risk group had significantly worse overall survival (OS). The high-risk patients exhibited disrupted mitochondrial metabolism and immune dysregulation with upregulated immune checkpoint molecules. Additionally, the high-risk group exhibited higher sensitivity to several drugs targeting the Akt/PI3K/mTORC1 signaling axis. Accompanying mitochondrial metabolic dysregulation, mtDNA stress was elevated, contributing to activation of the senescence-associated secretory phenotype (SASP) in the high-risk group. In conclusion, the identified signature provides a robust tool for risk stratification and offers insights into the interplay between mitophagy, immune modulation, and therapeutic responses for breast cancer. Full article

Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF. Full article

Aedes albopictus, one of the most rapidly spreading invasive mosquito species, has expanded from Asia to establish populations on every continent except Antarctica, showcasing exceptional adaptability, particularly in island environments. This study provides the first molecular characterization of Ae. albopictus in the Canary Islands, Spain. Genotyping was conducted using rDNA 5.8S-ITS2 and mtDNA cox1 sequencing, with haplotype analysis and phylogenetic network assessment. Among 49 sequences, 28 distinct 5.8S-ITS2 haplotypes were identified, with individual specimens containing 5 to 17 haplotypes (mean, 10.6). Most haplotypes (26/28; 92.85%) were unique to Tenerife, while only two (7.14%) were shared with other regions. H1 was the most frequent haplotype, shared with Valencia and China, while H2, a short-length haplotype, was shared with Mallorca. For cox1, only two haplotypes were detected: cox1-H1, reported in Europe, China, and Brazil, and a novel haplotype, cox1-H28. This genetic diversity suggests the species’ potential capacity to colonize new environments. The findings provide a foundation for further research in the Canary Islands and globally, particularly in regions with high tourism and arbovirus risks, emphasizing the importance of ongoing surveillance and genetic studies to understand the dynamics and public health impacts of invasive mosquito species. Full article

Currently, the molecular background based on mitochondrial DNA (mtDNA) analysis of canine testicular tumours is underestimated. The available data mostly focus on histopathological evaluations, with a few reports of nuclear genome (nDNA) studies. Tumourigenesis represents a highly complex and diverse genetic disorder, which can also encompass defects in mtDNA. The aim of this study was to identify molecular changes in whole mitochondrial genome sequences obtained from dogs affected by testicular tumours. Samples of blood, tumour, and healthy tissue were collected from each animal, and mtDNA (ultimately 45 samples) was subsequently sequenced. Thereafter, protein analyses were performed to assess the impact of the identified molecular alterations on the amino acid level. The total number of observed changes included 722 SNPs, 12 mutations, 62 indels, 5 indel mutations, and 35 heteroplasmic sites. The highest number of mtDNA variants in protein-coding genes COX1, COX3, ATP6, ND1, ND4, and ND5 was observed. Interestingly, SNPs were found in 10 out of 22 tRNA genes. Most of the identified mtDNA defects were synonymous changes at the amino acid level. Also, polymorphisms and heteroplasmy were frequently observed in the variable number of tandem repeat (VNTR) regions, especially in its fragment spanning 16,138–16,358 bp. Based on the obtained results, it was possible to select 11 polymorphisms that occurred in all the tested samples (benign, malignant) and an additional five SNPs identified only in benign neoplasms. The comprehensive analysis of malignant testicular tumours demonstrated a significant diversity in their molecular profiles, with changes ranging from 17 to 101 per sample. Full article

(1) Background: An adult dog was presented to a board-certified veterinary neurologist for evaluation of chronic weakness, exercise intolerance and lactic acidemia. (2) Methods: A mitochondrial myopathy was diagnosed based on the histological and histochemical phenotype of numerous COX-negative muscle fibers. Whole-genome sequencing established the presence of multiple extended deletions in the mitochondrial DNA (mtDNA), with the highest prevalence between the 1–11 kb positions of the approximately 16 kb mitochondrial chromosome. Such findings are typically suggestive of an underlying nuclear genome variant affecting mitochondrial replication, repair, or metabolism. (3) Results: Numerous variants in the nuclear genome unique to the case were identified in the whole-genome sequence data, and one, the insertion of a DYNLT1 retrogene, whose parent gene is a regulator of the mitochondrial voltage-dependent anion channel (VDAC), was considered a plausible causal variant. (4) Conclusions: Here, we add mitochondrial deletion disorders to the spectrum of myopathies affecting adult dogs. Full article

This study presents the first record of T. lindbergi from the southwestern Atlantic Ocean, based on specimens collected from the smalleye croaker Nebris microps Cuvier (Sciaenidae), off the coast of Maranhão Island, State of Maranhão, Brazil. Our approach included a morphological analysis complemented by DNA sequencing (28S, ITS2 rDNA, and cox1 mtDNA). Our phylogenetic analysis revealed the affinity of T. lindbergi to its congener T. laticaudi Parukhin, 1969, a digenean parasite commonly found in hydrophiine snakes inhabiting the Pacific Ocean. The interspecific divergence between T. lindbergi and T. laticaudi measures 3.80% for 28S, 7.49–7.64% for ITS2, and 16.29–16.70% for cox1. Our findings expand the documented geographic range of T. lindbergi into the southwestern Atlantic Ocean, report a novel host record, and increase the number of hemiurids known from Brazil to 30 species. Additionally, this study represents the initial documentation of a marine digenean fish within the North Brazil Shelf. Full article

The family Scolopacidae presents a valuable subject for evolutionary research; however, molecular studies of Scolopacidae are still relatively understudied, and the phylogenetic relationships of certain species remain unclear. In this study, we sequenced and obtained complete mitochondrial DNA (mtDNA) from Actitis hypoleucos and partial mtDNA from Numenius arquata, Limosa limosa, and Limnodromus semipalmatus. The complete mtDNA contained 13 protein-coding genes (PCGs), two ribosomal RNA genes, 22 tRNA genes, and a control region. Scolopacidae contained three types of start codons and five types of stop codons (including one incomplete stop codon, T--). In 13 protein-coding genes, average uncorrected pairwise distances (Aupd) revealed that ATP8 was the least conserved while COX3 had the lowest evolutionary rate. The ratio of Ka/Ks suggested that all PCGs were under purifying selection. Using two methods (maximum likelihood and Bayesian inference) to analyze the phylogenetic relationships of the family Scolopacidae, it was found that the genera Xenus and Actitis were clustered into another sister group, while the genus Phalaropus is more closely related to the genus Tringa. The genera Limnodromus, Gallinago, and Scolopax form a monophyletic group. This study improves our understanding of the evolutionary patterns and phylogenetic relationships of the family Scolopacidae. Full article

Adult trematodes of the genus Metorchis were found in the gallbladders of ducklings that had been experimentally fed freshwater fishes of the genera Rhynchocypris and Rhodeus that were naturally infected by Metorchis metacercariae. Some of the trematodes were identified as Metorchis ussuriensis, whose morphology of developmental stages and molecular data had previously been described in detail. The other trematodes were confirmed as species Metorchis butoridi on the basis of morphological features: subterminal oral sucker, vitelline follicles with interrupted bands, and rosette-shaped testes. An analysis of phylogenetic relationships within Opisthorchiidae using nuclear and mitochondrial markers confirmed that the obtained trematodes were actually from the genus Metorchis. The morphological and molecular features indicated that a number of trematodes found in East Asia and described as Metorchis orientalis belong to M. butoridi. Also, the M. orientalis individuals from Europe are, in fact, representatives of another Metorchis species. Full article

There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral aspartame consumption on cerebral cortex injury in the rat brain, and further evaluate the various underlying molecular mechanisms, with a special focus on oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis pathways. Sprague Dawley rats (nineteen, female) were randomly sub-divided into three groups: (i) normal diet with vehicle: control group (five rats), (ii) low dose of aspartame group (LA): seven rats received 30 mg/kg body weight (bw) daily doses of aspartame, (iii) high dose of aspartame group (HA): seven rats received 60 mg/kg bw daily doses of aspartame. After 8 weeks, the LA and HA groups showed lower expression levels of brain-derived neurotrophic factor (BDNF), antioxidant enzyme activity (SOD2, CAT), antioxidant marker (Nrf2), inflammatory response (IκB), mitochondrial biogenesis (Sirt1, PGC1α, Nrf1, TFAM), mitochondrial DNA (mtDNA) copy number, and apoptosis-related proteins (Bax, Caspase-3) expressions. Aspartame administration also elevated oxidative stress levels (Malondialdehyde, MDA), 8-hydroxy-2-deoxy guanosine (8-OHdG), PGE₂ and COX-2 expressions, pro-inflammatory cytokines (TNFα, IL6, IL1β), antioxidant marker expression (Keap1), inflammatory responses (iNOS, NFκB), and glial fibrillary acidic protein (GFAP) levels in the cerebral cortex of the rats, thereby contributing to the reduced survival of pyramidal cells and astrocyte glial cells of the cerebral cortex. Therefore, these findings imply that aspartame-induced neurotoxicity in rats’ cerebral cortex could be regulated through four mechanisms: inflammation, enhanced oxidant stress, decreased mitochondrial biogenesis, and apoptosis pathways. Full article

Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency. Full article