Search Results (462)

Distant hybridization induces genomic instability in offspring, driving the occurrence of gene recombination and mutation. Analysis of the genomic genetic composition can be used to infer the genetic evolutionary relationships between species. Based on the improved diploid carp (IDC) and the improved diploid scattered mirror carp (IDMC) lineages derived from distant hybridization between female common carp and male blunt snout bream, this study analyzed the genetic variation in their mitochondrial genomes to investigate the impact of distant hybridization on mitochondrial DNA (mtDNA) structural variation. Analysis of complete mitochondrial genome sequence structure and composition revealed subtle structural divergence across generations in both the IDC and IDMC lineages. Analysis of the protein-coding gene sequence structure demonstrated mitochondrial genome structure instability in nascent hybrid diploid lineages. Yet, subsequent self-crossing significantly narrowed the range of structural variation within each lineage. Furthermore, analysis of the genetic variation in the mitochondrial genome sequence structure revealed that paternal base insertions occurred in both F₁ lineages, accompanied by mutations predominantly consistent with those in crucian carp. The results of this study also indicated that the strictness of the paternal mtDNA elimination mechanism varied significantly among polymorphic individuals across different generations of the hybrid lineages, reflecting the randomness of paternal leakage. Full article

The accumulation of somatic mutations contributes to clonal evolution and biological properties of cancers. Acquired mutations in mitochondrial (mt)DNA have been studied, but with the exception of those in isocitrate dehydrogenase genes, no comprehensive assessment of mutations in nuclear mitochondrial genes has been reported in sequential glioblastoma (GBM). We obtained ten pairs of GBM samples at diagnosis (GBM-P) and at recurrence (GBM-R). Extracted DNA was subjected to whole exome and mtDNA sequencing. After filtering out germline variants, bioinformatics analysis was performed using a mitochondrial gene panel of 483 nuclear-encoded, and 37 mtDNA-encoded genes. Variant classification was performed using established clinical- and molecular criteria, integrating population-frequency data, bioinformatic predictions, functional evidence, segregation information, and curated entries from the Mitomap and ClinVar databases. Benign single nucleotide variants in mtDNA-encoded genes of RNR1, RNR2, ATP6, CYB, CO2, TV, ATP8, and ND2 were detected, which changed little over time. However, three variants in TI, ND5 and ND1 with possible or likely pathogenic significance were found in the GBM-R samples. In contrast, pathogenic or likely pathogenic variants in 29 nuclear genes were found in GBM-P and GBM-R samples. Not only the overall number, but also the number of protein-truncating variants in nuclear genes increased over time. Conclusions: This study sheds light on the accumulation of mutations in nuclear genes of mitochondrial proteins in sequential GBM samples. As such variants may influence metabolic, proliferative and invasive properties as well as the necrotic propensity of the tumor, a comprehensive analysis of these genes merits further studies. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental competence contribute to infertility. The disease is driven by a multifactorial interplay of somatic mutations, epigenetic remodeling, immune dysregulation, and aberrant steroid signaling, which together create a pro-inflammatory, oxidative, and fibrotic microenvironment. Elevated cytokines, reactive oxygen species, and disrupted granulosa-cell function within the follicular niche impair meiotic progression, cytoplasmic maturation, and mitochondrial integrity, potentially accelerating oocyte aging and diminishing reproductive longevity. Epigenetic and post-transcriptional disturbances—including altered DNA methylation, histone modifications, and RNA-splicing defects—further reinforce estrogen dominance, progesterone resistance, and impaired decidualization, with downstream consequences for ovarian–endometrial communication. Although morphological abnormalities have been documented in oocytes from women with endometriosis, clinical outcomes remain heterogeneous, highlighting the need for integrative models that connect molecular alterations to functional reproductive endpoints. A deeper understanding of these mechanisms is essential for identifying biomarkers of oocyte competence and modifiable strategies—ranging from nutritional optimization to reduction of environmental risk factors—in clinical care to safeguard the reproductive potential of women with endometriosis. Full article

Human papillomavirus (HPV) infection is a leading cause of cervical cancer and a significant contributor to anogenital and oropharyngeal malignancies worldwide. While the oncogenic functions of HPV oncoproteins E6 and E7 in disrupting nuclear tumor suppressor pathways are well established, their influence on mitochondrial biology has only recently emerged as a critical facet of HPV-driven carcinogenesis. This review synthesizes current evidence on the qualitative and quantitative alterations of mitochondrial DNA (mtDNA) and their functional consequences in HPV-associated cancers. We discuss how E6 and E7 modulate mitochondrial dynamics, bioenergetics, and redox balance, contributing to metabolic reprogramming, resistance to apoptosis, and adaptation to tumor microenvironmental stress. We also examine the clinical significance of mtDNA mutations, deletions, and copy number variations as potential biomarkers for diagnosis, prognosis, and therapy response. Advances in multi-omics approaches, high-throughput sequencing, and patient-derived organoid models have accelerated the exploration of mitochondria as therapeutic targets. Integrating mitochondrial profiling into HPV-related cancer research holds promise for identifying novel metabolic vulnerabilities and guiding the development of mitochondria-directed treatment strategies. Full article

The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We demonstrated that stress responses, including serum deprivation, oxidative stress, and anticancer drug treatment, increase WWOX expression in human SCC-15 cells and wild-type mouse embryonic fibroblasts (MEFs) through transcriptional activation. Serum deprivation induces higher levels of reactive oxygen species and cell death in Wwox^+/+ than Wwox^−/− MEFs. Anti-apoptotic Bcl-2 family proteins regulate mitochondrial homeostasis and prevent serum deprivation-induced oxidative stress and cell death. Our results showed that serum starvation decreases protein expression levels of Bcl-X_L and Mcl-1 in Wwox^+/+ but not in Wwox^−/− MEFs. Serum starvation also fails to downregulate Bcl-X_L and Mcl-1 protein expression in WWOX-knockdown SCC-15 cells. Replenishment of ectopic WWOX induces downregulation of Bcl-X_L and Mcl-1 protein levels in Wwox^−/− MEFs after serum starvation. We determined that WWOX-mediated downregulation of Bcl-XL and Mcl-1 is accomplished through a lysosome-dependent protein degradation pathway. Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox^+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death. Full article

Background: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare multisystem disorder caused by mitochondrial DNA mutations, most commonly the m.3243A>G variant in the MT-TL1 gene. Although neurological manifestations predominate, cardiac involvement, including hypertrophic cardiomyopathy (HCM), heart failure (HF), and arrhythmias, may be the initial or dominant presentation and often remains underrecognized. Case Presentation: We report a 43-year-old man with chronic kidney disease (CKD) and long-standing bilateral sensorineural hearing loss who presented with progressive dyspnea and acute decompensated HF. Transthoracic echocardiography revealed severe left ventricular (LV) systolic dysfunction with diffuse hypertrophy. Cardiac magnetic resonance showed non-ischemic cardiomyopathy with diffuse late gadolinium enhancement and increased LV wall thickness. Coronary angiography excluded obstructive disease. Initial endomyocardial biopsy performed at a referring center showed nonspecific hypertrophy and fibrosis without diagnostic features. Given the multisystem involvement, a metabolic or genetic etiology was suspected. Whole-exome sequencing identified the pathogenic m.3243A>G MT-TL1 mutation, confirming MELAS syndrome. The patient was managed with guideline-directed HF therapy, received an implantable cardioverter-defibrillator for primary prevention, and was subsequently evaluated for heart transplantation. Conclusions: This case highlights the importance of considering mitochondrial disorders in the differential diagnosis of unexplained cardiomyopathy, particularly when cardiac dysfunction coexists with renal impairment and auditory deficits. Comprehensive multimodality evaluation and genetic testing are essential to establishing a unifying diagnosis and optimizing management. Full article

Mitochondria are the energy factories of a cell and mitochondrial morphology, quantity, membrane potential, and DNA copy number can change depending on metabolic requirements and/or genetic defects. Different mutations in mitochondrial DNA might affect mitochondrial morphology and membrane potential differently. In this study we investigated mitochondrial morphology and membrane potential in vitro in mesoangioblast-derived human myotubes harboring a pathogenic mtDNA mutation and analyzed mitochondrial behavior following fusion with healthy mesoangioblasts. Myotubes were differentiated in vitro from mesoangioblasts obtained from two mitochondrial myopathy patients, M02 (96% m.3271T>C) and M11 (73% m.3291T>C), and from a functionally healthy male control, M06 (3% m.3243A>G). On day 5 of differentiation, healthy male mesoangioblasts (mM06) were added to mutant myotube cultures to allow cell fusion. On day 11, mitochondrial morphology and membrane potential were assessed by three-dimensional live-cell imaging using spinning disk confocal microscopy with tetramethylrhodamine methyl ester (TMRM). Following live imaging, cells were fixed and subjected to Y-chromosome fluorescence in situ hybridization (FISH), enabling identification and retrospective analysis of hybrid (i.e., fused with male control mesoangioblasts) and non-hybrid (i.e., not fused with these control mesoangioblasts) myotubes within the same imaging fields. Quantitative image analysis at the level of individual myotubes revealed that, when normalized to sarcoplasmic volume, mitochondrial volume, object number, and membrane potential did not differ between mutant and control myotubes despite heteroplasmy levels exceeding 70%. Fusion of healthy mM06 mesoangioblasts did not impair myotube formation and resulted in redistribution of mitochondrial content without an increase in mitochondrial object number, consistent with integration of donor mitochondria into the existing mitochondrial network. Across conditions, mitochondrial parameters were strongly influenced by myotube size, underscoring the importance of accounting for biological variation when quantifying mitochondrial features. Together, these findings demonstrate that high mtDNA mutation loads do not necessarily alter mitochondrial morphology or membrane potential under standard in vitro differentiation conditions and provide mechanistic insight into mitochondrial behavior following mesoangioblast fusion in human myotubes. Fusion of healthy mesoangioblasts supports integration of donor mitochondria into the existing network without compromising myogenesis, consistent with mitochondrial mixing rather than replacement. Full article

Studying intraspecific differentiation in closely related species is essential to clarify the phylogenetic relationships and mechanisms of early stage speciation, particularly in evolutionarily young lineages affected by human-driven population declines. The endangered saker falcon (Falco cherrug), with its ambiguous phylogenetic links to the gyrfalcon (F. rusticolus), exemplifies this scenario. This study presents a comprehensive genetic analysis of F. cherrug and F. rusticolus using mtDNA markers and microsatellite loci, focusing on the diversity of southern Siberian saker falcon populations. The genotyping results for these populations were correlated with phenotypic data obtained from long-term monitoring (1999–2021). Our findings provide novel insights into the current subspecific differentiation and the remnants of a nascent subspecies structure that existed before the recent demographic collapse. Furthermore, our results support the hypothesis of the gyrfalcon’s origin as a descendant species of the Asian saker falcon, i.e., an evolutionarily young lineage undergoing divergence. Our data contribute to the understanding of the Hierofalco evolutionary history, particularly through the analysis of heterogeneous mutation rates among mitochondrial haplogroups. This study underscores the critical importance of conservation efforts for wild endangered populations through long-term monitoring integrated with combined genetic approaches. Full article

Familial cancers are caused by inherited mutations in specific genes that regulate cell growth, division, and repair. Approximately 5–10% of all cancer cases have a hereditary component, where germline mutations in certain genes increase an individual’s susceptibility to developing cancer. Two major categories of genes are involved in cancer development: tumour suppressor genes and oncogenes. Both play critical roles in regulating normal cell behaviour, and when mutated, they can contribute to uncontrolled cell proliferation and tumour formation. In addition to genetic mutations, epigenetic alterations also play a significant role in familial cancer. Epigenetics refers to changes in gene expression due to DNA methylation, histone modifications, and the dysregulation of non-coding RNAs without alter the underlying DNA sequence. Familial cancer syndromes follow various inheritance patterns, including autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance, each with distinct characteristics. Identifying genetic mutations associated with familial cancers is a cornerstone of genetic counselling, which helps individuals and families navigate the complex intersection of genetics, cancer risk, and prevention. Early identification of mutations enables personalized strategies for risk reduction, early detection, and, when applicable, targeted treatment options, ultimately improving patient outcomes. Full article

Mitochondrial dysfunction plays a central role in cardiac aging. Damaged mitochondria release excessive free radicals from the electron transport chain (ETC), leading to an increased production of reactive oxygen species (ROS). The accumulation of ROS, together with impaired ROS clearance mechanisms, results in oxidative stress, further disrupts mitochondrial dynamics, and diminishes bioenergetic capacity. Furthermore, the dysfunctional mitochondria exhibit an impaired endogenous antioxidant system, exacerbating this imbalance. These alterations drive the structural and functional deterioration of the aging heart, positioning mitochondria at the center of mechanisms underlying age-associated cardiovascular decline. In this review, we summarize the current evidence on how mitochondrial oxidative stress, mutations on mitochondrial DNA (mtDNA), and disruptions in the fission—fusion balance contribute to cardiomyocyte aging. This review also explores ways to mitigate oxidative stress, particularly with mitochondria-targeted antioxidants, and discusses the emerging potential of mitochondrial transplantation to replace dysfunctional mitochondria. Full article

Tarantulas (family Theraphosidae) are ecologically significant invertebrate predators in terrestrial ecosystems, but many species face threats from habitat fragmentation and unsustainable collection for the international pet trade. Brachypelma albiceps, a CITES Appendix II-listed species, lacks comprehensive mitochondrial genome characterization, limiting phylogenetic and evolutionary studies. Here, we report a complete mitochondrial genome sequence for B. albiceps (13,856 bp; GC content 32.84%) and provide detailed annotation. The genome exhibits typical metazoan mitochondrial organization, containing 13 protein-coding genes (PCGs), 22 tRNAs, and 2 rRNAs, with an AT-rich nucleotide composition (67.16%) characteristic of arthropod mitochondria. Comparative analyses of B. albiceps and six other Mygalomorphae species revealed strong biases toward A/T-ending codons and avoidance of G/C-ending codons. ENC–GC3s, neutrality, and PR2 analyses consistently indicate that natural selection plays a dominant role in shaping synonymous codon usage, with mutation pressure also contributing. Phylogenetic reconstruction based on 10 high-quality mitochondrial protein-coding genes from 23 spider species confirmed the placement of B. albiceps within the family Theraphosidae and its close phylogenetic relationship to Cyriopagopus species. These results provide valuable genomic resources for the Theraphosidae systematics, enhance our understanding of codon bias evolution, and provide critical DNA barcode data for forensic identification of CITES-regulated specimens in the illegal wildlife trade. Full article

Mitochondrial tRNA genes are critical hotspots for pathogenic mutations and several mitochondrial diseases. They account for approximately 70–75% of disease-causing mtDNA variants despite comprising only 5–10% of the mitochondrial genome. These mutations interfere with mitochondrial translation and affect oxidative phosphorylation, resulting in remarkably heterogeneous multisystem disorders. Under this light, we systematically reviewed PubMed, Scopus, and MITOMAP databases through October 2025, indexing all clinically relevant pathogenic mt-tRNA mutations classified by affected organ systems and underlying molecular mechanisms. Approximately 500 distinct pathogenic variants were identified across all 22 mt-tRNA genes. Beyond typical syndromes like MELAS, MERRF, Leigh syndrome, and Kearns–Sayre syndrome that are linked to mt-tRNA mutations, they increasingly implicate cardiovascular diseases (cardiomyopathy, hypertension), neuromuscular disorders (myopathies, encephalopathies), sensory impairment (hearing loss, optic neuropathy), metabolic dysfunction (diabetes, polycystic ovary syndrome), renal disease, neuropsychiatric conditions, and cancer. Beyond sequence mutations, defects in post-transcriptional modification systems emerge as critical disease mechanisms affecting mt-tRNA function and stability. The mutations on tRNA genes described herein represent potential targets for emerging genome editing therapies, although several translational challenges remain. However, targeted correction of pathogenic mt-tRNA mutations holds transformative potential for precision intervention on mitochondrial diseases. Full article

Age-related changes are associated with mitochondrial dysfunction, which is often caused by the accumulation of mutations in mitochondrial DNA (mtDNA). One common model of aging and age-related diseases involves mice with a mutant DNA polymerase γ (PolG^mut) whose proofreading function is impaired, which leads to the accumulation of mutations in mtDNA. The main limitation of such a model is that introducing a mutation into the mouse’s own gene leads to the accumulation of mutations in mtDNA over several generations, making it impossible to rule out whether mtDNA mutations or compensatory effects are the cause of functional impairments such as accelerated aging. This paper describes two lines of transgenic animals with inducible expression of PolG^mut. This inducible system prevents mutation accumulation in the germline, promoting stable reproduction and reproducibility of mice, increasing experimental flexibility for various studies of mitochondrial diseases. PolG^mut activation at different stages of life and different tissues allows us to study the progression of pathological changes during mitochondrial aging over time and detect the onset of mutation accumulation. The simplicity, reproducibility, and temporal control of this system represent a significant methodological improvement for studying mitochondrial mutagenesis and the pathophysiology of aging. Using this model, we demonstrated that the most pronounced pathology in these animals is accelerated thymus involution and the accumulation of cytotoxic effector CD8+ T cells in the peripheral immune organs, while no significant abnormalities were observed in other organs and systems. These data probably indicate that mtDNA mutations primarily impair T-cell immune function. Full article

Background: Cavariella salicicola (Hemiptera: Aphidinae) is a pest on Salix spp. and various Umbelliferae (Apiaceae) vegetables. However, the taxonomic status and phylogenetic relationship of the genus Cavariella within Aphidinae remain controversial due to the small body size and easily confused external morphology. Methods: The complete mitochondrial genome of C. salicicola collected from Oenanthe javanica was sequenced using the Illumina platform and compared with C. theobaldi. The codon usage bias of two Cavariella aphids was assessed through Enc plot, PR2 plot, and neutrality plot analyses. Furthermore, phylogenetic trees were constructed based on both Maximum Likelihood and Bayesian Inference analysis. Results: The C. salicicola mitochondrial genome comprises 15,720 bp and represents a typical circular DNA molecule with a high AT content of 83.8%. It contains the standard 37 genes, including 2 ribosomal RNAs (rRNAs), 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), and 2 long non-coding regions (control and repeat regions). Varying degrees of codon usage bias were found across different PCGs, and the bias was predominantly influenced by natural selection rather than mutational pressure. The ratio of nonsynonymous to synonymous substitutions (Ka/Ks) indicated that all PCGs in C. salicicola, as well as most other Aphidinae species, are under strong purifying selection. The phylogenetic analysis based on Maximum Likelihood and Bayesian Inference both strongly supported the monophyly of Aphidinae, Macrosiphini, and Aphidini. Crucially, the monophyletic genus Cavariella was resolved as a sister group to all other sampled species within the tribe Macrosiphini. Conclusions: This study provides new molecular data to support the sister relationship of the genus Cavariella to other Macrosiphini aphids. This study will enhance our understanding of phylogenetic relationships within the subfamily Aphidinae. Full article

Inhibition of respiratory chain complex I (NADH dehydrogenase) is a widely encountered biochemical consequence of drug intoxication and a primary consequence of mtDNA mutations and other mitochondrial defects. In an organ-selective form, it is also deployed as antidiabetic pharmacological treatment. Complex I inhibition evokes a pronounced metabolic reprogramming of uncertain purposefulness, as in several cases, anabolism appears to be fostered in a state of bioenergetic shortage. A hallmark of complex I inhibition is the enhanced biosynthesis of serine, usually accompanied by an induction of folate-converting enzymes. Here, we have revisited the differential transcriptional induction of these metabolic pathways in three published models of selective complex I inhibition: MPP-treated neuronal cells, methionine-restricted rats, and patient fibroblasts harboring an NDUFS2 mutation. We find that in a coupled fashion, serinogenesis and circular folate cycling provide an unrecognized alternative pathway of complete glucose oxidation that is mostly dependent on NADP instead of the canonic NAD cofactor (NADP:NAD ≈ 2:1) and thus evades the shortage of oxidized NAD produced by complex I inhibition. In contrast, serine utilization for anabolic purposes and C₁-folate provision for S-adenosyl-methionine production and transsulfuration cannot explain the observed transcriptional patterns, while C₁-folate provision for purine biosynthesis did occur in some models, albeit not universally. We conclude that catabolic glucose oxidation to CO₂, linked with NADPH production for indirect downstream respiration through fatty acid cycling, is the general purpose of the remarkably strong induction of serinogenesis after complex I inhibition. Full article