Search Results (82)

Alterations in the mitochondrial genome (mtDNA) have been shown to be key in cancer development and could be useful as biomarkers for diagnosis, prognosis, and treatment. To identify mtDNA variants associated with breast cancer, we analyzed the whole mtDNA sequence from paired tissues (tumor–peripheral blood) of women with this malignancy and from peripheral blood samples of healthy women. The mtDNA mutational landscape, heteroplasmy levels of the variants, and mitochondrial ancestry were established. Comparative analysis between cases and controls revealed significant differences in the number and location of variants, as well as in the heteroplasmy levels. Cases showed higher mutation number in MT-ND5, tRNAs, and rRNAs genes; increased proportion of missense variants; and elevated mtDNA content, than controls. Notably, a high blood mtDNA mutational burden (OR = 3.83, CI: 1.89–7.95, p = 5.3 × 10⁻⁵) and five mtDNA variants showed association with the risk of breast cancer. Furthermore, a low tumor mutational burden (HR = 7.82, CI: 1.0–63.6, p = 0.05) and the haplogroup L (HR = 12.16, CI: 2.0–72.8, p = 0.0062) were associated with decreased overall and disease-free survival, respectively. Our study adds evidence of the potential usefulness of mtDNA variants as risk and prognosis biomarkers for breast cancer. Full article

Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer–T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response. Full article

Human mitochondrial DNA (mtDNA) is a relevant marker in evolutionary and population genetics, including ancient DNA (aDNA) research, due to inherent characteristics. However, aDNA is prone to damage and sequencing artefacts, potentially confounding evolutionary interpretations. To assess evolutionary patterns in ancient and modern mtDNA, we built a phylogeny comprising 63,965 modern and 3757 ancient public mitogenomes, classified mutations by genomic region and functional effect, and analysed distribution, frequency, and predicted pathogenicity of private and pre-terminal mutations, investigating purifying selection. We compared mutation class ratios (non-synonymous, rRNA, tRNA, nonsense vs. synonymous) across ancient and modern terminal branches and pre-terminal nodes. The predicted pathogenicity of non-synonymous mutations was evaluated across major European haplogroups using three tools. Ancient variants exhibited higher ratios of potentially deleterious mutations and significantly elevated pathogenicity scores compared to modern and pre-terminal branches, highlighting a mutation load likely inflated by damage-related artefacts. Remarkably, nonsense mutations—largely incompatible with life—were over 70 times more frequent in aDNA. The correlation between mutation ratios and predicted deleteriousness across haplogroups suggests a pattern incompatible with biological persistence or relaxed selection alone. These findings highlight the importance of rigorous quality control for ancient data in evolutionary inference, molecular clock calibration, and pathogenic variant identification. Full article

Background. The coevolution of nuclear and mitochondrial genomes has guaranteed mitochondrial function for millions of years. The introduction of European (EUR) and African (AFR) genomes into the Ameridian continent during the Columbus exchange in Latin America created an opportunity to naturally test different combinations of nuclear and mitochondrial genomes. However, the impact of potential “mitonuclear discordance” (MND, differences in ancestries) has not been evaluated in Latin American admixed individuals (AMR) affected with developmental disorders, even though MND alters mitochondrial function and reduces viability in other organisms. Methods. To characterize MND in healthy and affected AMR individuals, we used AMR genotype data from the 1000 Genomes Project (n = 385), two cohorts of 22q.11 deletion syndrome patients 22qDS-ARG (n = 26) and 22qDS-CHL (n = 58), and a cohort of patients with multiple congenital anomalies and/or neurodevelopmental disorders (DECIPHERD, n = 170). Based on their importance to mitochondrial function, genes were divided into all mitonuclear genes (n = 1035), high-mt (n = 167), low-mt (n = 793), or OXPHOS (n = 169). We calculated local ancestry using FLARE and estimated MND as the fraction of nuclear mitochondrial genes ancestry not matching the mtDNA ancestry and ∆MND as (MNDoffspring—MNDmother)/MNDmother. Results. Generally, MND showed distinctive population and haplogroup distributions (ANOVA p < 0.05), with haplogroup D showing the lowest MND of 0.49 ± 0.17 (mean ± s.d.). MND was significantly lower in 22qDS-ARG patients at 0.43 ± 0.24 and DECIPHERD patients at 0.56 ± 0.12 compared to healthy individuals at 0.60 ± 0.09 (ANOVA p < 0.05). OXPHOS and high-mt showed the same trend, but with greater differences between healthy and affected individuals. Conclusions. MND seems to inform population history and constraint among affected individuals, especially for OXPHOS and high-mt genes. Full article

The Hungarian Grey (HG) cattle breed was almost extinct after WW2; only 200 cows and six bulls survived. Despite the historical significance of the HG, no comprehensive genomic analysis has been conducted to clarify its genetic diversity and evolutionary history. Previous studies have relied on random or limited pedigree sampling, lacking a fully representative dataset determining genetic and conservation status. Here, the founder sampling of 110 individuals and the analysis of their mitochondrial DNA (mtDNA) sequence variation aim to investigate the phylogenetic placement of the breed using, for the first time, a fully representative sample. All identified haplogroups belong to the taurine T macro-haplogroup, with a predominance of T3 (89.1%), followed by T2 (4.5%), T1 (3.6%), and T1′2′3 (2.7%). The phylogenetic analysis confirms the absence of ancient haplogroups derived from European aurochs, suggesting a purely taurine origin for the HG breed. The high haplotype diversity (Hd = 0.94) and the genetic similarity to other Podolian breeds, particularly Maremmana cattle, indicate a preserved genetic background despite centuries of selective breeding. The lack of intensive crossbreeding practices has maintained the original beef production purpose of the breed, distinguishing it from the crossbred Podolian cattle used for dual-purpose or dairy production. Full article

This Systematic Literature Review (SLR) consolidates current research on mitochondrial DNA (mtDNA) analysis in horses, focusing on genetic variation, maternal lineage tracing, and haplogroup identification. The article selection process screened 1380 articles, with 76 fulfilling the inclusion criteria. Data extraction covered sampling techniques, studied mtDNA regions, sequencing methods, and haplogroup identification. Following the methodology of the PRISMA guidelines, this review encompasses studies published since 2012, obtained from Scopus, PubMed, Research4Life, Web of Science, and ScienceDirect. The major findings emphasise the use of mtDNA for tracing ancestry, validating maternal lineages, and identifying haplogroups along with their geographic distributions. This review identifies challenges, including the need to update the haplogroup classification system and potential information loss due to sequence trimming. Additionally, it examines promising avenues for future research, such as the implementation of next-generation sequencing and the merging of haplogroup data with performance traits, which could influence conservation initiatives and breeding programs. This review emphasises the necessity for standardised classification systems and further research on underrepresented breeds and regions to improve our understanding of equine genetic diversity. Full article

An investigation of the mtDNA haplogroup in 96 Taiwanese women with diminished ovarian response (DOR) and normal ovarian response (NOR) showed that only the haplogroup R is less likely to experience DOR than other mtDNA haplogroups. When analyzing the relationship between age and mitochondria-related markers (mtDNA copy number, ROS levels, and telomere length), it was observed that ROS levels and telomere length exhibited age-dependent changes, and the number of retrieved oocytes decreased with age. However, in the R haplogroup, these mitochondria-related markers remained stable and did not show significant changes with age. Additionally, in the R haplogroup, the number of oocytes did not decline with age, suggesting a unique protective effect associated with this haplogroup. Our study supports the notion that the mtDNA haplogroup may serve as a biomarker for infertility in Taiwanese women. Full article

The Danube Clouded Yellow (Colias myrmidone) has experienced one of the most dramatic declines among European butterflies. To estimate genetic diversity in the last population in Poland that has survived in the Knyszyn Forest (KF), we analyzed mitochondrial (COI) and nuclear (EF-1α) polymorphisms in individuals sampled in 2014 and 2022. The results were compared with genetic data obtained in 2014 from a recently extirpated nearby population (Czerwony Bór, CB). Because mtDNA polymorphisms in insects can be modulated by endosymbionts, the samples were screened for Wolbachia. The polymorphism of EF-1α indicated that diversity was gradually decreasing. The KF experienced rapid demographic processes, manifested by a significant change in allele frequency. The small differentiation in nuclear markers between the KF and CB in 2014 suggests that the regional population used to be genetically uniform. Four COI haplotypes that were identified in this study probably belong to two different haplogroups. Wolbachia was detected only in individuals with one specific haplotype, and the prevalence was female-biased, suggesting the induction of two reproductive manipulations. The most common COI haplotype found in Poland was the same as that reported from other parts of Europe, not only for C. myrmidone but also C. caucasica. These results allow us to question the distinctiveness of each taxa. Full article

We report on a sporadic patient suffering Leigh syndrome characterized by bilateral lesions in the lenticular nuclei and spastic dystonia, intellectual disability, sensorineural deafness, hypertrophic cardiomyopathy, exercise intolerance, and retinitis pigmentosa. Complete sequencing of mitochondrial DNA revealed the heteroplasmic nucleotide change m.15635T>C affecting a highly conserved amino acid position (p.Ser297Pro) in the cytochrome b (MT-CYB) gene on a haplogroup K1c1a background, which includes a set of four non-synonymous polymorphisms also present in the same gene. Biochemical studies documented respiratory chain impairment due to complex III defect. This variant fulfils the criteria for being pathogenic and was previously reported in a sporadic case of fatal neonatal polyvisceral failure. Full article

Lipizzan is a famous horse breed dating back to 1580 when the original stud of Lipica was established by the Hasburg Archduke Charles II. Currently, the Italian State Stud of Lipizzan Horses (ASCAL) is a conservation nucleus managed through strict mating rules where mitochondrial DNA sequences are used to verify the correct assignment of mares to a historical pedigree maternal lineage. Here, we analyzed the D-loop sequences of Lipizzan horses from the ASCAL in Monterotondo (Rome, Italy) in order to confirm their pedigree assignment to known female founder families. The concurrent investigation of the paternal counterpart based on variation in the male-specific region of the Y chromosome (MSY) showed a prevalence of HT02 (80%), typical of the Neapolitan/Oriental wave. The mtDNA polymorphisms identified shaped nine haplotypes that were unequivocally assigned to each of nine classical mare families of the stud (Africa, Almerina, Argentina, Deflorata, Djebrin, Fistula, Ivanka, Sardinia, Spadiglia), while the Europa and Theodorosta families shared a tenth haplotype. New polymorphisms were identified in a not previously studied region (np 16100–16350). The mtDNA phylogenetic analysis revealed that the Lipizzans of the Monterotondo stud belong to six haplogroups (B, C, G, L, M, Q), out of the 18 recorded for the equine species. This work enabled us to identify and preserve ten haplotypes from the historical maternal lines in a small stud kept in genetic segregation for over 100 years. Full article

Animal biodiversity is essential for maintaining the functionality of local food systems and ensuring sustainable livelihoods. Starting in 2000, the Food and Agriculture Organization of the United Nations (F.A.O.) has drawn attention to the decline in cattle populations, including the Transylvanian Pinzgau breed from Romania. Renowned for its hardiness, adaptability, and enhanced resistance to diseases and climate change, the Transylvanian Pinzgau is regarded as an important genetic asset for advancing livestock production. As a result, tracking genetic diversity has become a key focus in breeding programs, particularly for small, endangered local populations that play a vital role in regional agro-ecological systems. This research paper sought to assess the genetic diversity of a group of 24 head of cattle from the Transylvania region by analyzing two mtDNA markers, cytochrome b and D-loop sequences, both widely recognized for their relevance and importance in the analysis of genetic diversity of cattle and phylogenetic studies. The findings, derived through statistical analysis of nucleotide sequences using specialized software, indicated that the analyzed cattle are part of the ancestral T haplogroup, with a direct lineage tracing back to Bos taurus. This information can aid in developing crossbreeding programs focused on conserving essential genetic resources, improving other cattle breeds, and protecting biodiversity. Full article

Understanding the genetic diversity patterns of endangered species is crucial for biodiversity conservation. The endangered salamander Hynobius yiwuensis, endemic to the mainland and Zhoushan Island in Zhejiang, China, has suffered from sharp population declines due to habitat loss. However, the levels and patterns of genetic diversity, differentiation, and population structure of H. yiwuensis remain poorly understood. Here, we explored the genetic diversity and phylogeography of H. yiwuensis based on partial mtDNA sequences (Cytb and CO1) through 111 individuals collected from seven localities. Relatively high overall haplotype diversity (h = 0.965) and low nucleotide diversity (π = 0.013) were detected. Our results, through phylogenetic trees and haplotype network analyses, revealed two divergent haplogroups, mainland and island, and the estimated divergence time indicated they diverged ~2.44 million years ago, which coincided with the period when Zhoushan Island became separated from the mainland. Full article

El Hierro is the smallest and westernmost island of the Canary Islands, whose population derives from an admixture of different ancestral components and that has been subjected to genetic isolation. We established the “El Hierro Genome Study” to characterize the health status and the genetic composition of ~10% of the current population of the island, accounting for a total of 1054 participants. Detailed demographic and clinical data and a blood sample for DNA extraction were obtained from each participant. Genomic genotyping was performed with the Global Screening Array (Illumina). The genetic composition of El Hierro was analyzed in a subset of 416 unrelated individuals by characterizing the mitochondrial DNA (mtDNA) and Y-chromosome haplogroups and performing principal component analyses (PCAs). In order to explore signatures of isolation, runs of homozygosity (ROHs) were also estimated. Among the participants, high blood pressure, hypercholesterolemia, and diabetes were the most prevalent conditions. The most common mtDNA haplogroups observed were of North African indigenous origin, while the Y-chromosome ones were mainly European. The PCA showed that the El Hierro population clusters near 1000 Genomes’ European population but with a shift toward African populations. Moreover, the ROH analysis revealed some individuals with an important portion of their genomes with ROHs exceeding 400 Mb. Overall, these results confirmed that the “El Hierro Genome” cohort offers an opportunity to study the genetic basis of several diseases in an unexplored isolated population. Full article

Variants of mitochondrial DNA (mtDNA) have been identified as risk factors for the development of Parkinson’s disease (PD). However, the underlying pathogenetic mechanisms remain unclear. Cybrid models carrying various genotypes of mtDNA variants were tested for resistance to PD-simulating MPP⁺ treatment. The most resistant line was selected for transcriptome profiling, revealing specific genes potentially influencing the resistant characteristic. We then conducted protein validation and molecular biological studies to validate the related pathways as the influential factor. Cybrids carrying the W3 mtDNA haplogroup demonstrated the most resistance to the MPP⁺ treatment. In the transcriptome study, PPP1R15A was identified, while further study noted elevated expressions of the coding protein GADD34 across all cybrids. In the study of GADD34-related mitochondrial unfolding protein response (mtUPR), we found that canonical mtUPR, launched by the phosphate eIF2a, is involved in the resistant characteristic of specific mtDNA to MPP⁺ treatment. Our study suggests that a lower expression of GADD34 in the late phase of mtUPR may prolong the mtUPR process, thereby benefitting protein homeostasis and facilitating cellular resistance to PD development. We herein demonstrate that GADD34 plays an important role in PD development and should be further investigated as a target for the development of therapies for PD. Full article

Mitochondrial (mt) DNA plays an important role in the fields of forensic and clinical genetics, molecular anthropology, and population genetics, with mixture interpretation being of particular interest in medical and forensic genetics. The high copy number, haploid state (only a single haplotype contributed per individual), high mutation rate, and well-known phylogeny of mtDNA, makes it an attractive marker for mixture deconvolution in damaged and low quantity samples of all types. Given the desire to deconvolute mtDNA mixtures, the goals of this study were to (1) create a new software, MixtureAceMT™, to deconvolute mtDNA mixtures by assessing and combining two existing software tools, MixtureAce™ and Mixemt, (2) create a dataset of in-silico MPS mixtures from whole mitogenome haplotypes representing a diverse set of population groups, and consisting of two and three contributors at different dilution ratios, and (3) since amplicon targeted sequencing is desirable, and is a commonly used approach in forensic laboratories, create biological mixture data associated with two amplification kits: PowerSeq™ Whole Genome Mito (Promega™, Madison, WI, USA) and Precision ID mtDNA Whole Genome Panel (Thermo Fisher Scientific by AB™, Waltham, MA, USA) to further validate the software for use in forensic laboratories. MixtureAceMT™ provides a user-friendly interface while reducing confounding features such as NUMTs and noise, reducing traditionally prohibitive processing times. The new software was able to detect the correct contributing haplogroups and closely estimate contributor proportions in sequencing data generated from small amplicons for mixtures with minor contributions of ≥5%. A challenge of mixture deconvolution using small amplicon sequencing is the potential generation of spurious haplogroups resulting from private mutations that differ from Phylotree. MixtureAceMT™ was able to resolve these additional haplogroups by including known haplotype/s in the evaluation. In addition, for some samples, the inclusion of known haplotypes was also able to resolve trace contributors (minor contribution 1–2%), which remain challenging to resolve even with deep sequencing. Full article