Mitochondrial DNA Research Articles

Ex ovo omnia - Why don't we know more about egg quality via imaging?

Determining egg quality is the foremost challenge in assisted reproductive technology (ART). Although extensive advances have been made in multiple areas of ART over the last forty years, oocyte quality assessment tools have not much evolved beyond standard morphological observation. The oocyte not only delivers half of the nuclear genetic material and all of the mitochondrial DNA to an embryo but also provides complete developmental support during embryonic growth. Oocyte mitochondrial numbers far exceed those of any somatic cell, yet little work has been done to evaluate the mitochondrial bioenergetics of an oocyte. Current standard oocyte assessment in in vitro fertilization (IVF) centers include the observation of oocytes and their surrounding cell complex (cumulus cells) via stereomicroscope or inverted microscope, which is largely primitive. Additional oocyte assessments include polar body grading and polarized light meiotic spindle imaging. However, the evidence regarding the aforementioned methods of oocyte quality assessment and IVF outcomes is contradictory and non-reproducible. High resolution microscopy techniques have also been implemented in animal and human models with promising outcomes. The current era of oocyte imaging continues to evolve with discoveries in artificial intelligence models of oocyte morphology selection albeit at a slow rate. In this review, past, current, and future oocyte imaging techniques will be examined with the goal of drawing attention to the gap which limits our ability to assess oocytes in real time. The implications of improved oocyte imaging techniques on patients undergoing IVF will be discussed as well as the need to develop point of care oocyte assessment testing in IVF labs.

Genetic determinants of renal scarring in children with febrile UTI.

Febrile urinary tract infections (UTIs) are among the most severe bacterial infections in infants, in which a subset of patients develops complications. Identifying infants at risk of recurrent infections or kidney damage based on clinical signs is challenging. Previous observations suggest that genetic factors influence UTI outcomes and could serve as predictors of disease severity. In this study, we conducted a nationwide survey of infant genotypes to develop a strategy for infection management based on individual genetic risk. Our aims were to identify genetic susceptibility variants for renal scarring(RS) and genetic host factors predisposing to dilating vesicoureteral reflux (VUR) and recurrent UTIs. To assess genetic susceptibility, we collected and analyzed DNA from blood using exome genotyping. Disease-associated genetic variants were identified through bioinformatics analysis, including allelic frequency tests and odds ratio calculations. Kidney involvement was defined using dimercaptosuccinic acid (DMSA) scintigraphy. In this investigation, a cohort comprising 1087 infants presenting with their first episode of febrile UTI was included. Among this cohort, a subset of 137 infants who underwent DMSA scanning was subjected to gene association analysis. Remarkable genetic distinctions were observed between patients with RS and those exhibiting resolved kidney involvement. Notably, the genetic signature indicative of renal scarring prominently featured mitochondrial genes. In this nationwide study of genetic susceptibility to RS after febrile UTIs in infancy, we identified a profile dominated by mitochondrial polymorphisms. This profile can serve as a predictor of future complications, including RS and recurrent UTIs.

Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease.

The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024.

Empagliflozin, a sodium-glucose cotransporter inhibitor enhancing mitochondrial action and cardioprotection in metabolic syndrome.

Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.

Connecting species-specific extents of genome reduction in mitochondria and plastids.

Mitochondria and plastids have both dramatically reduced their genomes since the endosymbiotic events that created them. The similarities and differences in the evolution of the two organelle genome types has been the target of discussion and investigation for decades. Ongoing work has suggested that similar mechanisms may modulate the reductive evolution of the two organelles in a given species, but quantitative data and statistical analyses exploring this picture remain limited outside of some specific cases like parasitism. Here, we use cross-eukaryote organelle genome data to explore evidence for coevolution of mitochondrial and chloroplast genome reduction. Controlling for differences between clades and pseudoreplication due to relatedness, we find that extents of mtDNA and ptDNA gene retention are related to each other across taxa, in a generally positive correlation that appears to differ quantitatively across eukaryotes, for example, between algal and non-algal species. We find limited evidence for coevolution of specific mtDNA and ptDNA gene pairs, suggesting that the similarities between the two organelle types may be due mainly to independent responses to consistent evolutionary drivers.

P32 Melanin confers protection against ultraviolet radiation-mediated mitochondrial DNA damage in skin of colour

P32 Melanin confers protection against ultraviolet radiation-mediated mitochondrial DNA damage in skin of colour

The rearrangement features and phylogenetic signals of mitochondrial genomes of gall midge subfamily Cecidomyiinae (Diptera: Cecidomyiidae) with first complete mitogenome of an economically important mango gall midge pest, Procontarina fructiculi from Guangxi, China

ABSTRACT In this study, we obtained the first complete mitochondrial genome of Procontarina fructiculi, an important mango gall midge pest from Guangxi, China. The mitogenome of P. fructiculi was sequenced and annotated for the first time, and compared with all the published and annotated data of Cecidomyiidae species to summarise the gall midge organisation and rearrangement features of mitochondrial genomes with phylogenetic analysis. The comparison of gall midge mitochondrial genome structure shows that the rearrangement of the mitochondrial gene structure is very common, and most rearrangements are embodied in rearrangement in the order of tRNAs. The phylogenetic results based on the maximum likelihood (ML) and Bayesian inference (BI) methods both highly supported the monophyly of Cecidomyiinae. Cecidomyiinae can be divided into two distinct clades (except Cecidomyiidae sp. 3): A: (Mayetiola destructor + Rhopalomyia pomum) and B: (Asphondylia rosetta + ((Procontarinia fructiculi + Orseolia oryzae) + ((Cecidomyiidae sp. 1 + Aphidoletes aphidimyza) + Cecidomyiidae sp. 2))). Based on the above results, some phylogenetic signals in rearrangement have been found in the mitochondrial genome structure of Cecidomyiinae for the first time.

Two residues in the DNA binding site of Pif1 helicase are essential for nuclear functions but dispensable for mitochondrial respiratory growth.

Pif1 helicase functions in both the nucleus and mitochondria. Pif1 tightly couples ATP hydrolysis, single-stranded DNA translocation, and duplex DNA unwinding. We investigated two Pif1 variants (F723A and T464A) that have each lost one site of interaction of the protein with the DNA substrate. Both variants exhibit minor reductions in affinity for DNA and ATP hydrolysis but have impaired DNA unwinding activity. However, these variants translocate on single-stranded DNA faster than the wildtype enzyme and can slide on the DNA substrate in an ATP-independent manner. This suggests they have lost their grip on the DNA, interfering with coupling ATP hydrolysis to translocation and unwinding. Yeast expressing these variants have increased gross chromosomal rearrangements, increased telomere length, and can overcome the lethality of dna2Δ, similar to phenotypes of yeast lacking Pif1. However, unlike pif1Δ mutants, they are viable on glycerol containing media and maintain similar mitochondrial DNA copy numbers as Pif1 wildtype. Overall, our data indicate that a tight grip of the trailing edge of the Pif1 enzyme on the DNA couples ATP hydrolysis to DNA translocation and DNA unwinding. This tight grip appears to be essential for the Pif1 nuclear functions tested but is dispensable for mitochondrial respiratory growth.

New member of Plasmodium (Vinckeia) and Plasmodium cyclopsi discovered in bats in Sierra Leone - nuclear sequence and complete mitochondrial genome analyses.

Malaria remains the most important arthropod-borne infectious disease globally. The causative agent, Plasmodium, is a unicellular eukaryote that develops inside red blood cells. Identifying new Plasmodium parasite species that infect mammalian hosts can shed light on the complex evolution and diversity of malaria parasites. Bats feature a high diversity of microorganisms including seven separate genera of malarial parasites. Three species of Plasmodium have been reported so far, for which scarce reports exist. Here we present data from an investigation of Plasmodium infections in bats in the western Guinean lowland forest in Sierra Leone. We discovered a new Plasmodium parasite in the horseshoe bat Rhinolophus landeri. Plasmodium cyclopsi infections in a member of leaf-nosed bats, Doryrhina cyclops, exhibited a high prevalence of 100%. Phylogenetic analysis of complete mitochondrial genomes and nine nuclear markers recovered a close relationship between P. cyclopsi and the new Plasmodium parasite with the rodent species Plasmodium berghei, a widely used in vivo model to study malaria in humans. The data suggests that the "rodent/bat" Plasmodium (Vinckeia) clade represents a diverse group of malarial parasites that would likely expand with a systematic sampling of small mammals in tropical Africa. Identifying the bat Plasmodium repertoire is central to our understanding of the evolution of Plasmodium parasites in mammals.

Genetic variability of Aedes aegypti (Diptera: Culicidae) in El Salvador and Honduras: presence of a widespread haplotype and implications for mosquito control.

This study examined population genetics of Aedes aegypti in El Salvador and Honduras, two adjacent countries in Central America. Aedes aegypti is associated with yellow fever, dengue, chikungunya, and Zika. Each year, thousands of cases of dengue are typically reported in El Salvador and Honduras. In El Salvador, collections were obtained from five Departments. In Honduras, samples were obtained from six municipalities in four Departments. Mitochondrial DNA cytochrome oxidase I (COI) was sequenced, and consensus sequences were combined with available sequences from El Salvador to determine haplotype number, haplotype diversity, nucleotide diversity, and Tajima's D. A haplotype network was produced to examine the relationship between genotypes. In El Salvador, there were 17 haplotypes, while in Honduras there were 4 haplotypes. In both El Salvador and Honduras, Haplotype 1 is most abundant and widespread. In El Salvador, haplotype H2 was also widespread in 10 of 11 sampled municipalities, but it was not present in Honduras. The capital of El Salvador (San Salvador) and the eastern region of ES had the highest haplotype diversity of regions sampled. Haplotype 1 and H2 each belong to different phylogenetic lineages of Ae. aegypti. The most geographically widespread haplotype (H1) may have been present the longest and could be a remnant from previous eradication programs. These data may contribute to future control programs for Ae. aegypti in the two countries.

Genomic analysis and phylogenetic characterization of Himalayan snow trout, Schizothorax esocinus based on mitochondrial protein-coding genes.

Mitochondrial DNA (mtDNA) has become a significant tool for exploring genetic diversity and delineating evolutionary links across diverse taxa. Within the group of cold-water fish species that are native to the Indian Himalayan region, Schizothorax esocinus holds particular importance due to its ecological significance and is potentially vulnerable to environmental changes. This research aims to clarify the phylogenetic relationships within the Schizothorax genus by utilizing mitochondrial protein-coding genes. Standard protocols were followed for the isolation of DNA from S. esocinus. For the amplification of mtDNA, overlapping primers were used, and then subsequent sequencing was performed. The genetic features were investigated by the application of bioinformatic approaches. These approaches covered the evaluation of nucleotide composition, codon usage, selective pressure using nonsynonymous substitution /synonymous substitution (Ka/Ks) ratios, and phylogenetic analysis. The study specifically examined the 13 protein-coding genes of Schizothorax species which belongs to the Schizothoracinae subfamily. Nucleotide composition analysis showed a bias towards A + T content, consistent with other cyprinid fish species, suggesting evolutionary conservation. Relative Synonymous Codon Usage highlighted leucine as the most frequent (5.18%) and cysteine as the least frequent (0.78%) codon. The positive AT-skew and the predominantly negative GC-skew indicated the abundance of A and C. Comparative analysis revealed significant conservation of amino acids in multiple genes. The majority of amino acids were hydrophobic rather than polar. The purifying selection was revealed by the genetic distance and Ka/Ks ratios. Phylogenetic study revealed a significant genetic divergence between S. esocinus and other Schizothorax species with interspecific K2P distances ranging from 0.00 to 8.87%, with an average of 5.76%. The present study provides significant contributions to the understanding of mitochondrial genome diversity and genetic evolution mechanisms in Schizothoracinae, hence offering vital insights for the development of conservation initiatives aimed at protecting freshwater fish species.

The genome sequence of the Barred Sallow moth, Tiliacea aurago ([Denis &amp; Schiffermüller], 1775)

We present a genome assembly from an individual male Tiliacea aurago (the Barred Sallow; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence is 798.0 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.41 kilobases in length. Gene annotation of this assembly on Ensembl identified 19,865 protein coding genes.

The genome sequence of the northern blowfly, Protophormia terraenovae (Robineau-Desvoidy, 1830)

We present a genome assembly from an individual male Protophormia terraenovae (the Northern Blowfly; Arthropoda; Insecta; Diptera; Calliphoridae). The genome sequence is 783.7 megabases in span. Most of the assembly is scaffolded into 7 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 15.75 kilobases in length. Gene annotation of this assembly on Ensembl identified 12,692 protein coding genes.

The genome sequence of the Green Pug moth, Pasiphila rectangulata (Linnaeus, 1758)

We present a genome assembly from an individual male Pasiphila rectangulata (the Green Pug; Arthropoda; Insecta; Lepidoptera; Geometridae). The genome sequence is 582.5 megabases in span. Most of the assembly is scaffolded into 30 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.74 kilobases in length. Gene annotation of this assembly on Ensembl identified 17,153 protein coding genes.

The genome sequence of an ichneumonid wasp, Ophion ellenae Johansson, 2019

We present a genome assembly from an individual female Ophion ellenae (ichneumonid wasp; Arthropoda; Insecta; Hymenoptera; Ichneumonidae). The genome sequence is 650.3 megabases in span. Most of the assembly is scaffolded into 13 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 29.49 kilobases in length.

The genome sequence of an ichneumonid wasp, Amblyjoppa fuscipennis (Wesmael, 1844)

We present a genome assembly from an individual male Amblyjoppa fuscipennis (an ichneumonid wasp; Arthropoda; Insecta; Hymenoptera; Ichneumonidae). The genome sequence is 278.5 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 35.62 kilobases in length.

The genome sequence of the Green Oak Leaf Roller, Tortrix viridana (Linnaeus, 1758)

We present a genome assembly from a female Tortrix viridana (the Green Oak Leaf Roller; Arthropoda; Insecta; Lepidoptera; Tortricidae). The genome sequence is 456.6 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z and W sex chromosomes. The mitochondrial genome has also been assembled and is 16.43 kilobases in length.

Altered mitochondrial function in fibroblast cell lines derived from disease carriers of spinal muscular atrophy

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive childhood-onset neuromuscular disease with a carrier frequency of ~1:50. Mitochondrial abnormalities are widespread in patients with SMA. Disease carriers for SMA (i.e., the parents of patients with SMA) are viewed as asymptomatic for SMA disease. As far as we are aware, mitochondria have not been previously examined in SMA carriers, yet as they are maternally inherited, mitochondrial function in SMA carriers has putative implications for disease pathogenesis.MethodsFibroblast cell lines derived from SMA carriers and controls were obtained from two different sources and cultured under standard conditions. The mitochondrial membrane potential, reactive oxygen species (ROS) production, citrate synthase activity, and bioenergetic analysis were examined as measures of mitochondrial function. The mitochondrial genome was also sequenced in a subset of the fibroblast cell lines to identify any mitochondrial DNA variants.ResultsHere, we show a depolarized mitochondrial membrane potential, increased levels of reactive oxygen species, and reduced citrate synthase activity in SMA carriers compared with controls. A likely pathogenic variant in the MT-CO3 gene (which encodes subunit III of cytochrome c oxidase) was also identified in a paternal carrier.ConclusionsThis study was conducted as a preliminary investigation of mitochondrial function in SMA carriers. Our findings suggest that disease carriers of SMA show differences in mitochondrial function, indicative of a subclinical mitochondrial phenotype. Further investigation in a larger sample set is warranted.

The genome sequence of the Rusty-dot Pearl moth, Udea ferrugalis (Hübner, 1796)

We present a genome assembly from an individual male Udea ferrugalis (the Rusty-dot Pearl moth; Arthropoda; Insecta; Lepidoptera; Crambidae). The genome sequence is 495.6 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.39 kilobases in length. Gene annotation of this assembly on Ensembl identified 18,035 protein coding genes.

The genome sequence of the Pearl-bordered Fritillary, Boloria euphrosyne (Linnaeus, 1758)

We present a genome assembly from an individual male Boloria euphrosyne (the Pearl-bordered Fritillary; Arthropoda; Insecta; Lepidoptera; Nymphalidae). The genome sequence is 400.4 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.17 kilobases in length. Gene annotation of this assembly on Ensembl identified 19,138 protein coding genes.