Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a polymerase gamma (POLG) exonuclease-deficient model, the PolgD257A mutator mice (D257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial (mt) dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the D257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mt morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress and parkin-mediated mitophagy in the ages analyzed in the retina or RPE of D257A mice. Additionally, D257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mt markers displayed different abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mtDNA mutations leads to impaired mt function and accelerated aging, resulting in retinal degeneration.

Sargassum hemiphyllum var. chinense, a prevalent seaweed along the Chinese coast, has economic and ecological significance. However, systematic positions within Sargassum and among the three orders of Phaeophyceae, Fucales, Ectocarpales, and Laminariales are in debate. Here, we reported the organellar genomes of S. hemiphyllum var. chinense (34,686-bp mitogenome with 65 genes and 124,323 bp plastome with 173 genes) and the investigation of comparative genomics and systematics of 37 mitogenomes and 22 plastomes of Fucales (including S. hemiphyllum var. chinense), Ectocarpales, and Laminariales in Phaeophyceae. Whole genome collinearity analysis showed gene number, type, and arrangement were consistent in organellar genomes of Sargassum with 360 SNP loci identified as S. hemiphyllum var. chinense and two genes (rps7 and cox2) identified as intrageneric classifications of Sargassum. Comparative genomics of the three orders of Phaeophyceae exhibited the same content and different types (petL was only found in plastomes of the order Fucales and Ectocarpales) and arrangements (most plastomes were rearranged, but trnA and trnD in the mitogenome represented different orders) in genes. We quantified the frequency of RNA-editing (canonical C-to-U) in both organellar genomes; the proportion of edited sites corresponded to 0.02% of the plastome and 0.23% of the mitogenome (in reference to the total genome) of S. hemiphyllum var. chinense. The repetition ratio of Fucales was relatively low, with scattered and tandem repeats (nine tandem repeats of 14-24 bp) dominating, while most protein-coding genes underwent negative selection (Ka/Ks < 1). Collectively, these findings provide valuable insights to guide future species identification and evolutionary status of three important Phaeophyceae order species.

According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca2+] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases.

The evidential value of an mtDNA match between biological remains and their potential donor is determined by the random match probability of the haplotype. This probability is based on the haplotype\'s population frequency estimate. Consequently, implementing a population study representative of the population relevant to a forensic case is vital to correctly evaluating the evidence. The emerging number of poaching cases and the limited availability of such data emphasizes the need for an improved fallow deer mtDNA population databank for forensic purposes, including targeting the entire mitochondrial control region. By sequencing a 945-base-pair-long segment of the mitochondrial control region in 138 animals from five populations in Hungary, we found four different haplotypes, including one which had not yet been described. Our results, supplemented with data already available from previous research, do not support the possibility of determining the population of origin, although some patterns of geographical separation can be distinguished. Estimates of molecular diversity indicate similarly low mtDNA diversity (Hd = 0.565 and π = 0.002) compared to data from other countries. The calculated random match probability of 0.547 shows a high probability of coincidence and, therefore, a limited capacity for exclusion. Our results indicate that despite the overall low genetic diversity of mtDNA within the Hungarian fallow deer samples, a pattern of differentiation among the regions is present, which can have relevance from a forensic point of view.

Endometrial cancer (EC) is a devastating and common disease affecting women\'s health. The NCI Surveillance, Epidemiology, and End Results Program predicted that there would be >66,000 new cases in the United States and >13,000 deaths from EC in 2023, and EC is the sixth most common cancer among women worldwide. Regulation of mitochondrial metabolism plays a role in tumorigenesis. In proliferating cancer cells, mitochondria provide the necessary building blocks for biosynthesis of amino acids, lipids, nucleotides, and glucose. One mechanism causing altered mitochondrial activity is mitochondrial DNA (mtDNA) mutation. The polyploid human mtDNA genome is a circular double-stranded molecule essential to vertebrate life that harbors genes critical for oxidative phosphorylation plus mitochondrial-derived peptide genes. Cancer cells display aerobic glycolysis, known as the Warburg effect, which arises from the needs of fast-dividing cells and is characterized by increased glucose uptake and conversion of glucose to lactate. Solid tumors often contain at least one mtDNA substitution. Furthermore, it is common for cancer cells to harbor mixtures of wild-type and mutant mtDNA genotypes, known as heteroplasmy. Considering the increase in cancer cell energy demand, the presence of functionally relevant carcinogenesis-inducing or environment-adapting mtDNA mutations in cancer seems plausible. We review 279 EC tumor-specific mtDNA single nucleotide variants from 111 individuals from different studies. Many transition mutations indicative of error-prone DNA polymerase γ replication and C to U deamination events were present. We examine the spectrum of mutations and their heteroplasmy and discuss the potential biological impact of recurrent, non-synonymous, insertion, and deletion mutations. Lastly, we explore current EC treatments, exploiting cancer cell mitochondria for therapy and the prospect of using mtDNA variants as an EC biomarker.

Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.

Subjective well-being (SWB) is an important measure for mental health status. Previous research has shown that physical activity can affect an individual\'s well-being, yet the underlying molecular mechanism remains to be clarified. In this study, we aim to evaluate the potential interactions between mitochondrial genes and physical activity (PA) as well as their combined effects on individual well-being. SWB phenotype data in UK Biobank were enrolled for this study including nine aspects such as work/job satisfaction, health satisfaction, family relationship satisfaction, friendships satisfaction, financial situation satisfaction, ever depressed for a whole week, general happiness, general happiness with own health and belief that own life is meaningful. We made analysis for each aspects separately. Firstly, mitochondria-wide association studies (MiWAS) was conducted to assess the association of mitochondrial Single Nucleotide Polymorphisms SNP with each aspect of SWB. Then an interaction analysis of mitochondrial DNA (mtDNA) mutation and PA was performed to evaluate their joint effect on SWB status. Meanwhile, these two analysis were made for female and male group separately as well as the total samples, all under the control of possible confounding factors including gender, age, Townsend Deprivation Index (TDI), education, alcohol consumption, smoking habits, and 10 principal components. MiWAS analysis identified 45 mtSNPs associated with 9 phenotypes of SWB. For example, m.15218A > G on MT-CYB in the health satisfaction phenotype of the total subjects. Gender-specific analyses found 30 mtSNPs in females and 58 in males, involving 13 mtGenes. In mtDNA-PA interaction analysis, we also identified 10 significant mtDNA-PA interaction sets for SWB. For instance, m.13020 T > C (MT-ND5) was associated with the SWB financial situation satisfaction phenotype in all subjects (P = 0.00577). In addition, MiWAS analysis identified 12 mtGene variants associated with SWB, as MT-ND1 and MT-ND2. However, in mtDNA-PA interactions we detected 7 mtDNA affecting psychiatric disorders occurring, as in the friendships satisfaction phenotype (m.3394 T > C on MT-ND1). Our study results suggest an implication of the interaction between mitochondrial function and physical activity in the risk of psychiatric disorder development.

Determine the geographic place of origin and maternal lineage of prehistoric human skeletal remains discovered in Puyil Cave, Tabasco State, Mexico, located in a region currently populated by Olmec, Zoque and Maya populations.
All specimens were radiocarbon (14C) dated (beta analytic), had dental modifications classified, and had an analysis of 13 homologous reference points conducted to evaluate artificial cranial deformation (ACD). Following DNA purification, hypervariable region I (HVR-1) of the mitogenome was amplified and Sanger sequenced. Finally, Next Generation Sequencing (NGS) was performed for total DNA. Mitochondrial DNA (mtDNA) variants and haplogroups were determined using BioEdit 7.2 and IGV software and confirmed with MITOMASTER and WebHome softwares.
Radiocarbon dating (14C) demonstrated that the inhabitants of Puyil Cave lived during the Archaic and Classic Periods and displayed tabular oblique and tabular mimetic ACD. These pre-Hispanic remains exhibited five mtDNA lineages: A, A2, C1, C1c and D4. Network analysis revealed a close genetic affinity between pre-Hispanic Puyil Cave inhabitants and contemporary Maya subpopulations from Mexico and Guatemala, as well as individuals from Bolivia, Brazil, the Dominican Republic, and China.
Our results elucidate the dispersal of pre-Hispanic Olmec and Maya ancestors and suggest that ACD practices are closely related to Olmec and Maya practices. Additionally, we conclude that ACD has likely been practiced in the region since the Middle-Archaic Period.

We tackle the problem of estimating species TMRCAs (Time to Most Recent Common Ancestor), given a genome sequence from each species and a large known phylogenetic tree with a known structure (typically from one of the species). The number of transitions at each site from the first sequence to the other is assumed to be Poisson distributed, and only the parity of the number of transitions is observed. The detailed phylogenetic tree contains information about the transition rates in each site. We use this formulation to develop and analyze multiple estimators of the species\' TMRCA. To test our methods, we use mtDNA substitution statistics from the well-established Phylotree as a baseline for data simulation such that the substitution rate per site mimics the real-world observed rates.
We evaluate our methods using simulated data and compare them to the Bayesian optimizing software BEAST2, showing that our proposed estimators are accurate for a wide range of TMRCAs and significantly outperform BEAST2. We then apply the proposed estimators on Neanderthal, Denisovan, and Chimpanzee mtDNA genomes to better estimate their TMRCA with modern humans and find that their TMRCA is substantially later, compared to values cited recently in the literature.
Our methods utilize the transition statistics from the entire known human mtDNA phylogenetic tree (Phylotree), eliminating the requirement to reconstruct a tree encompassing the specific sequences of interest. Moreover, they demonstrate notable improvement in both running speed and accuracy compared to BEAST2, particularly for earlier TMRCAs like the human-Chimpanzee split. Our results date the human - Neanderthal TMRCA to be [Formula: see text] years ago, considerably later than values cited in other recent studies.

Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a Polymerase gamma (POLG) deficiency model, the POLGD257A mutator mice (PolgD257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the POLGD257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mitochondria morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress observed in the retina or RPE of POLGD257A mice. Additionally, POLGD257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mitochondrial markers displayed decreased abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mitochondrial DNA mutations leads to impaired mitochondrial function and accelerated aging, resulting in retinal degeneration.