bims-humivi 2025-06-08 papers

bioRxiv. 2025 May 13. pii: 2025.05.07.652752. [Epub ahead of print]

Joint impact on thermotolerance of Saccharomyces species divergence in mitochondrial and nuclear genomes.

Jun-Ting Johnson Wang, Ping Ling Priscilla Ng, Maceo E Powers, Rachel B Brem.

Many traits of interest in biology evolved long ago and are fixed in a particular species, distinguishing it from other sister taxa. Elucidating the mechanisms underlying such ancient traits has been a central goal for evolutionary biologists. The yeast Saccharomyces cerevisiae is unique among its relatives for its ability to thrive at high temperature, via a genetic architecture that remains incompletely understood. We sought to understand the contribution of species variation in mitochondrial DNA to yeast thermotolerance. We used mitochondrial transgenesis to show that S. cerevisiae mitotypes were sufficient for a partial boost to thermotolerance and respiration in the S. paradoxus background. These mitochondrial alleles worked best when the background also harbored a pro-thermotolerance nuclear genotype, attesting to positive epistasis between the two genomes. The benefits of S. cerevisiae alleles in terms of respiration and growth at high temperature came at the cost of worse performance in cooler conditions. Together, our results establish this system as a case in which mitoalleles have fitness benefits and work well in multiple backgrounds; given the high mutation rate of the mitochondrial compartment, they were also likely extra easy for the ancestral population to acquire. We thus propose a broader model in which mitochondrial variants may prove to be especially good candidates in the search for genetic mechanisms of the adaptive process.

DOI: https://doi.org/10.1101/2025.05.07.652752

J Physiol. 2025 May 31.

Mitochondrial haplotype and sex modulate responses to endurance exercise training.

Bumsoo Ahn, Tianhao Wei, Ryan Pettit-Mee, Eunyoung Kim, Robert V Musci, Jonathan Wanagat, Hoang Van M Nguyen, Arlan Richardson, Hyunyoung Kim.

Heterogeneity in the response to exercise training is widely demonstrated in the literature. Although the variability in exercise acclimation is not entirely understood, a large portion of exercise response variability is attributable to genetic heritability potentially due to inherited maternal mitochondrial characteristics. Humans exhibit a heterogenous genome and mitochondrial haplotype; however much of the preclinical research proposed to investigate molecular transducers of exercise has been implemented using mouse models that lack mitochondrial and nuclear genomic diversity. Leveraging a novel rat model of heterogeneous genome, OKC-HET rats, we investigated the impact of mitochondrial (mt) haplotype on exercise training. We hypothesized that rats with divergent mitochondrial genomes will respond differently to endurance exercise training. OKC-HET rats aged 18-19 months old were subjected to 8 weeks of voluntary wheel running as their endurance exercise training programme. We found mt haplotype-specific effects on responses to endurance exercise and motor co-ordination, which were consistent with mitochondrial bioenergetics and markers of oxidative stress. Mitochondrial copy number and the expression of mitochondrial proteins were similar between the two mt haplotypes, suggesting intrinsic alterations of mitochondrial functions by the two distinct mitochondrial genomes. Motor co-ordination and fragmentation of acetylcholine receptors were also affected by mitochondrial haplotype. The mt haplotype effects on training responses were specific to biological sex also. Collectively we report that mitochondrial haplotype significantly affects responses to endurance exercise in a sex-specific manner. KEY POINTS: Mitochondrial haplotype affects the responses to endurance exercise. Sex modulates the effects of mitochondrial haplotype in the responses to endurance training. Mitochondrial DNA (mtDNA) deletion frequency increases following endurance exercise. mtDNA deletion frequency is higher in males than females after endurance exercise in OKC-HET rats.

Keywords: endurance exercise; mitochondrial DNA; mitochondrial bioenergetics; mitochondrial haplotype; motor co‐ordination; neuromuscular junction; sex

DOI: https://doi.org/10.1113/JP288330

Hum Fertil (Camb). 2025 Dec;28(1): 2501547

Association of mitochondrial DNA content and embryo morphology in fully expanded euploid blastocysts.

Ivo Karač, Gary G Ramsey, Romana Gračan, Sanja Vujisić Živković, Kristian Bodulić.

Over the past two decades, mitochondrial DNA (mtDNA) content has been studied as a potential biomarker for embryo viability and implantation success during in vitro fertilization (IVF) procedures. However, its reliability for embryo selection remains uncertain. Therefore, our study aimed to examine the relationship between blastocyst mtDNA content and blastocyst quality, timing of fully expanded blastocyst formation, and cleavage-stage embryo quality in blastocysts biopsied at the uniform expansion stage. We analyzed bioinformatics data from 125 day-5 and day-6 blastocysts from women aged 18 to 35 years. Each blastocyst was biopsied at expansion stage 4 and classified as euploid through preimplantation genetic testing for aneuploidy using next-generation sequencing. Blastocysts were categorized into four groups based on quality and the day of biopsy. Poor-quality day-6 blastocysts exhibited lower mtDNA levels compared to good-quality day-5 blastocysts (p = 0.006), poor-quality day-5 blastocysts (p = 0.008), and good-quality day-6 blastocysts (p = 0.003). Embryos with day-3 grades lower than 2.5 displayed lower blastocyst mtDNA levels compared to those graded 1 (p < 0.001), 1.5 (p < 0.001), and 2 (p < 0.001). These findings suggest further insights into the interplay between blastocyst mtDNA content and preimplantation embryo morphology. Nonetheless, mtDNA remains an unreliable biomarker for assessing embryo viability, warranting further investigation to determine its clinical relevance.

Keywords: Blastocyst; euploid; mitochondrial DNA; morphology; next-generation sequencing: embryo; preimplantation diagnosis

DOI: https://doi.org/10.1080/14647273.2025.2501547

BMC Med Genomics. 2025 Jun 02. 18(1): 99

Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania.

The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host-pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.tb) genomic data from 1000 adult TB patients from Tanzania and used a "genome-to-genome" approach to search for associations between human and M.tb genetic variants and to identify interacting genetic loci. Our analyses revealed two significant host-pathogen genetic associations. The first significant association (p = 4.7e-11) links a human intronic variant in PRDM15 (rs12151990), a gene involved in apoptosis regulation, with an M.tb variant in Rv2348c (I101M), which encodes a T cell-stimulating antigen. The second significant association (p = 6.3e-11) connects a human intergenic variant near TIMM21 and FBXO15 (rs75769176) - also associated with TB severity (p = 0.04) - with an M.tb variant in FixA (T67M). While FBXO15 is involved in the regulation of antigen processing and TIMM21 affects mitochondrial function, FixA's role remains undefined due to limited functional characterization. Additionally, we observed that a group of M.tb T cell epitope variants were significantly associated with HLA-DRB1 variation, suggesting that, despite their rarity, certain epitopes may still be subjected to immune selective pressure. Together, these findings identify previously unknown sites of genomic conflicts between humans and M.tb, advancing our understanding of how this pathogen evades selection pressure and persist in human populations.

Keywords: Genome-wiide association study; Host-pathogen interactions; Human genetics of infection; Tuberculosis

DOI: https://doi.org/10.1186/s12920-025-02164-x

Mitochondrion. 2025 Jun 03. pii: S1567-7249(25)00054-6. [Epub ahead of print] 102057

Mitochondrial health, prenatal distress, and gestational age: investigation of cf-mtDNA and GDF15 in two pregnancy studies from the USA and Turkey.

Qiuhan Huang, David Shire, Fiona Hollis, Sameera Abuaish, Martin Picard, Catherine Monk, Elif Aysimi Duman, Caroline Trumpff.

BACKGROUND: Pregnancy outcomes are influenced by maternal distress but the pathways underlying these effects are still unknown. Mitochondria, crucial for energy production and stress adaptation, may link psychosocial stress to its biological effects, especially during pregnancy when energy demands significantly increase. This study explores two mitochondrial markers-circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)-as potential mitochondrial health indicators linking maternal distress to pregnancy outcomes in two longitudinal studies from the USA and Turkey.
METHODS: We analyzed biological, demographic, and psychological data from women in two pregnancy studies: EPI (N = 187, USA) and BABIP (N = 198, Turkey). Data were collected at multiple timepoints during the perinatal period, including late 2nd and 3rd trimester, with EPI also including additional data at early 2nd trimester and 4-14 months postpartum. Prenatal maternal psychological distress was measured as perceived stress, anxiety, and depressive symptoms. Plasma cf-mtDNA and GDF15 levels were assessed using qPCR and ELISA, respectively. Statistical analyses included Wilcoxon signed-rank tests, Spearman correlations, and Mann-Whitney tests.
RESULTS: Plasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p = 0.035) and gestational age (p = 0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (all p-values < 0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (all p-values < 0.05).
CONCLUSIONS: This study identified distinct patterns of plasma cf-mtDNA and GDF15 levels during the perinatal period across studies from two countries, linking these mitochondrial markers to maternal distress and pregnancy outcomes.

Keywords: GDF15; Longitudinal studies; Maternal distress; Perinatal period; Pregnancy outcomes; Psychobiology; cf-mtDNA

DOI: https://doi.org/10.1016/j.mito.2025.102057