bims-humivi 2025-06-29 papers

bims-humivi

Biomed News

on Human mito-nuclear genetic interplay

Issue of 2025–06–29
six papers selected by
Mariangela Santorsola, Università di Pavia

Exploring the Impact of Mitonuclear Discordance on Disease in Latin American Admixed Populations.
Mitochondrial Transfer from Human Platelets to Rat Dental Pulp-Derived Fibroblasts in the 2D In Vitro System: Additional Implication in PRP Therapy.
There is no transfer of mitochondria from donor hematopoietic cells to recipient mesenchymal stromal cells after allogeneic hematopoietic stem cells transplantation in humans.
Cytoplasmic Male Sterility Declines in the Presence of Resistant Nuclear Backgrounds.
Skeletal Muscle Mitochondria Contain Nuclear-Encoded RNA Species Prior to and Following Adaptation to Exercise Training in Rats.
RNase H1 levels dramatically affect mitochondrial genome maintenance with little impact on nuclear R-loops in murine B cells.

Genes (Basel). 2025 May 27. pii: 638. [Epub ahead of print]16(6):

Exploring the Impact of Mitonuclear Discordance on Disease in Latin American Admixed Populations.

Mauricio Ruiz, Daniela Böhme, Gabriela M Repetto, Boris Rebolledo-Jaramillo.

  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.

Keywords:  admixed Latinos; mitochondrial genomics; mitonuclear discordance

DOI:  https://doi.org/10.3390/genes16060638
Int J Mol Sci. 2025 Jun 08. pii: 5504. [Epub ahead of print]26(12):

Mitochondrial Transfer from Human Platelets to Rat Dental Pulp-Derived Fibroblasts in the 2D In Vitro System: Additional Implication in PRP Therapy.

Koji Nishiyama, Tomoni Kasahara, Hideo Kawabata, Tetsuhiro Tsujino, Yutaka Kitamura, Taisuke Watanabe, Masayuki Nakamura, Tomoharu Mochizuki, Takashi Ushiki, Tomoyuki Kawase.

  Platelet mitochondria have recently been increasingly considered "co-principal" along with platelet growth factors to facilitate tissue regeneration in platelet-rich plasma therapy cooperatively. To develop a convenient method to test this potential, we examined mitochondrial transfer using a simple two-dimensional culture system. Living human platelets were prepared from PRP obtained from 12 non-smoking healthy male adults (age: 28-63 years) and suspended in medium. Platelet lysates were prepared from sonicated platelet suspensions in PBS. After treatment with ultraviolet-C irradiation, a mitochondrial respiration inhibitor, or a synchronized culture reagent, rat dental pulp-derived fibroblasts (RPC-C2A) were co-cultured with platelets or platelet lysates for 24 h. Mitochondrial transfer was evaluated by visualization using a fluorescent dye for mitochondria or an antibody against human mitochondria. Ultraviolet-C-irradiated cells substantially lost their viability, and treatment with living platelets, but not platelet lysates, significantly rescued the damaged fibroblasts. Fibroblast mitochondria appeared to increase after co-culture with resting platelets. Although more microparticles existed around the platelets on the fibroblast surface, the activated platelets did not show significant increases in any parameters of mitochondrial transfer. This simple co-culture system demonstrated mitochondrial transfer between xenogeneic cells, and this phenomenon should be considered as an additional implication in PRP therapy.

Keywords:  fibroblasts; in vitro; mitochondria; platelet-rich plasma; platelets; transfer

DOI:  https://doi.org/10.3390/ijms26125504
Hematol Transfus Cell Ther. 2025 Jun 18. pii: S2531-1379(25)00127-0. [Epub ahead of print]47(3): 103859

There is no transfer of mitochondria from donor hematopoietic cells to recipient mesenchymal stromal cells after allogeneic hematopoietic stem cells transplantation in humans.

Natalya Sats, Vadim Surin, Tatiana Abramova, Aleksandra Sadovskaya, Nataliya Petinati, Nikolay Kapranov, Ksenia Nikiforova, Nina Drize, Luisa Karaseva, Olga Pokrovskaya, Larisa Kuzmina, Elena Parovichnikova.

   INTRODUCTION: Multipotent mesenchymal stromal cells are progenitors of the bone marrow stromal microenvironment that support hematopoiesis. Mitochondria, which can be transferred between cells via nanotubes or extracellular vesicles, play a key role in the functions of mesenchymal stromal cells. In a murine model, donor hematopoietic stem and progenitor cells transfer functional mitochondria to bone marrow mesenchymal stromal cells of the recipient. The aim of this study was to find out whether such transfer occurs in humans after allogeneic hematopoietic stem cell transplantation.
METHODS: This study included nine patients with acute leukemia who received a reduced intensity conditioning regimen. Donor hematopoietic stem and progenitor cells mobilized into peripheral blood were the source of transplanted stem cells. Total DNA was isolated from bone marrow mesenchymal stromal cells of each patient before and after transplantation and their respective donors' leukocytes. A fragment of mitochondrial DNA including the full-length control region was sequenced. The mitochondrial DNA sequence of each patient's mesenchymal stromal cells was compared before and after the procedure and with the respective donor leukocytes.
RESULTS: Donor mitochondrial DNA was not detected in the mesenchymal stromal cells of any patient after transplantation even as trace amounts. Co-culturing donor leukocytes with intact and irradiated mesenchymal stromal cells in vitro did not lead to detection of donor mitochondrial DNA transfer.
CONCLUSION: The data show that there is no mitochondrial transfer from donor hematopoietic stem and progenitor cells to recipient mesenchymal stromal cells after transplantation. Thus, the results indicate that one cannot count on improved mesenchymal stromal cell metabolism due to mitochondrial transfer. It is necessary to look for other ways to restore the stromal microenvironment.

Keywords:  Hematopoietic stem cell transplantation; Mesenchymal stromal cells; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1016/j.htct.2025.103859
Am Nat. 2025 Jul;206(1): 16-30

Cytoplasmic Male Sterility Declines in the Presence of Resistant Nuclear Backgrounds.

Fanny Laugier, Kévin Béthune, Florian Plumel, Céline Froissard, Jean-Marc Donnay, Timothée Chenin, François Rousset, Patrice David.

  AbstractGenomic conflicts arise when different genes in a genome are selected for opposite phenotypic effects. One well-known conflict occurs in plants, between mitochondrial genes causing cytoplasmic male sterility (CMS) and their nuclear suppressors, called restorers of male fertility. The evolution of CMS-restorer polymorphisms has been modeled many times, but empirical validations remain indirect. Here we use a new biological model, a freshwater snail, to directly observe evolutionary trajectories. In this species, CMS-associated mitogenomes coexist with male-fertile ones in populations. Models predict such a coexistence when nuclear restorers make CMS mitogenomes less fit than male-fertile ones, thus preventing the fixation of CMS. During 11 generations of experimental evolution, we observed rapid decreases in the frequency of CMS mitogenomes in a restorer-rich nuclear background, with an estimated ∼20% fitness disadvantage, consistent with theoretical conditions for the maintenance of cytonuclear polymorphism. In parallel, in an ancillary experiment, eggs laid by isolated snails carrying CMS showed a reduced hatching rate. Although significant, this reduction did not reach 20%, suggesting that fitness differentials in populations are enhanced by competition or rely on unmeasured traits. Our study illustrates the speed at which evolution can proceed in the context of cytonuclear conflicts over sex allocation.

Keywords:  Physa acuta; cost; cytoplasmic male sterility; experimental evolution; restoration

DOI:  https://doi.org/10.1086/735820
FASEB J. 2025 Jul 15. 39(13): e70702

Skeletal Muscle Mitochondria Contain Nuclear-Encoded RNA Species Prior to and Following Adaptation to Exercise Training in Rats.

Jessica L Silver, Séverine Lamon, Stella Loke, Gisella Mazzarino, Larry Croft, Mark Ziemann, Megan Soria, Glenn D Wadley, Adam J Trewin.

  Skeletal muscle mitochondria adaptation to exercise training is mediated by molecular factors that are not fully understood. Mitochondria import over 1000 proteins encoded by the nuclear genome, but the RNA population resident within the organelle is generally thought to be exclusively encoded by the mitochondrial genome. However, recent in vitro evidence suggests that specific nuclear-encoded miRNAs and other noncoding RNAs (ncRNAs) can reside within the mitochondrial matrix. Whether these are present in mitochondria of skeletal muscle tissue, and whether this is affected by endurance training-a potent metabolic stimulus for mitochondrial adaptation-remains unknown. Rats underwent 4 weeks of moderate-intensity treadmill exercise training, then were humanely killed and tissues were collected for molecular profiling. Mitochondria from gastrocnemius skeletal muscle were isolated by immunoprecipitation, further purified, and then the resident RNA was sequenced to assess the mitochondrial transcriptome. Exercise training elicited typical transcriptomic responses and functional adaptations in skeletal muscle, including increased mitochondrial respiratory capacity. We identified 24 nuclear-encoded coding or noncoding RNAs in purified mitochondria, in addition to 50 nuclear-encoded miRNAs that met a specified abundance threshold. Although none were differentially expressed in the exercise vs. control group at FDR < 0.05, exploratory analyses suggested that the abundance of 3 miRNAs was altered (p < 0.05) in mitochondria isolated from trained compared with sedentary skeletal muscle. We report the presence of a specific population of nuclear-encoded RNAs in the mitochondria isolated from rat skeletal muscle tissue, which could play a role in regulating exercise adaptations and mitochondrial biology.

Keywords:  exercise; mitochondria; skeletal muscle; transcriptome

DOI:  https://doi.org/10.1096/fj.202500157R
bioRxiv. 2025 Apr 30. pii: 2025.04.30.651504. [Epub ahead of print]

RNase H1 levels dramatically affect mitochondrial genome maintenance with little impact on nuclear R-loops in murine B cells.

Kiran Sakhuja, Stella R Hartono, Lionel A Sanz, Eriko Ijiri, Caitlin Darling, Louis Dye, James R Iben, Hyongi Chon, Susana Cerritelli, Robert Crouch, Frédéric Chédin.

Overexpression of RNase H1, a ribonuclease that degrades RNA:DNA hybrids and R-loops, can suppress genome instability phenotypes in a range of maladaptive conditions. This has been interpreted to suggest that genotoxic co-transcriptional R-loops arise under these conditions and are resolved by RNase H1. Here, we manipulated RNase H1 levels using conditional knockout and overexpression models in primary murine B cells and mapped the resulting genomic R-loop landscapes. Rnaseh1 deletion resulted in a dramatic loss of mitochondrial replication and compromised B cell responses, consistent with a critical mitochondrial function for RNase H1. Genome-wide R-loops were, however, not significantly affected. More surprisingly, overexpressing active nuclear RNase H1 did not lead to significant reduction of R-loop levels or change their distribution. These results were confirmed using a human cell line in which active, nuclear RNase H1 can be induced. Our findings indicate that co-transcriptional R-loops are not efficiently resolved by RNase H1 and suggest that the identity of the RNA/DNA hybrids at the root of the genome instability phenotypes suppressed by RNase H1 may need to be re-interpreted.

DOI: https://doi.org/10.1101/2025.04.30.651504