bims-polgdi 2025-06-29 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–06–29
fourteen papers selected by
Luca Bolliger, lxBio

Mitochondrial DNA: leakage, recognition, and associated human diseases.
Mitochondrial DNA depletion syndrome and its cardiac complication.
Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors.
Saliva and blood cell-free mtDNA reactivity to acute psychosocial stress.
Hypoxia-induced metabolic reprogramming in mesenchymal stem cells: unlocking the regenerative potential of secreted factors.
Inheritance bias of deletion-harbouring mtDNA in yeast: The role of copy number and intracellular selection.
Exosome-Mediated Mitochondrial Delivery of Antisense Oligonucleotides.
Flow Cytometric Quantification of Mitochondrial Properties: A High-Throughput Approach for Single Organelle Analysis.
Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency.
Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome.
Tumors may get energy boost from nerve cells' mitochondria.
Psychiatric manifestations in a patient with a pathogenic variant in the MT-TL1 gene associated with MELAS.
Intranasal Therapeutics for Neurodegenerative Disorders: Overcoming the Blood-Brain Barrier with Smart Formulations and Devices.
Crossing the Blood-Brain Barrier: Innovations in Receptor- and Transporter-Mediated Transcytosis Strategies.

J Biochem. 2025 Jun 20. pii: mvaf037. [Epub ahead of print]

Mitochondrial DNA: leakage, recognition, and associated human diseases.

Hyota Takamatsu.

  Mitochondria are intracellular organelles originating from intracellular symbiotic bacteria that play essential roles in life activities such as energy production, metabolism, Ca2+ storage, signal transduction, and cell death. Mitochondria also function as hubs for host defense against harmful stimuli such as infection and inflammation control. However, when cells are exposed to stress, mitochondrial homeostasis is disrupted, and mitochondrial DNA (mtDNA) can leak into the cytoplasm or extracellular space. Leaked mtDNA activates innate immune sensors, causing severe inflammation and contributing to the pathogenesis of human diseases. In this review, we summarize the mechanisms by which mtDNA leaks from the mitochondria and subsequently induces inflammation. We also review the relationship between mtDNA leakage and human diseases.

Keywords:  human diseases; innate immune response; mitochondria quality control; mitochondrial DNA; mtDNA leakage

DOI:  https://doi.org/10.1093/jb/mvaf037
Front Cardiovasc Med. 2025 ;12 1582219

Mitochondrial DNA depletion syndrome and its cardiac complication.

Shengfang Bao, Jiajun Ye, Jiaqi Zhou, Chen Zheng, Yuejuan Xu, Sun Chen.

  Mitochondrial depletion syndrome (MTDPS) is a heterogeneous group of genetic disorders characterized by a significant reduction in mitochondrial DNA (mtDNA) copy number, leading to the impaired mitochondrial function. The pathogenesis of MTDPS includes impaired mtDNA replication, damaged nucleotide metabolism and dysregulated mitochondrial dynamics. Due to its high energy demands, the heart is sensitive to the mitochondrial dysfunction. And the energy deficiency caused by the MTDPS contributes to the development of the mitochondrial cardiomyopathy. In this review, we summarize the cardiac phenotypes in the MTDPS, and the role of the mitochondrial injury in the myocardial damage. In specific, the association of the MTDPS-causing genes and their cardiac phenotypes are detailed. Moreover, the current treatment strategies for MTDPS are summarized. This review aims to integrate the current knowledge on the MTDPS and its cardiac phenotypes in order to provide insights for the further research and the clinic management.

Keywords:  cardiomyopathy; mitochondrial DNA depletion syndrome; mitochondrial damage; mitochondrial dynamics; mitochondrial dysfunction; mtDNA replication; nucleotide metabolism

DOI:  https://doi.org/10.3389/fcvm.2025.1582219
PLoS Biol. 2025 Jun;23(6): e3003207

Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors.

Indi P Joore, Sawsan Shehata, Irena Muffels, Jose Castro-Alpízar, Elena Jiménez-Curiel, Emilia Nagyova, Natacha Levy, Ziqin Tang, Kimberly Smit, Wilbert P Vermeij, Richard Rodenburg, Raymond Schiffelers, Edward E S Nieuwenhuis, Peter M van Hasselt, Sabine A Fuchs, Martijn A J Koppens.

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

DOI: https://doi.org/10.1371/journal.pbio.3003207
Psychoneuroendocrinology. 2025 Jun 06. pii: S0306-4530(25)00229-X. [Epub ahead of print]179 107506

Saliva and blood cell-free mtDNA reactivity to acute psychosocial stress.

Caroline Trumpff, David Shire, Jeremy Michelson, Natalia Bobba-Alves, Temmie Yu, Richard P Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.

  Human blood contains cell-free mitochondrial DNA (cf-mtDNA) that dynamically increases in concentration in response to acute mental stress. Like other neuroendocrine stress markers, we previously found that cf-mtDNA is also detectable in saliva, calling for studies examining saliva cf-mtDNA reactivity to mental stress. In the present study, participants from the MiSBIE (Mitochondrial Stress, Brain Imaging, and Epigenetics) study (n = 68, 66 % women), were exposed to a brief socio-evaluative stressor, which induced a striking 280 % or 2.8-fold increase in saliva cf-mtDNA concentration within 10 min (g=0.55, p < 0.0001). In blood drawn concurrently with saliva sampling, stress increased cf-mtDNA by an average 32 % at 60 min in serum (g=0.20), but not in anticoagulated plasma where cf-mtDNA decreased by 19 % at 60 min (g=0.25). Examining the influence of mitochondrial health on cf-mtDNA reactivity in participants with rare mitochondrial diseases (MitoD), we report that a subset of MitoD participants exhibit markedly blunted saliva cf-mtDNA stress reactivity, suggesting that bioenergetic defects within mitochondria may influence the magnitude of saliva, and possibly blood cf-mtDNA responses. Our results document robust saliva cf-mtDNA stress reactivity and provide a methodology to examine the psychobiological regulation of cell-free mitochondria in future studies.

Keywords:  Acute psychological stress; Cell-free mitochondrial DNA (cf-mtDNA); Energy; Mitochondrion; Repeated measures; Saliva

DOI:  https://doi.org/10.1016/j.psyneuen.2025.107506
Front Cell Dev Biol. 2025 ;13 1609082

Hypoxia-induced metabolic reprogramming in mesenchymal stem cells: unlocking the regenerative potential of secreted factors.

Wendy V Jaraba-Álvarez, Ashanti C Uscanga-Palomeque, Vanesa Sanchez-Giraldo, Claudia Madrid, Hector Ortega-Arellano, Karolynn Halpert, Carolina Quintero-Gil.

  Mesenchymal stem cells (MSCs) are a cornerstone of regenerative medicine, primarily due to their ability to secrete bioactive factors that modulate inflammation, promote tissue repair, and support regeneration. Recent research highlights the importance of preserving the native cellular microenvironment to optimize MSC function and survival post-transplantation. Preconditioning strategies, such as hypoxia exposure, have emerged as powerful tools to enhance MSC therapeutic potential by mimicking physiological conditions in their natural niche. This perspective article explores the metabolic adaptations induced by hypoxia in MSCs, focusing on shifts in mitochondrial function, glycolysis, oxidative phosphorylation, and metabolic intermediates that enhance cellular survival and bioactivity. We also discuss how these metabolic changes influence the composition and function of MSC-derived secreted factors, particularly exosomes and other extracellular vesicles, in modulating tissue repair. Furthermore, we provide an overview of preclinical and clinical studies that have evaluated hypoxia-preconditioned MSCs and their byproducts, assessing their efficacy in various therapeutic contexts. Special attention is given to the role of hypoxia-induced mitochondrial adaptations in improving MSC function and the emerging potential of metabolic inhibitors or respiration modulators as strategies to further refine MSC-based therapies. By integrating metabolic insights with clinical evidence, we aim to offer a comprehensive perspective on optimizing MSC culture conditions to enhance their regenerative properties, acknowledging that this remains a theoretical standpoint, as conventional culture methods are generally not conducted under hypoxic conditions. This approach holds promise for the development of more effective therapeutic strategies that leverage metabolic modulation to improve MSC-based interventions for a range of diseases.

Keywords:  cellular microenvironment; extracellular vesicles (EV); hypoxia preconditioning; mesenchymal stem cells (MSC); mitochondria; regenerative medicine

DOI:  https://doi.org/10.3389/fcell.2025.1609082
PLoS Genet. 2025 Jun;21(6): e1011737

Inheritance bias of deletion-harbouring mtDNA in yeast: The role of copy number and intracellular selection.

Nataliia D Kashko, Georgii Muravyov, Iuliia Karavaeva, Elena S Glagoleva, Maria D Logacheva, Sofya K Garushyants, Dmitry A Knorre.

During sexual reproduction, fungi usually inherit mtDNA from both parents, however, the distribution of the mtDNA in the progeny can be biased toward some mtDNA variants. For example, crossing Saccharomyces cerevisiae strain carrying wild type (rho+) mtDNA with the strain carrying mutant mtDNA variant with a large deletion (rho-) can produce up to 99-100% of rho- diploid progeny. Two factors could contribute to this phenomenon. First, rho- cells may accumulate more copies of mtDNA molecules per cell than wild-type cells, making rho- mtDNA the prevalent mtDNA molecule in zygotes. This consequently leads to a high portion of rho- diploid cells in the offspring. Second, rho- mtDNA may have a competitive advantage within heteroplasmic cells, and therefore could displace rho+ mtDNA in a series of generations, regardless of their initial ratio. To assess the contribution of these factors, we investigated the genotypes and phenotypes of twenty two rho- yeast strains. We found that indeed rho- cells have a higher mtDNA copy number per cell than rho+ strains. Using an in silico modelling of mtDNA selection and random drift in heteroplasmic yeast cells, we assessed the intracellular fitness of mutant mtDNA variants. Our model indicates that both higher copy numbers and intracellular fitness advantage of the rho- mtDNA contribute to the biased inheritance of rho- mtDNA.

DOI: https://doi.org/10.1371/journal.pgen.1011737
Nucleic Acid Ther. 2025 Jun 18.

Exosome-Mediated Mitochondrial Delivery of Antisense Oligonucleotides.

Dora von Trentini, Ivan J Dmochowski.

  We present a general method for in-cellulo delivery of 2'-O-methyl (2'-OMe) RNA oligonucleotides (oligos) to mitochondria for antisense applications, with potential for implementation in other mitochondrial DNA (mtDNA)-targeted therapies. Exosomes, which are nanoscale, naturally occurring extracellular vesicles (EVs), have been employed for biotechnology applications in oligonucleotide delivery in recent years. We discovered that exosomes from fetal bovine serum (FBS) can be used as a simple and biologically compatible delivery agent of 2'-OMe RNA antisense oligonucleotides to cellular mitochondria, leading to target protein knockdown. While most RNA interference and antisense mechanisms occur in the cytoplasm or nucleus, the need for mitochondrial targeting has become increasingly apparent. Mitochondrial disease describes a variety of currently incurable syndromes that especially affect organs requiring significant energy including the muscles, heart, and brain. Many of these syndromes result from mutations in mtDNA, which codes for the 13 proteins of the oxidative phosphorylation system and are thus often implicated in inherited metabolic disorders.

Keywords:  2′-OMe RNA; antisense oligonucleotides; exosome-based delivery; extracellular vesicles; fetal bovine serum; mitochondrial localization

DOI:  https://doi.org/10.1089/nat.2024.0067
Int J Mol Sci. 2025 Jun 07. pii: 5481. [Epub ahead of print]26(12):

Flow Cytometric Quantification of Mitochondrial Properties: A High-Throughput Approach for Single Organelle Analysis.

Andrew J Piasecki, Hannah C Sheehan, Jonathan L Tilly, Dori C Woods.

  Recent advances in flow cytometry facilitate the detection of subcellular components, such as organelles and vesicles. Fluorescence-activated mitochondria sorting (FAMS) is a flow cytometry-based technique that allows for quantitative analysis and sorting of mitochondria as individual organelles from various tissues and in vitro cell culture. This manuscript details three novel applications of this technique to study mitochondrial function on an organelle-specific level, which is not possible with other approaches. Specifically, we detail the further development and versatility of this nanoscaled flow cytometry approach, including assays to quantitatively assess mitochondrial subpopulations, mitochondrial protein translocation, and both free-floating and EV-encapsulated secreted mitochondria. We demonstrate a multi-parameter quantitative assay for the analysis of mitochondrial autophagy using antibodies targeting the proteins PINK1 and Parkin corresponding to ΔΨM and further show how these can be assessed for mtDNA content on a single organelle level. Further, we establish parameters for the size and surface marker-based analysis of EVs, many of which contain identifiable and respiring mitochondria, as well as free-floating respiratory-competent mitochondria. These results display the versatility of nanoscaled flow cytometry in terms of both sample input and target organelle and provide an important methodological means for the quantitative assessment of mitochondrial features.

Keywords:  extracellular vesicle sorting; flow cytometry; fluorescence-activated mitochondria sorting; mitochondria; organelle sorting

DOI:  https://doi.org/10.3390/ijms26125481
Exp Mol Med. 2025 Jun 26.

Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency.

Hyun Kyu Kim, Yena Song, Minji Kye, Byeongho Yu, Hyung Kyu Choi, Sung-Hwan Moon, Man Ryul Lee.

Somatic cell reprogramming into human induced pluripotent stem cells entails significant intracellular changes, including modifications in mitochondrial metabolism and a decrease in mitochondrial DNA copy number. However, the mechanisms underlying this decrease in mitochondrial DNA copy number during reprogramming remain unclear. Here we aimed to elucidate these underlying mechanisms. Through a meta-analysis of several RNA sequencing datasets, we identified genes responsible for the decrease in mitochondrial DNA. We investigated the functions of these identified genes and assessed their regulatory mechanisms. In particular, the expression of the thymidine kinase 2 gene (TK2), located in the mitochondria and required for mitochondrial DNA synthesis, is decreased in human pluripotent stem cells as compared with its expression in somatic cells. TK2 was significantly downregulated during reprogramming and markedly upregulated during differentiation. Collectively, this decrease in TK2 levels induces a decrease in mitochondrial DNA copy number and contributes to shaping the metabolic characteristics of human pluripotent stem cells. However, contrary to our expectations, treatment with a TK2 inhibitor impaired somatic cell reprogramming. These results suggest that decreased TK2 expression may result from metabolic conversion during somatic cell reprogramming.

DOI: https://doi.org/10.1038/s12276-025-01476-3
Exp Mol Med. 2025 Jun 24.

Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome.

Ye Seul Kim, Sukdong Yoo, Yoon Ji Jung, Jung Won Yoon, Yong Seong Kwon, Nayeon Lee, Chong Kun Cheon, Jae Ho Kim.

Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN, which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. Here we explored the possibility of using stem-cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem (iPS) cells from healthy individuals and from patients with BTHS and differentiated them into cardiomyocytes. The iPS-cell-differentiated cardiomyocytes (CMs) derived from patients with BTHS exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT and cTnI, and smaller cell size than normal iPS-cell-derived CMs. Multielectrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired and mitophagy was decreased in BTHS CMs compared with normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.

DOI: https://doi.org/10.1038/s12276-025-01472-7
Science. 2025 Jun 26. 388(6754): 1357-1358

Tumors may get energy boost from nerve cells' mitochondria.

Mitch Leslie.

Study shows the organelles traveling through "bridges" into nearby cancer cells.

DOI: https://doi.org/10.1126/science.aea0605
BMJ Case Rep. 2025 Jun 25. pii: e264055. [Epub ahead of print]18(6):

Psychiatric manifestations in a patient with a pathogenic variant in the MT-TL1 gene associated with MELAS.

Anindita Gujrati, Manjiri Chaitanya Datar, Anushka Mukesh Makhija, Jyoti Vittaldas Shetty.

  MELAS (mitochondrial encephalopathy lactic acidosis and stroke-like episodes) syndrome is a condition characterised by varied systemic involvement with neurological manifestations. It is a rare, inherited, neurodegenerative disorder caused by mitochondrial dysfunction that leads to energy production disturbances. Psychiatric manifestations may be detected rarely in this genetic condition. We present a case of a female in her mid-40s who had a heteroplasmic mutation in the MT-TL1 gene associated with MELAS and developed frank psychiatric manifestations.

Keywords:  Genetics; Mood disorders (including depression); Neuro genetics

DOI:  https://doi.org/10.1136/bcr-2024-264055
Mol Pharm. 2025 Jun 23.

Intranasal Therapeutics for Neurodegenerative Disorders: Overcoming the Blood-Brain Barrier with Smart Formulations and Devices.

Siddhant Kumar, Akshay Yadav, Rahul K Verma, Akhilesh Kumar, Piyush Kumar Gupta, Rahul Shukla.

  Neurodegenerative diseases have always posed a significant therapeutic challenge due to the restrictive nature of the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a noninvasive approach to bypass the BBB, enabling targeted brain drug delivery while improving drug retention and transport. This review explores the physiological basis of the nose-to-brain pathway and various formulation strategies including mucoadhesive systems, permeation enhancers, and magnetophoretic approaches. Additionally, strategies to enhance intranasal delivery, such as P-glycoprotein inhibitors, cell-penetrating peptides, and enzyme inhibitors, are discussed alongside nanotechnology-based carriers, including surface-modified and bioconjugated systems. The role of specialized intranasal drug delivery devices (e.g., ViaNase, Optimist, and SipNose) in enhancing precision dosing is also highlighted. Despite its promise, intranasal delivery faces challenges such as limited therapeutic windows, scalability issues, and the constraint of the nasal cavity volume, which can accommodate only 200 μL of liquid per nostril. Optimizing drug stability, achieving accurate dosing, and enhancing bioavailability without nasal irritation remain key hurdles. Future research should focus on the development of commercially feasible nanoformulations and innovative medical devices to improve drug targeting and treatment efficacy for patients with neurodegenerative diseases.

Keywords:  Bioconjugated Nanocarriers; Intranasal Devices; Mucoadhesive; Nanotechnology; Neurodegenerative Disorders; Nose-to-Brain Delivery; Stimuli-Responsive Gel

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c00386
Pharmaceutics. 2025 May 28. pii: 706. [Epub ahead of print]17(6):

Crossing the Blood-Brain Barrier: Innovations in Receptor- and Transporter-Mediated Transcytosis Strategies.

Ling Ding, Pratiksha Kshirsagar, Prachi Agrawal, Daryl J Murry.

  The blood-brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including neurodegenerative disorders, brain tumors, and psychiatric conditions. Many chemical drugs and biopharmaceuticals are unable to cross the BBB, and conventional drug delivery methods often fail to achieve sufficient brain concentrations, leading to reduced therapeutic efficacy and increased risk of systemic toxicity. In recent years, targeted drug delivery strategies have emerged as promising approaches to overcome the BBB and enhance the delivery of therapeutic agents to the brain. Among these, receptor-mediated transcytosis (RMT) and transporter-mediated transcytosis (TMT) are two of the most extensively studied mechanisms for transporting drugs across brain endothelial cells into the brain parenchyma. Advances in materials science and nanotechnology have facilitated the development of multifunctional carriers with optimized properties, improving drug targeting, stability, and release profiles within the brain. This review summarizes the physiological structure of the BBB and highlights recent innovations in RMT- and TMT-mediated brain drug delivery systems, emphasizing their potential not only to overcome current challenges in CNS drug development, but also to pave the way for next-generation therapies that enable more precise, effective, and personalized treatment of brain-related diseases.

Keywords:  blood–brain barrier; brain delivery; nanomaterials; transcytosis

DOI:  https://doi.org/10.3390/pharmaceutics17060706