bims-polgdi 2025-09-28 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–09–28
25 papers selected by
Luca Bolliger, lxBio

Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
Cross-Organ Mitochondrial Communication in Stress and Disease.
Exploring ovarian aging: unraveling the link between mitochondria status and oocyte as a determinant of gamete quality.
The Impacts of Dengue Virus Infection on Mitochondrial Functions and Dynamics.
The First Heterozygous TWNK Nonsense Mutation Associated with Progressive External Ophthalmoplegia: Evidence for a New Piece in the Puzzle of Mitochondrial Diseases.
Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.
MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.
Gene therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies.
Loganin, an Iridoid Glycoside, Alleviates Paclitaxel-Induced Skeletal Muscle Toxicity by Enhancing Mitochondrial Function, Boosting Antioxidant Defenses, and Reducing Cellular Senescence.
From Ancient Philosophy to Endosymbiotic Theory: The Bacterial Origin and Key Role of Mitochondria in Immune Responses.
Cell-Free Circulating Mitochondrial DNA Levels Following High-Frequency Jet Ventilation-A Post Hoc Analysis.
Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.
Analysis of urine cell-free DNA copy number and fragment size from healthy individuals.
Strategic Targeting of Mitochondria: Bridging Biology and Therapy for Health Benefits.
Plasma-derived mitochondrial transplantation attenuates paraspinal muscle atrophy following spinal surgery.
A Nanoformulation of Ubiquinol and Selenium Promotes Proliferation of Human Induced Pluripotent Stem Cells.
Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.
Autophagy in Proteostasis AND AGING in C. ELEGANS.
The B-lymphoblastoid model in Barth syndrome.
Rare missense substitutions in the mitochondrial DNA genes in patients with ventricular tachycardia.
Vascular-Perfusable Human 3D Brain-on-Chip.
Causes of Mortality in Patients with Inborn Errors of Immunity: An 18-year retrospective cohort study.
Macromolecular Crowding in Mitochondria.
The National Rare Disease Strategy Ireland 2025-2030.

Biomolecules. 2025 Aug 29. pii: 1252. [Epub ahead of print]15(9):

Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.

Davide Steffan, Camilla Pezzini, Martina Esposito, Anais Franco-Romero.

  Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.

Keywords:  CNS; aging; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/biom15091252
Nature. 2025 Sep 24.

Ribonucleotide incorporation into mitochondrial DNA drives inflammation.

Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.

Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.

DOI: https://doi.org/10.1038/s41586-025-09541-7
Annu Rev Pharmacol Toxicol. 2025 Sep 22.

Cross-Organ Mitochondrial Communication in Stress and Disease.

Koning Shen, Jenni Durieux, Andrew Dillin.

Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1146/annurev-pharmtox-062124-024150
Syst Biol Reprod Med. 2025 Dec;71(1): 461-484

Exploring ovarian aging: unraveling the link between mitochondria status and oocyte as a determinant of gamete quality.

Manuel Belli, Marta Gatti, Luigi Sansone, Matteo Antonio Russo, Maria Grazia Palmerini, Stefania Annarita Nottola, Mohammad Ali Khalili, Guido Macchiarelli.

  The variation in reproductive age among individuals is significant, with many cases of infertility involving premature ovarian aging. This issue, combined with the societal trend of delaying childbearing, leads to age-related ovarian dysfunction. Ovarian aging is related to a decline of ovarian reserve, as oocyte quantity, quality, and precocious senescence, and may affect fertility and the overall individual well-being. Mitochondria play a central role in the maintenance of any cell health. Then mitochondrial dysfunctions may be responsible also for a negative impact on the quality, number, and function of oocytes, leading to different age-related reproductive disorders, impaired oogenesis, and embryogenesis. Although a large number of researches have shown clearly that mitochondrial dysfunction and morphology changes affect the maintenance and function of all major organs and tissues, such as the brain, heart, skeletal muscle, liver, and others the mechanisms contributing to early ovarian aging, a decrease of oocyte quality, and infertility remain unclear. In this review, we summarize the role of mitochondrial dysfunction in ovarian aging, presenting recent findings on morpho-functional changes in these organelles, and highlighting how their dysfunction accelerates ovary and cell senescence. We also explore their impact on oocyte functions. The reported data highlight the critical role of mitochondria in maintaining and enhancing oocyte quality, indicating that future studies should further focus on the mechanisms underlying mitochondrial damage and on identifying mitochondrial targets that may offer promising strategies to preserve, recover, and extend fertility in aging women.

Keywords:  Molecular and cellular fertility rehabilitation; functional recovery from infertility; mitochondria; oocyte; ovarian aging

DOI:  https://doi.org/10.1080/19396368.2025.2562633
Int J Mol Sci. 2025 Sep 15. pii: 8968. [Epub ahead of print]26(18):

The Impacts of Dengue Virus Infection on Mitochondrial Functions and Dynamics.

Showkot Ahmed, Réka Dorottya Varga, Jinsung Yang.

  Dengue virus (DENV) is a mosquito-borne flavivirus responsible for a significant global disease burden, especially in tropical and subtropical regions. DENV critically manipulates host cell mitochondria to ensure its replication and survival. The clinical manifestations are well-studied and how dengue infection significantly alters the mitochondrial dynamics, and the subsequent functional cellular homeostasis has been unveiled. This review discusses the strategies by which DENV alters mitochondrial functions and dynamics. It particularly focuses on the virus-induced suppression of mitochondrial quality control mechanisms like mitophagy. Moreover, the dichotomous role of mitophagy in supporting DENV replication is highlighted. By incorporating recent studies about DENV-host interactions at the mitochondrial interface, mitochondria, as regulators and targets in dengue pathogenesis, are suggested as possible molecular targets for therapeutic intervention.

Keywords:  biogenesis; cellular homeostasis; dengue virus; mitochondria; mitochondrial bioenergetics; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.3390/ijms26188968
Biomolecules. 2025 Sep 18. pii: 1337. [Epub ahead of print]15(9):

The First Heterozygous TWNK Nonsense Mutation Associated with Progressive External Ophthalmoplegia: Evidence for a New Piece in the Puzzle of Mitochondrial Diseases.

Diego Lopergolo, Gianna Berti, Gian Nicola Gallus, Silvia Bianchi, Filippo Maria Santorelli, Alessandro Malandrini, Nicola De Stefano.

   BACKGROUND: The TWNK gene encodes a protein that colocalizes with mitochondrial DNA (mtDNA) in mitochondrial nucleoids. It acts as mtDNA helicase during replication, thus playing a pivotal role in the replication and maintenance of mtDNA stability. TWNK mutations are associated with a wide spectrum of clinical phenotypes and a marked heterogeneity. However, heterozygous nonsense variants in the gene have never been described in association with disease.
METHODS: We analyzed a next-generation sequencing (NGS) targeted gene panel in a cohort including 40 patients with high clinical suspicion of mitochondrial disorders. Selected patients underwent a complete neurological examination, electrophysiology tests, and muscle biopsy. Segregation analysis was performed in available family members. The 3D structure of twinkle was visualized and analyzed using Swiss Model and Pymol version 3.1.6.1.
RESULTS: We found four TWNK-mutated subjects from two unrelated families. They exhibited a variable clinical spectrum, ranging from asymptomatic individuals to subjects with psychiatric disorder, chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. All the subjects shared the heterozygous TWNK p.Glu665Ter variant.
DISCUSSION AND CONCLUSIONS: We describe the clinical phenotype and muscle biopsy findings associated with the first reported heterozygous nonsense TWNK variant, thus expanding the current knowledge of Twinkle-related disorders. Our findings are in line with the high intrafamilial clinical variability associated with TWNK mutations. Although PEO and skeletal muscle involvement remain hallmarks of the disease, extra-muscular features should be carefully assessed.

Keywords:  TWINKLE; Twinkle-related disorders; mitochondrial disease; myopathy

DOI:  https://doi.org/10.3390/biom15091337
Antioxidants (Basel). 2025 Sep 21. pii: 1138. [Epub ahead of print]14(9):

Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.

Mi Xiang, Mengling Yang, Lijuan Zhang, Xiaohu Ouyang, Alexey Sarapultsev, Shanshan Luo, Desheng Hu.

  Cardiovascular diseases hinge on a vicious, self-amplifying cycle in which mitochondrial deoxyribonucleic acid (mtDNA) dysfunction undermines cardiac bioenergetics and unleashes sterile inflammation. The heart's reliance on oxidative phosphorylation (OXPHOS) makes it exquisitely sensitive to mtDNA insults-mutations, oxidative lesions, copy-number shifts, or aberrant methylation-that impair ATP production, elevate reactive oxygen species (ROS), and further damage the mitochondrial genome. Damaged mtDNA fragments then escape into the cytosol, where they aberrantly engage cGAS-STING, TLR9, and NLRP3 pathways, driving cytokine storms, pyroptosis, and tissue injury. We propose that this cycle represents an almost unifying pathogenic mechanism in a spectrum of mtDNA-driven cardiovascular disorders. In this review, we aim to synthesize the pathophysiological roles of mtDNA in this cycle and its implications for cardiovascular diseases. Furthermore, we seek to evaluate preclinical and clinical strategies aimed at interrupting this cycle-bolstering mtDNA repair and copy-number maintenance, reversing pathogenic methylation, and blocking mtDNA-triggered innate immune activation-and discuss critical gaps that must be bridged to translate these approaches into precision mitochondrial genome medicine for cardiovascular disease.

Keywords:  cardiovascular disease; cellular biology; mitochondrial DNA; therapeutic strategy

DOI:  https://doi.org/10.3390/antiox14091138
BMC Genomics. 2025 Sep 25. 26(1): 810

MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.

Haruko Nakagawa, Yasuyuki Shima, Yohei Sasagawa, Itoshi Nikaido.

   BACKGROUND: Deletion variants in mitochondrial DNA (mtDNA) are associated with various diseases, such as mitochondrial disorders and neurodegenerative diseases. Traditionally, mtDNA deletions have been studied using bulk DNA sequencing, but bulk methods average signals across cells, thereby masking the cell-type-specific mutational landscapes. Resolving mtDNA deletions at single-cell resolution is beneficial for understanding how these mutations affect distinct cell populations. To date, no specialized method exists for detecting cell-type-specific mtDNA deletions from single-cell RNA sequencing data. Notably, mtDNA possesses unique molecular features: a high copy number, stable transcription, and compact structure of the mitochondrial genome. This results in a relatively high abundance of mtDNA-derived reads even in single-cell RNA sequencing data, suggesting the possibility of detecting mtDNA deletion variants directly from transcriptomic data.
RESULTS: Here, we present MitoDelta, a computational pipeline that enables the detection of mtDNA deletions at cell-type resolution solely from single-cell RNA sequencing data. MitoDelta combines a sensitive alignment strategy with robust statistical filtering based on a beta-binomial distribution model, allowing accurate identification of deletion events even from noisy single-cell transcriptomes. To capture cell-type-specific deletion patterns, MitoDelta analyzes reads pooled by annotated cell types, enabling quantification of deletion burden across distinct cellular populations. We benchmarked MitoDelta against existing mtDNA deletion detection tools and demonstrated superior overall performance. As a practical application, we applied MitoDelta to a published single-nucleus RNA sequencing dataset for Parkinson's disease and revealed distinct mtDNA deletion burdens across neuronal subtypes.
CONCLUSIONS: MitoDelta enables the transcriptome-integrated, cell-type-specific detection of mtDNA deletions from single-cell RNA sequencing data alone, offering a valuable framework for reanalyzing public datasets and studying mitochondrial genome alterations at cell-type resolution. This integrated approach enables insights into how mtDNA deletions are distributed across specific cell types and cellular states, providing new opportunities to investigate the role of mtDNA deletions in cell-type-specific disease mechanisms. The tool is available at https://github.com/NikaidoLaboratory/mitodelta .

Keywords:  Deletion variant; Mitochondrial DNA; Single-cell transcriptomics; Variant caller

DOI:  https://doi.org/10.1186/s12864-025-11931-0
Mol Ther. 2025 Sep 23. pii: S1525-0016(25)00765-8. [Epub ahead of print]

Gene therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies.

Caterina Garone, Silvia Sabeni, Sara Carli.

Mitochondrial disorders are a clinically heterogeneous group of diseases due to defects in nuclear or mitochondrial DNA-encoded genes leading to mitochondrial dysfunction and oxidative phosphorylation deficiency in the affected tissues. The dual genetic controls, the biochemical heterogeneity, and the clinical variability challenge the development of effective treatment. In this review, we will focus on gene therapy and mRNA drug approaches for nuclear-encoded gene defects causing isolated, combined, or multiple oxidative phosphorylation defects and mitochondrial-encoded gene defects for which a gene replacement approach has been tested, and on the allotopic expression of mtDNA genes. An overview of the available in vitro and in vivo disease models and pre-clinical data of safety and efficacy is provided and highlights challenges in correcting the biochemical defect in the most affected tissues. Future perspectives with the use of novel gene-editing approaches or gene replacement delivery with nanoparticles are also considered as a novel strategy for treating mitochondrial disorders.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.036
Kaohsiung J Med Sci. 2025 Sep 27. e70117

Loganin, an Iridoid Glycoside, Alleviates Paclitaxel-Induced Skeletal Muscle Toxicity by Enhancing Mitochondrial Function, Boosting Antioxidant Defenses, and Reducing Cellular Senescence.

Yu-Fan Chuang, Cai-Rong Wu, Wan-Hsuan Chang, Ying-Jung Su, Hung-Te Hsu, Fan-Li Lin, Yi-Ching Lo.

  Mitochondrial dysfunction and energy imbalance caused by chemotherapy are key contributors to skeletal muscle atrophy, which severely impacts the quality of life in cancer patients. Paclitaxel, a commonly used chemotherapeutic agent, is known to promote muscle wasting and cellular senescence, largely by impairing mitochondrial function. In this study, we investigated the protective role of loganin, a naturally occurring iridoid glycoside, in preventing paclitaxel-induced damage to skeletal muscle cells. Using C2C12 cells, we assessed whether loganin could counteract the harmful effects of paclitaxel. Our results demonstrated that loganin significantly improved cell viability and protected mitochondrial function, as reflected by better preservation of mitochondrial DNA content, membrane potential, and ATP production, while further enhancing mitochondrial biogenesis through upregulation of PGC-1α, TFAM, and NRF1. In parallel, loganin activated metabolic regulators SIRT1 and AMPK, while restoring PDK4 expression, suggesting improved energy regulation. Additionally, glycogen levels and myotube morphology were maintained, alongside sustained myosin heavy chain expression. Loganin effectively reduced both cellular and mitochondrial reactive oxygen species and increased antioxidant defenses, including superoxide dismutase activity and glutathione levels. Notably, it also suppressed paclitaxel-induced senescence and inflammation, as shown by decreased p21 expression, reduced NFκB phosphorylation, and lower levels of Cdkn1a and Il6 as well as reduced SA-β-gal staining. Overall, our findings demonstrate that loganin offers comprehensive protection against paclitaxel-induced skeletal muscle injury by preserving mitochondrial function, supporting metabolic homeostasis, reducing oxidative stress, and limiting senescence. These results highlight the potential of loganin as a preventive adjunctive agent to mitigate chemotherapy-related muscle toxicity.

Keywords:  cellular senescence; loganin; mitochondrial dysfunction; paclitaxel‐induced myotoxicity; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/kjm2.70117
Microorganisms. 2025 Sep 15. pii: 2149. [Epub ahead of print]13(9):

From Ancient Philosophy to Endosymbiotic Theory: The Bacterial Origin and Key Role of Mitochondria in Immune Responses.

Alexandra Mpakosi, Christiana Kaliouli-Antonopoulou, Vasileios Cholevas, Stamatios Cholevas, Ioannis Tzouvelekis, Maria Mironidou-Tzouveleki, Emmanuel A Tsantes, Deny Tsakri, Marianna Vlachaki, Stella Baliou, Petros Ioannou, Rozeta Sokou, Stefanos Bonovas, Andreas G Tsantes.

  The endosymbiotic theory, which is the crucial starting point of eukaryogenesis, was first mentioned in the philosophy of the pre-Socratic Greek philosopher Empedocles. According to him, everything merges into units with differential survival. Similarly, during eukaryogenesis, the fusion of two distinct units resulted in the creation of a new cell type that possessed a newly formed organelle, the mitochondrion. Since then, the mitochondrion has been a key regulator of health and immunity. Furthermore, many of its characteristics and functions are due to its endosymbiotic bacterial origin. For example, it possesses damage-associated molecular patterns that can activate inflammatory signaling pathways, has circular DNA with CpG-rich motifs, as well as a double phospholipid membrane, and divides by fission. Mitochondrial function plays a critical role in maintaining cellular homeostasis, as they meet the cell's energy needs and regulate many of its functions. However, after cellular damage due to infection, radiation, or toxins, mitochondrial stress and dysfunction can occur and mitochondrial DNA can be released into the cytosol. Cytosolic mitochondrial DNA can then activate proinflammatory signaling pathways, mediated by TLR9 and cGAS, as well as inflammasomes, triggering inflammation and autoimmunity.

Keywords:  cellular homeostasis; endosymbiosis; eukaryotic cell; evolution; immune responses; inflammasome; mitochondrial DNA; proinflammatory signaling pathways

DOI:  https://doi.org/10.3390/microorganisms13092149
J Clin Med. 2025 Sep 17. pii: 6528. [Epub ahead of print]14(18):

Cell-Free Circulating Mitochondrial DNA Levels Following High-Frequency Jet Ventilation-A Post Hoc Analysis.

Marita Windpassinger, Michal Prusak, Kurt Ruetzler, Olga Plattner, Isabella Stanisz, Patrick Haider.

  Background: Mitochondrial DNA (mtDNA), normally enclosed within mitochondria, can be released into circulation in response to cellular stress, hypoxia, or inflammation. Its detection in plasma has been proposed as a marker of cellular injury, particularly in the context of mechanical ventilation. High-frequency jet ventilation is a specialized approach of open-airway ventilation, delivering small tidal volumes through jet gas streams, applied with high pressure and oxygen fraction. It remains unclear whether this mode of ventilation contributes to mitochondrial stress. We therefore hypothesized that circulating mtDNA levels would increase after jet ventilation due to the combined effects of high oxygen exposure and mechanical strain. Furthermore, we explored whether the magnitude of mtDNA change correlates with the duration of ventilation and arterial oxygenation levels. Methods: Plasma levels of cell-free circulating mitochondrial DNA were measured in 30 patients before and following jet ventilation in laryngotracheal surgery. Post hoc analysis of a primary monocentric, randomized cross-over study was conducted to investigate ventilation distribution in high-frequency jet ventilation techniques. Results: Mitochondrial DNA levels significantly decreased after jet ventilation (median T0: 13.57; T1: 6.78; p = 0.0087). No significant associations were found between mtDNA change and jet ventilation duration, type of surgery, or ASA classification. Despite variable air entrainment in the open-jet ventilation system, the arterial partial pressure of oxygen increased significantly during the procedure. Conclusions: Jet ventilation was associated with a significant decrease in circulating mtDNA levels. This contrasts with our initial hypothesis of mtDNA elevation under ventilation-induced stress. These findings suggest that jet ventilation may exert less mitochondrial damage than previously expected.

Keywords:  anesthesia; cell-free circulating mitochondrial DNA; high-frequency jet ventilation; oxidative stress

DOI:  https://doi.org/10.3390/jcm14186528
Int J Physiol Pathophysiol Pharmacol. 2025 ;17(4): 131-147

Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.

Amir K Richardson, Devadoss J Samuvel, Yasodha Krishnasamy, John J Lemasters, Zhi Zhong.

   OBJECTIVES: Clinically, liver regeneration is often impaired by infections causing endotoxemia, although mechanisms are unclear. Since energy supply is essential for liver regeneration, we assessed whether formoterol (FMT), a β2-adrenergic agonist that increases peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis (MB), restores liver regeneration after partial hepatectomy (PHX) in endotoxin (LPS)-treated mice.
METHODS: Mice underwent sham-operation, two-thirds PHX, PHX with LPS injection (PHX+LPS, 5 mg/kg, i.p.), or PHX+LPS followed by FMT (0.1 mg/kg, i.p.) after 2 h.
RESULTS: At 48 h after PHX, 5'-bromo-2'-deoxyuridine incorporation, mitotic cells, proliferating cell nuclear antigen, and cyclin-D1 markedly increased, signifying liver regeneration. By contrast, after PHX+LPS, liver regeneration was almost completely suppressed. FMT restored liver regeneration after PHX+LPS. PGC1α, mitochondrial transcription factor-A (controlling mitochondrial DNA replication/transcription), and mitochondrial oxidative phosphorylation proteins ATP synthase-β and NADH dehydrogenase-3 decreased after PHX+LPS, signifying suppressed MB. FMT largely reversed these effects. Mitochondrial oxidative stress stimulates inflammation by activating inflammasomes. In addition to promoting MB, PGC1α reportedly inhibits oxidative stress and inflammation. 8-Hydroxy-deoxyguanosine, NLRP3, and inflammatory cytokines increased after PHX+LPS, demonstrating increased oxidative stress and inflammasome activation. Many necro-inflammatory foci occurred in liver sections after PHX+LPS. FMT increased expression of antioxidant protein thioredoxin-2, decreased oxidative stress, and blunted inflammatory responses. Additionally, FMT decreased alanine aminotransferase release and necrosis caused by PHX+LPS.
CONCLUSIONS: FMT restores liver regeneration during endotoxemia and decreases liver injury and inflammation, most likely by increasing PGC1α. Therefore, FMT is a promising therapy for liver failure caused by loss of liver mass complicated with sepsis.

Keywords:  Endotoxin; formoterol; liver regeneration; liver resection; mitochondrial biogenesis; oxidative stress

DOI:  https://doi.org/10.62347/JMWH4994
Clin Chim Acta. 2025 Sep 23. pii: S0009-8981(25)00506-6. [Epub ahead of print] 120627

Analysis of urine cell-free DNA copy number and fragment size from healthy individuals.

Jufen Wang, Zilong Wu, Bingyu Wu, Xinghao Lin, Wenhe Wu, Jun Li.

   OBJECTIVE: This study characterizes urine cell-free DNA (cfDNA) copy number and fragment size in healthy individuals and explores their associations with routine clinical parameters.
METHODS: Sixty healthy subjects were enrolled, providing paired blood and urine samples. Six primer pairs targeting nuclear (GAPDH-61/168/241) and mitochondrial DNA (ND1-57/167/240) were designed for absolute qPCR. Optimal urine collection, pre-treatment, and cfDNA detection protocols were evaluated. Correlations between cfDNA characteristics (fragment size and copy number) and clinical parameters (complete blood count, urinalysis, hepatic/renal function biomarkers) were analyzed.
RESULTS: Non-extracted urine retained a higher proportion of fragments <100 bp and > 2000 bp than extracted samples. The optimal pre-treatment involved immediate EDTA addition, centrifugation at 4 °C, and storage at -80 °C. Urine cfDNA comprised short, medium, and long fragments. Cell-free mitochondrial DNA (cf-mtDNA) showed the highest copy numbers in short fragments, decreasing with length, whereas cell-free nuclear DNA (cf-nDNA) peaked in medium fragments. ND1-57 Cq values correlated negatively with neutrophil percentage (P < 0.01) and positively with lymphocyte percentage (P < 0.05). Lymphocyte percentage was moderately correlated with ND1 short fragment (ND1-S, P < 0.01) and weakly with the ND1-S to ND1 medium fragment (ND1-M) ratio (P < 0.05). Absolute lymphocyte count correlated weakly with ND1-S (P < 0.01) and ND1-M (P < 0.05). Neutrophil percentage correlated weakly with ND1-S (P < 0.01) and ND1-S to ND1 long fragment (ND1-L) ratio (P < 0.05).
CONCLUSION: Urine cfDNA displays three distinct fragment sizes, with cf-mtDNA predominantly found in short fragments and showing stronger associations with physiological parameters than cf-nDNA.

Keywords:  Biomarker; Cell-free mtDNA; Cell-free nDNA; Pre-treatment conditions; Urine

DOI:  https://doi.org/10.1016/j.cca.2025.120627
Cell Biochem Biophys. 2025 Sep 27.

Strategic Targeting of Mitochondria: Bridging Biology and Therapy for Health Benefits.

Gino A Kurian, Srijan Jayaraman, Eren Rose Gino.



Keywords:  Mitochondrial inner membrane targeting; Mitochondrial matrix and precision medicine; Mitochondrial outer membrane targeting; Mitochondrial transport; Targeted drug delivery

DOI:  https://doi.org/10.1007/s12013-025-01915-y
Regen Biomater. 2025 ;12 rbaf090

Plasma-derived mitochondrial transplantation attenuates paraspinal muscle atrophy following spinal surgery.

Ikhyun Lim, Seong-Hoon Kim, Mi Jin Kim, Chang-Koo Yun, Kyunghoon Min, Yong-Soo Choi.

  Paraspinal muscle atrophy (PMA) is a common complication after spinal surgery, often leading to reduced spinal stability and prolonged discomfort. While mitochondrial dysfunction has emerged as a key contributor to PMA, existing therapies do not adequately address this underlying pathophysiology. In this study, we investigated the regenerative potential of plasma-derived mitochondria (pMT) as a cell-free and autologous biomaterial to mitigate PMA. Mitochondria were isolated from human peripheral blood and confirmed to maintain their structural integrity and respiratory activity. In an in vitro model of muscle atrophy, pMT treatment improved cell viability, enhanced ATP production and restored mitochondrial function. In a rat model of surgery-induced PMA, intramuscular injections of pMT led to improved muscle morphology, including increased fiber cross-sectional area, along with reduced mechanical hypersensitivity. Transcriptomic analyses revealed that pMT transplantation modulated key pathways related to mitochondrial biogenesis and oxidative phosphorylation, while downregulating pro-apoptotic signals. These findings were corroborated by protein-level assessments showing restoration of muscle-specific markers and normalization of mitochondrial homeostasis. Taken together, this study highlights the therapeutic potential of pMT transplantation in addressing mitochondrial dysfunction and promoting muscle regeneration following spinal surgery. These findings suggest that pMT may serve as a minimally invasive, scalable and autologous regenerative approach to restore skeletal muscle integrity in clinically relevant contexts.

Keywords:  laminectomy; mitochondrial transplantation; muscle regeneration; paraspinal muscle atrophy; plasma-derived mitochondria

DOI:  https://doi.org/10.1093/rb/rbaf090
Antioxidants (Basel). 2025 Sep 10. pii: 1100. [Epub ahead of print]14(9):

A Nanoformulation of Ubiquinol and Selenium Promotes Proliferation of Human Induced Pluripotent Stem Cells.

Filomain Nguemo, Hai Zhang, Annette Koester, Susan Rohani, Sureshkumar Perumal Srinivasan, Jürgen Hescheler.

  Human induced pluripotent stem cells (hiPSCs) hold immense promise for regenerative medicine. However, a critical barrier to the clinical application of hiPSCs is the difficulty in promoting robust cell proliferation while preserving their pluripotent state. Efficient hiPSC expansion without loss of pluripotency is crucial for generating high quality cells or therapeutic applications, disease modeling, and drug discovery. In our study, we investigated the effects of QuinoMit Q10® fluid (QMF-Se), a nanoformulated supplement containing Ubiquinol (the active form of Coenzyme Q10) and Selenium, on hiPSC growth and maintenance in vitro. Interesting, QMF-Se supplementation significantly enhances hiPSC proliferation compared to control cultures. This increase in cell number was accompanied by heightened mitochondrial activity, suggesting improved cellular energy metabolism. Importantly, the expression of core pluripotency markers OCT4, NANOG, and SOX2 remained unaltered, confirming that the stem cells retained their undifferentiated status. Moreover, we observed that QMF-Se treatment conferred protective effects during the freeze-thaw process, reducing cell death and supporting post-thaw recovery. These results indicate that QMF-Se may improve both cell culture efficiency and cryopreservation outcomes. Overall, our findings highlight the potential of QMF-Se as a valuable additive for hiPSC culture systems, contributing to more efficient and reliable expansion protocols in regenerative medicine research.

Keywords:  QuinoMit Q10 fluid; cryopreservation; hiPSCs; mitochondria; proliferation

DOI:  https://doi.org/10.3390/antiox14091100
J Neurol. 2025 Sep 23. 272(10): 648

Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.

Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.

   BACKGROUND: Primary mitochondrial diseases comprise a group of inherited disorders that frequently affect the central nervous system. Previous studies have reported brain imaging findings commonly associated with mitochondrial disease. However, longitudinal data on volumetric brain abnormalities, their progression in time, and associations with clinical features of the disease remain limited.
METHODS: We conducted a retrospective observational study of 36 patients with genetically confirmed mitochondrial disease at Turku University Hospital (Turku, Finland). A total of 73 brain magnetic resonance scans (1-8 per patient) were analysed using the cNeuro® image quantification tool to assess lobar and regional cortical atrophy. Associations with clinical features, including stroke-like episodes (SLEs), sex, and genetic subtype, were investigated.
RESULTS: Cerebral atrophy was present in all patients and was most pronounced in the temporal and occipital lobes. Patients with a history of SLEs exhibited significantly greater atrophy in both temporal lobes and the right occipital and parietal lobes. Follow-up imaging (available for 15 patients) revealed progressive atrophy, particularly in the occipital lobes, in patients with SLEs. No significant differences in atrophy severity or progression were found between patients with the m.3243A > G variant and those with other genetic causes.
CONCLUSIONS: Cerebral atrophy is a common and often progressive feature of mitochondrial disease, even in patients without clinical brain symptoms. Atrophy predominantly affects posterior brain regions, and its progression is particularly evident in patients with SLEs. These findings underline the neurodegenerative nature of mitochondrial disease and highlight the need to develop neuroprotective therapies.

Keywords:  Cerebral atrophy; Longitudinal imaging; Magnetic resonance imaging; Mitochondrial disease; Neurodegeneration; Stroke-like episodes

DOI:  https://doi.org/10.1007/s00415-025-13354-z
Cell Stress Chaperones. 2025 Sep 18. pii: S1355-8145(25)00060-4. [Epub ahead of print] 100115

Autophagy in Proteostasis AND AGING in C. ELEGANS.

Caitlin M Lange, Ryo Higuchi-Sanabria, Caroline Kumsta.

  Proteostasis (protein homeostasis), the balance of protein synthesis, folding, and degradation, is critical for cellular function and organismal health. Its disruption leads to the accumulation of misfolded and aggregated proteins, hallmarks of aging and age-related diseases including neurodegeneration. Autophagy, a conserved lysosome-mediated degradation pathway, is central to proteostasis by clearing toxic proteins and damaged organelles. In Caenorhabditis elegans, studies across conserved longevity paradigms and models of neurodegenerative diseases have defined key mechanisms by which autophagy maintains proteostasis during aging and stress. Beyond its degradative functions, autophagy contributes to spatial quality control by promoting the formation of potentially protective protein inclusions and coordinating with the ubiquitin-proteasome system. Emerging evidence also points to noncanonical autophagy pathways, such as unconventional secretion and inter-tissue communication, that broaden its role in systemic proteostasis. Together, these advances underscore autophagy's multifaceted contribution to protein quality control, with wide-ranging implications for aging, stress resistance and neurodegenerative disease.

Keywords:  Aggresome; Aging; Autophagy; C. elegans; Inclusion body; Inter-tissue signaling; Longevity; Neurodegeneration; Protein Aggregation; Proteostasis; Secretion; Stress Response

DOI:  https://doi.org/10.1016/j.cstres.2025.100115
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Sep 23. pii: S1388-1981(25)00099-X. [Epub ahead of print] 159691

The B-lymphoblastoid model in Barth syndrome.

John Z Chan, Michelle V Tomczewski, Antonia N Berdeklis, Robin E Duncan.

  Barth Syndrome (BTHS) is an ultra-rare, X-linked mitochondrial disorder caused by a variety of different mutations in the cardiolipin remodeling gene TAFAZZIN that results in cardiac and skeletal myopathy, as well as immunological deficits. Epstein-Barr virus-mediated transformation of B-lymphocytes has been used to generate B-lymphoblastoid cells that retain many of the characteristics of the initial cell line, but can be propagated extensively in culture to generate biological materials enabling study of the basic, natural function of this enzyme in cells, as well as disease-relevant effects and interventions. Notably, these model lines from individual donors are of particular value for understanding a disease with variable penetrance such as BTHS, where variation in genetic background can alter symptom severity considerably, even among closely-related individuals with the same mutation. Here, we review the generation, benefits, and limitations of the B-lymphoblastoid cell model in BTHS research, and provide an overview of recent advances in understanding the role of TAFAZZIN in mitochondrial biology from this model. Implications of these findings for understanding the pathology of BTHS, and determining future directions, are also provided, along with a review of recent advances in our understanding of the mechanism of TAFAZZIN function in cardiolipin degradation, remodeling and stability.

Keywords:  Barth syndrome (BTHS); Cardiolipin; Electron transport chain; Lymphoblastoid; Mitochondria; Monolysocardiolipin; Reactive oxygen species; TAFAZZIN

DOI:  https://doi.org/10.1016/j.bbalip.2025.159691
Vavilovskii Zhurnal Genet Selektsii. 2025 Sep;29(5): 676-684

Rare missense substitutions in the mitochondrial DNA genes in patients with ventricular tachycardia.

M V Golubenko, N P Babushkina, V A Korepanov, N R Valiakhmetov, T A Atabekov, K N Vitt, A A Zarubin, O A Makeeva, S A Afanasiev, R E Batalov, A A Garganeeva, M S Nazarenko, V P Puzyrev.

  Human mitochondrial DNA (mtDNA) exhibits high population-level polymorphism. While certain pathogenic mtDNA variants are known to cause hereditary mitochondrial syndromes, often presenting with cardiac arrhythmias, life-threatening ventricular tachycardia (VT) itself is a major risk factor for sudden death in cardiovascular diseases. The aim of the work was to study rare ("private") missense substitutions in the mtDNA of patients with documented episodes of ventricular tachycardia in comparison with patients with ischemic heart disease without life-threatening heart arrhythmias and individuals without clinical manifestations of cardiovascular diseases. The sequencing of mtDNA was performed using high-throughput sequencing methods. Specialized algorithms predicting the effect of gene variants were used to assess the effect of missense substitutions. Comparative analysis of the spectrum of the identified amino acid substitutions in the studied groups showed that about 40 % of the individuals in all three groups were carriers of "private" missense variants in mtDNA. However, among such substitutions, the variants classified by the APOGEE2 predictor as "variants of uncertain significance" (VUS) were more common in the group of patients with heart arrhythmias than in the control group, where "private" missense substitutions of the VUS category were not detected (p = 0.0063 for Fisher's exact test). In addition, the groups differed in their phred-ranked Combined Annotation Dependent Depletion (CADD) scores, which were lower for individuals in the control group. The results indicate that rare mtDNA variants may contribute to predisposition to cardiovascular disease - in particular, to the risk of developing ventricular tachycardia by some patients.

Keywords:  genetic variant pathogenicity assessment; heart arrhythmia; missense substitutions effects; mitochondrial DNA; ventricular tachycardia

DOI:  https://doi.org/10.18699/vjgb-25-74
bioRxiv. 2025 Sep 19. pii: 2025.09.18.676925. [Epub ahead of print]

Vascular-Perfusable Human 3D Brain-on-Chip.

Alice E Stanton, Rebecca L Pinals, Aaron Choi, Nhat Truong, Eulim Kang, Alan Jiang, Claudia F Lozano Cruz, Sydney Hawkins, Ryana Sarcar, Alexandra Volkova, Oisín King, Emre Agbas, Masayuki Nakano, Ching-Chi Chiu, Adele Bubnys, Shannon Wright, Colin Staab, Rami Bikdash, Emily Forden, Robert Langer, Li-Huei Tsai.

Development and delivery of treatments for neurological diseases are limited by the tight and selective human blood-brain barrier (BBB). Although animal models have been important research and preclinical tools, the rodent BBB exhibits species differences and fails to capture the complexity of human genetics. Microphysiological systems incorporating human-derived cells hold great potential for modeling disease and therapeutic development, with advantages in screening throughput, real-time monitoring, and tunable genetic backgrounds when combined with induced pluripotent stem cell (iPSC) technology. Existing 3D BBB-on-chip systems have incorporated iPSC-derived endothelial cells but not the other major brain cell types from iPSCs, each of which contributes to brain physiology and disease. Here we developed a 3D Brain-Chip system incorporating endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia from iPSCs. To enable this multicellular 3D co-culture in-chip, we designed a GelChip microfluidic platform using a 3D printing-based approach and dextran-based engineered hydrogel. Leveraging this platform, we co-cultured and characterized iPSC-derived brain-on-chips and modeled the brain microvasculature of APOE4 , the strongest known genetic risk factor for sporadic Alzheimer's disease. These 3D brain-on-chips provide a versatile system to assess BBB vascular morphology and function, investigate downstream neurological effects in disease, and screen therapeutics to optimize delivery to the brain.
Significance Statement: The blood-brain barrier (BBB) is both a contributing factor to neurological disease and a major obstacle to its treatment, yet human-relevant models remain limited. Most existing brain-on-chip systems incorporate only subsets of BBB cell types and cannot capture the full cellular complexity of the human neurovascular unit. Here, we establish a vascular-perfusable 3D Brain-Chip using human induced pluripotent stem cell-derived brain cells including endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia. This system enables systematic analysis of human genetic risk factors, such as APOE4 in Alzheimer's disease, and provides a powerful platform to investigate BBB function and dysfunction and accelerate the development of more effective neurological therapies.

DOI: https://doi.org/10.1101/2025.09.18.676925
Sultan Qaboos Univ Med J. 2025 ;25(1): 689-696

Causes of Mortality in Patients with Inborn Errors of Immunity: An 18-year retrospective cohort study.

Salem Al-Tamemi, Musab Al Jabri, Eiman Abdalla, Ibrahim Al-Busaidi, Khalfan Al-Zeedy, Laila Al Yazidi.

   Objectives: Inborn errors of immunity (IEI) are a diverse group of disorders arising from defects in the development and/or function of the immune system. However, data concerning the microbiological aspects of infections and direct causes of mortality in patients with IEI are limited and fragmented. This study aimed to elucidate the causes of disease and terminal events leading to death in a cohort of patients with IEI.
Methods: This retrospective study included deceased patients who were diagnosed with primary immunodeficiency at Sultan Qaboos University Hospital in Muscat, Oman, over an 18-year period between 2005 and 2023. Data on clinical features, infections, isolated microorganisms and terminal events leading to death were collected and analyzed.
Results: A total of 53 cases were included in this study. The mean age at death was 9.1 ± 10.4 years (median: 3.9 years, interquartile range: 15.2 years, range: 0.2-45.2 years). Prior to death, the most frequently isolated microorganisms included Pseudomonas spp. (41.5%), Pseudomonas aeruginosa (34%), Candida spp. (28.3%), cytomegalovirus (26.4%) and Hemophilus influenzae (20.8%), among others. The predominant terminal events leading to death were septicemia/septic shock (64.2%), pneumonia/adult respiratory distress syndrome/multiorgan dysfunction syndrome (49.1%), disseminated viral disease (22.6%) and bronchiectasis/pulmonary hypertension/haemorrhage (20.8%).
Conclusion: Understanding factors contributing to terminal events in IEI patients can inform early intervention strategies and potentially reduce mortality rates.

Keywords:  Age; Causes of Death; Infections; Mortality; Oman; Primary Immunodeficiency Diseases

DOI:  https://doi.org/10.18295/2075-0528.2896
Subcell Biochem. 2025 ;109 241-256

Macromolecular Crowding in Mitochondria.

Semen V Nesterov, Vladimir N Uversky.

  The chapter reviews the various effects of crowding on mitochondrial structure and function. Data illustrate that, as a rule, the concentration of macromolecules in the mitochondrial matrix and inner membrane is at least as high as in other parts of the cytoplasm, while the intermembrane space is sparse. The effect of crowding on mitochondrial shape, the role of disordered protein domains, and the role of changes in crowding during mitochondrial swelling are discussed. Because of the excluded volume in the matrix, real changes in ion and metabolite concentrations under swelling are substantially higher than believed, and the inner membrane is highly curved at least partly due to crowding of the matrix. The high concentration of integral proteins in the mitochondrial inner membrane leads to enrichment with non-bilayer lipid cardiolipin to compensate for their induced membrane deformations. Also crowding may be one of the stimuli for the formation of enzyme supercomplexes. All reviewed data suggest that the structure of mitochondria is adapted exactly to the conditions of high crowding, and crowding itself is one of the key factors in the regulation of mitochondrial structure and function, the role of which is significantly underestimated in the scientific literature.

Keywords:  Enzyme supercomplexes; Intermembrane space; Intrinsically disordered proteins; Matrix; Mitochondrial function; Mitochondrial shape; Mitochondrial structure; Mitochondrial swelling

DOI:  https://doi.org/10.1007/978-3-032-03370-3_11
Ir Med J. 2025 Sep 18. 118(8): 126

The National Rare Disease Strategy Ireland 2025-2030.

J F A Murphy.