bims-polgdi Biomed News
on POLG disease
Issue of 2025–12–21
39 papers selected by
Luca Bolliger, lxBio
  1. Current understanding of mitochondrial DNA genetic diseases and gene therapy.
  2. Quantifying variability of mitochondrial markers in m3243A > G myopathy.
  3. Mitochondrial transfer as a novel therapeutic approach in ischemic stroke treatment: Current challenges and future perspectives.
  4. Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
  5. Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease.
  6. Obstetric history of women with m.3243A>G: an observational cohort study.
  7. Comprehensive Iranian guidelines for the diagnosis and management of mitochondrial disorders: an evidence- and consensus-based approach.
  8. A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes.
  9. Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.
  10. Mitochondria-Targeted Nanosystems in the Treatment of Central Nervous System Diseases.
  11. EVs from Stem Cells Improve Mitochondrial Dysfunction in Neuronal Disorders.
  12. Modeling rare genetic disease with gene-edited induced pluripotent stem cells: relevance of the starting stock line.
  13. Mitochondria to the rescue: organelle trafficking in renal health and disease.
  14. An efficient preprocessing workflow tailored for mitochondrial genome assembly from fragmented DNA.
  15. Counseling and Prognostic Challenges in Survivorship and Mortality in Primary Mitochondrial Disease: Reshaping a Once Bleak Landscape.
  16. Patients' research priorities and participation in primary ciliary dyskinesia research.
  17. Stochasticity contributes to explaining minority and majority MOMP during apoptosis.
  18. Equity-focused implementation to enhance access to rare disease genomic research and understand diverse perspectives.
  19. Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.
  20. Mitochondrial RNA cytosolic leakage drives the SASP.
  21. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  22. Mitochondrial Dysfunction Drives Oxidative Stress and Energy Imbalance in a Murine Model of Spondyloarthritis.
  23. Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
  24. Multidimensional study on mitochondrial dysfunction in pulmonary hypertension.
  25. Identification of Intronic Variants in NDUFA3 as a Cause of Leigh Syndrome by Whole Genome Sequencing and RNA Sequencing.
  26. VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
  27. Functional Screening of NDUFAF6 Variants in Knockout Cells and Complementary Computational Analysis.
  28. There and back again: a cell biologist's journey from organelles to molecules.
  29. The Blood-Brain Barrier as an Integration Hub in Alzheimer's Disease: How Microbiota Metabolites Modulate Central Signal Processing.
  30. Unequal mitochondrial segregation promotes asymmetric fates during neurogenesis.
  31. The phenotype and genotype of KCNMA1 - related disorders in China.
  32. ZLN005 Alleviates the Dopaminergic Degeneration via PGC-1α-Mediated Mitochondrial Homeostasis in Parkinson's Disease.
  33. Hybrid Extracellular Vesicles for Efficient Loading and Functional Delivery of mRNA.
  34. The value of functional genomics: a contingent valuation.
  35. Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.
  36. Dl-3-n-butylphthalide Protects against Ischemic Stroke by Enhancing Mitochondrial Function via MT-CO1 Upregulation.
  37. Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
  38. Rapid whole genome sequencing in newborn screening for metabolic diseases.
  39. The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
  1. Yi Chuan. 2025 Dec;47(12): 1300-1325
    Current understanding of mitochondrial DNA genetic diseases and gene therapy.
    Cheng Tang, Shun-Qing Xu, Han-Zeng Li.
      Mitochondria, as crucial organelles within eukaryotic cells, have their proteins and RNAs encoded by both the nuclear genome and the mitochondrial genome. They play vital roles in energy regulation, cellular metabolism, signal transduction, and various other physiological activities. Additionally, mitochondria interact with multiple organelles to collectively maintain cellular homeostasis. Mitochondria can also be transferred between cells and tissues through mechanisms such as migrasomes. Mitochondrial DNA (mtDNA) mutations often cause severe inherited rare diseases, characterized by tissue specificity, heterogeneity, multiple mutation sites, and challenges in achieving a complete cure. Gene editing of mtDNA holds promise for fundamentally curing such diseases. Traditional gene-editing nucleases, such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nuclease (TALENs), as well as novel gene editors like DddA-derived cytosine base editors (DdCBEs), have been demonstrated to correct certain mtDNA mutations. However, CRISPR-based technologies-despite their superior programmability and efficiency-are currently limited due to the technical bottleneck of inefficient sgRNA delivery into mitochondria. This article systematically reviews the structure and function of mitochondria, related diseases, and the current state of mtDNA gene-editing therapies. Furthermore, it explores future directions for optimizing therapeutic tools to overcome the challenge of sgRNA delivery, thereby addressing the treatment barriers posed by pathogenic mtDNA mutations in inherited rare diseases.
    Keywords:  CRISPR; mitochondria; mtDNA associated rare diseases; mtDNA editing
    DOI:  https://doi.org/10.16288/j.yczz.25-032
  2. Sci Rep. 2025 Dec 19.
    Quantifying variability of mitochondrial markers in m3243A > G myopathy.
    Tiago M Bernardino Gomes, Jordan B Childs, Valeria Di Leo, Charlotte Warren, Gavin Hudson, Doug M Turnbull, Conor Lawless, Amy E Vincent.
      Myopathy is a prevalent and disabling feature of mitochondrial disease, in which skeletal muscle accumulates fibres with mitochondrial dysfunction in a variable mosaic pattern. This intra-individual spatial heterogeneity, a key consideration in longitudinal assessments, remains largely uncharacterised, hindering mechanistic studies and clinical trials by obscuring or confounding findings. We quantified this variability in m.3243 A > G-related myopathy, a leading cause of adult mitochondrial disease. Post-mortem biopsies from quadriceps femoris and tibialis anterior muscles of four patients were analysed for single-fibre deficiency in oxidative phosphorylation (OXPHOS) complex I and IV, while homogenate mitochondrial DNA (mtDNA) copy number and m.3243 A > G heteroplasmy were respectively determined by quantitative PCR and pyrosequencing. Bootstrapped combinatorial analyses established thresholds for minimum meaningful change above the 97.5th percentile, while accounting for anatomical biopsy distancing. Spatial variability in the proportion of OXPHOS-deficient fibres increased with distancing; within the same muscle, this threshold was 13.8% for NDUFB8 and 9.8% for MT-CO1. Variability in mtDNA copy number modestly increased with distance, while m.3243 A > G heteroplasmy remained largely stable, with within-muscle thresholds of 1,136 copies per nucleus and 8.2%, respectively. These findings provide assay-specific thresholds and offer mechanistic and translational insights for trial design, patient monitoring, and reliable detection of disease progression or therapeutic response.
    Keywords:  Heteroplasmy; M.3243A > G; Mitochondria; Mitochondrial DNA copy number; Myopathy; Oxidative phosphorylation
    DOI:  https://doi.org/10.1038/s41598-025-33106-3
  3. Neuroprotection. 2025 Sep;3(3): 253-265
    Mitochondrial transfer as a novel therapeutic approach in ischemic stroke treatment: Current challenges and future perspectives.
    Shuchen Meng, Min Bai, Changsheng Ma, Bo Han, Mengyuan Duan, Liying Zhang, Jinfen Guo, Changku Shi, Ke Li, Maotao He.
      Ischemic stroke, the second leading cause of human mortality, presents a formidable challenge to healthcare. Following ischemic insult, the brain undergoes intricate pathological transformations, prominently marked by mitochondrial damage, including swelling, fission, and mitophagy, collectively termed mitochondrial quality control disorder. Mitochondria, pivotal in energy regulation and oxidative stress modulation, play a critical role in neuronal apoptosis post-stroke. To solve the problems caused by mitochondrial quality control disorders, mitochondrial transfer has become a new therapeutic strategy for central nervous system diseases. Mitochondrial transfer refers to the process by which certain cell types export their mitochondria and pass them on to other cell types, a process also known as intercellular mitochondrial transfer. Mechanistically, mitochondrial transfer occurs via tunneling nanotubes, extracellular vesicles, and free mitochondrial transfer, exerting multifaceted effects such as anti-inflammatory, anti-lipid peroxidation, ferroptosis modulation, and enhancement of mitochondrial metabolism. This review explores the therapeutic efficacy, current obstacles, and future prospects of mitochondrial transfer in ischemic stroke, offering insights to researchers and instilling hope in patients for conquering this debilitating condition.
    Keywords:  ischemic stroke; mitochondrial dysfunction; mitochondrial therapy; mitochondrial transfer
    DOI:  https://doi.org/10.1002/nep3.70004
  4. Cell Chem Biol. 2025 Dec 18. pii: S2451-9456(25)00390-3. [Epub ahead of print]32(12): 1439-1441
    Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
    Chih-Yao Chung, Kritarth Singh, Brigida R Pinho, Jorge M A Oliveira, Michael R Duchen.
      Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.010
  5. NPJ Aging. 2025 Dec 16. 11(1): 99
    Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease.
    Adam J Hruby, Ryo Higuchi-Sanabria.
      Senescent cells, characterized by a state of irreversible proliferative arrest and inflammatory profile, have emerged as drivers of age-related decline. Growing evidence suggests that alterations in mitochondrial function and morphology play a key role in the induction and maintenance of senescence, as well as in promotion of the proinflammatory senescence-associated secretory phenotype (SASP). In this review, we seek to survey the relationship between mitochondrial dysfunction and senescence, focusing on the consequences of changes in oxidative phosphorylation efficiency, calcium handling, mitochondrial metabolites, mitochondrial dynamics and quality control, and release of damage-associated molecular patterns. We first describe these changes before illustrating the pathways and mechanisms through which mitochondrial dysfunction results in cell cycle arrest and the SASP. Lastly, we showcase evidence relating cellular senescence to neurodegenerative disease and propose that mitochondrial dysfunction may act as a bridge between the two.
    DOI:  https://doi.org/10.1038/s41514-025-00291-4
  6. J Med Genet. 2025 Dec 18. pii: jmg-2025-110875. [Epub ahead of print]
    Obstetric history of women with m.3243A>G: an observational cohort study.
    Petra Kuikka, Hilkka Nikkinen, Kari Majamaa, Mika Henrik Martikainen.
       BACKGROUND: Mitochondrial diseases are genetic disorders arising from pathogenic variants in nuclear or mitochondrial DNA (mtDNA) characterised by respiratory chain dysfunction. Clinical manifestations are diverse, and treatment is mostly symptomatic. Mitochondria are maternally inherited, but new reproductive technologies may prevent the transmission of pathogenic mtDNA. We decided to investigate the pregnancies of women with the m.3243A>G mtDNA variant.
    METHODS: 16 women with m.3243A>G were included in this retrospective, observational cohort study. Medical records were screened for pregnancies managed at Oulu University Hospital (Oulu, Finland) during the years 1960-2020. Main outcomes were obstetric complications as well as maternal and neonatal morbidity. All eligible pregnancies (n=38) were reviewed for the course of pregnancy and delivery as well as maternal and neonatal health.
    RESULTS: The median of maternal m.3243A>G load in muscle or buccal epithelium was 59% (range 30-76%). There were 30 deliveries and 31 born children. Among singleton pregnancies, gestational diabetes was present in seven (24%), gestational hypertension or pre-eclampsia in three (10%) and preterm delivery in two (7%). Mean birth weight was 3537 g (1020-5310 g), with a z-score of 0.80±1.37 for girls and 0.77±1.05 for boys. Seven newborns (12%) were treated in the neonatal intensive care unit.
    CONCLUSION: Women harbouring m.3243A>G may have an elevated risk for obstetric complications, such as gestational diabetes and gestational hypertension. Their babies may have an elevated risk of preterm birth and need for intensive care. Pregnancies of women with m.3243A>G should be followed carefully.
    Keywords:  Genetic Diseases, Inborn; Neurology; Neuromuscular Diseases; Reproductive Health; Reproductive medicine
    DOI:  https://doi.org/10.1136/jmg-2025-110875
  7. Orphanet J Rare Dis. 2025 Dec 19. 20(1): 623
    Comprehensive Iranian guidelines for the diagnosis and management of mitochondrial disorders: an evidence- and consensus-based approach.
    Setila Dalili, Noushin Rostampour, Seyedeh Tahereh Mousavi, Saeid Sadeghi Joni, Nejat Mahdieh, Afagh Hassanzadeh Rad, Seyede Tahoura Hakemzadeh, Sara Nikpour, Ali Talea, Hossein Moravvej.
      Mitochondrial disorders are a heterogeneous group of inherited metabolic diseases resulting from dysfunctions in oxidative phosphorylation. These conditions predominantly affect high-energy-demand organs such as the brain, heart, liver, and muscles, leading to diverse clinical manifestations and diagnostic challenges. This article presents the first comprehensive Iranian guideline for the diagnosis and management of mitochondrial diseases, developed through an evidence-based and consensus-driven methodology. We conducted a structured literature review across major biomedical databases from 2000 to 2023 and engaged a multidisciplinary panel of Iranian experts to establish context-specific recommendations. The guideline covers clinical presentations, laboratory biomarkers, neuroimaging features, genetic diagnostics, and treatment approaches including "cocktail therapy" and acute management protocols. It also integrates a mitochondrial disease scoring system to standardize diagnosis and provides detailed insights into safe anesthesia practices for affected individuals. Special attention is given to practical implementation in resource-limited settings. These guidelines aim to enhance diagnostic accuracy, optimize management strategies, and improve the quality of life for patients with mitochondrial disorders across Iran and similar healthcare systems.
    Keywords:  Diagnosis; Genetic testing; Mitochondrial diseases
    DOI:  https://doi.org/10.1186/s13023-025-04127-y
  8. Elife. 2025 Dec 16. pii: RP98889. [Epub ahead of print]13
    A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes.
    Yury S Bykov, Solene Zuttion, Dunya Edilbi, Marina Polozova, Johanna Arnold, Sergey Malitsky, Maxim Itkin, Bruno Senger, Ofir Klein, Yeynit Asraf, Hadar Meyer, Hubert D Becker, Roza Kucharczyk, Maya Schuldiner.
      The majority of mitochondrial proteins are encoded in the nuclear genome. Many of them lack clear targeting signals. Therefore, what constitutes the entire mitochondrial proteome is still unclear. We here build on our previously developed bi-genomic (BiG) split-GFP assay (Bader et al., 2020) to solidify the list of matrix and inner membrane mitochondrial proteins. The assay relies on one fragment (GFP1-10) encoded in the mitochondrial DNA enabling specific visualization of only the proteins tagged with a smaller fragment, GFP11, and localized to the mitochondrial matrix or the inner membrane. We used the SWAp-Tag (SWAT) strategy to tag every protein with GFP11 and mated them with the BiG GFP strain. Imaging the collection in six different conditions allowed us to visualize almost 400 mitochondrial proteins, 50 of which were never visualized in mitochondria before, and many are poorly studied dually localized proteins. We use structure-function analysis to characterize the dually localized protein Gpp1, revealing an upstream start codon that generates a mitochondrial targeting signal and explore its unique function. We also show how this data can be applied to study mitochondrial inner membrane protein topology and sorting. This work brings us closer to finalizing the mitochondrial proteome and the freely distributed library of GFP11-tagged strains will be a useful resource to study protein localization, biogenesis, and interactions.
    Keywords:  S. cerevisiae; automated microscopy; biochemistry; cell biology; chemical biology; dual localization; mitochondria; mitochondrial proteome; protein targeting; yeast genetics
    DOI:  https://doi.org/10.7554/eLife.98889
  9. Front Cell Infect Microbiol. 2025 ;15 1714998
    Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.
    Yang Yang, Yuanyuan Zeng, Zeyi Liu, Jian-An Huang.
      Mitochondria have emerged as multifunctional organelles central to cellular metabolism, innate immunity, and cell fate determination. Increasing evidence demonstrates that pathogens-including viruses, bacteria, fungi, and parasites-target mitochondria to modulate host immune responses and metabolic reprogramming. Disruption of mitochondrial dynamics, excessive reactive oxygen species (ROS) generation, mitochondrial DNA (mtDNA) release, and altered mitophagy represent key hallmarks of pathogen-induced mitochondrial dysfunction. These processes not only compromise cellular bioenergetics but also influence immune signaling cascades, such as cGAS-STING and NLRP3 inflammasome pathways, thereby shaping infection outcomes. This review synthesizes the latest findings on how distinct pathogen classes orchestrate mitochondrial damage and explores their implications for infection biology and immune regulation. Furthermore, we highlight emerging mitochondria-targeted therapeutic strategies and future research directions aimed at mitigating infection-induced mitochondrial pathology.
    Keywords:  host defense; infection; mitochondria; mitochondrial dynamics; pathogens
    DOI:  https://doi.org/10.3389/fcimb.2025.1714998
  10. Int J Nanomedicine. 2025 ;20 14667-14694
    Mitochondria-Targeted Nanosystems in the Treatment of Central Nervous System Diseases.
    Xiaolan Zhang, Jiahui Chen, Bingjie Wan, Yanrong Zheng, Xiaojie Chen.
      Mitochondrial dysfunction represents a pivotal pathological mechanism underlying diverse diseases, particularly those affecting the central nervous system (CNS). Consequently, therapeutic strategies capable of effectively restoring mitochondrial function hold significant promise for treating CNS disorders. Nanotechnology has emerged as a powerful platform in this endeavor, leveraging the modifiability, controllability, and targeting capabilities of nanosystems to intervene at the mitochondrial level. This review delineates the critical role of mitochondrial integrity in CNS pathophysiology and summarizes key mitochondria-targeting strategies, including small-molecule ligands, mitochondrial-penetrating peptides, mitochondrial membrane-derived vesicles, and biomimetic membrane coatings. We also discuss the efficacy of mitochondria-targeted nanosystems in rescuing mitochondrial dysfunction across major CNS conditions, exemplified by neurodegenerative diseases, brain tumors, ischemic stroke, and traumatic brain injury. Ultimately, this review also points out current translational challenges and future research directions pivotal for advancing mitochondrial nanomedicine. Collectively, this work synthesizes progress in mitochondrial nanotherapeutics, highlighting their transformative potential while outlining critical barriers and opportunities for clinical translation in CNS disorders.
    Keywords:  Drug delivery; Mitochondria-targeted therapy; Mitochondrial dysfunction; Nanosystems
    DOI:  https://doi.org/10.2147/IJN.S562666
  11. Mol Neurobiol. 2025 Dec 19. 63(1): 313
    EVs from Stem Cells Improve Mitochondrial Dysfunction in Neuronal Disorders.
    Sadaf Jahan, Dipak Kumar, Shaheen Ali, Arif Jamal Siddiqui, Mohammed Alaidarous, Johra Khan, Andleeb Khan.
      Mitochondrial dysfunction is a critical pathological trait of numerous neurodegenerative and inflammatory central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Cellular stressors can directly modulate mitochondrial metabolism and increase the production of reactive oxygen species (ROS), thereby triggering mitochondrial retrograde signaling that alters nuclear gene expression and promotes the release of deleterious signal components into the cytoplasm. These processes contribute to neuronal injury and the progression of disease pathology. Emerging evidence underlines the therapeutic potential of extracellular vesicles (EVs) derived from stem cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in reversing mitochondrial dysfunction. These nanoscale vesicles, which encapsulate transcription factors, nucleic acids, proteins, lipids, and even mitochondria, facilitate intercellular communication and influence the biological behaviour of recipient cells. Notably, stem cell-derived EVs have been shown to enhance mitochondrial function by improving the maximal oxygen consumption rate and spare respiratory capacity in injured neuronal cells. The molecular cargo within EVs, including miR-21, miR-29, and antioxidant enzymes, has been implicated in regulating mitochondrial biogenesis, reducing oxidative stress, and modulating pathways associated with apoptosis, mitophagy, and energy metabolism. Importantly, EVs can cross the blood-brain barrier (BBB), offering a minimally invasive strategy for targeted CNS delivery. In conclusion, stem cell-derived EVs represent a promising, cell-free therapeutic approach to restoring mitochondrial homeostasis and preventing neuronal disorders.
    Keywords:  Extracellular vesicles; Mitochondrial dysfunction; Neurodegeneration; Neuronal disorders; Oxidative stress; Stem cells
    DOI:  https://doi.org/10.1007/s12035-025-05623-9
  12. Stem Cells Transl Med. 2025 Nov 24. pii: szaf065. [Epub ahead of print]14(12):
    Modeling rare genetic disease with gene-edited induced pluripotent stem cells: relevance of the starting stock line.
    Ashok R Dinasarapu, Diane J Sutcliffe, Erkin Ozel, Anike Thite, Lauren Grychowski, Jasper E Visser, Ellen J Hess, Sharon M Kolk, H A Jinnah.
      Induced pluripotent stem cells (iPSCs) are commonly used to model human genetic diseases. Two main strategies are used. The first involves making iPSC lines from individual cases with a disease, and the second involves making disease-relevant gene edits in established iPSC lines. Because generating gene-edited lines is time consuming and expensive, most studies begin with one starting iPSC stock line and evaluate several gene-edited sublines. The current studies focus on gene-editing to model Lesch-Nyhan disease (LND), which is caused by mutations in the HPRT1 gene. The same pathogenic c.508C>T edit was made in four well-established stock lines, and three gene-edited lines were isolated from each. RNA sequencing (RNAseq) was, then, used to evaluate the impact of the gene edit. Gene-edited lines were compared to their corresponding stock lines, as well as to each other. An aggregate analysis of all lines combined was also conducted to determine the most robust findings across all lines. Results from gene editing were further compared with iPSC lines derived from individual cases with LND, to determine how closely findings from gene editing match results obtained with case-derived lines. There were two main findings. First, the same gene edit has a different impact on gene expression when starting with different starting stock lines. Second, the gene editing strategy does not produce the same results as the case-derived strategy. Potential explanations for these differences are addressed, along with the relevance of these two different strategies for disease modeling.
    Keywords:  HPRT1; Lesch–Nyhan disease; disease modeling; human induced pluripotent stem cell; hypoxanthine-guanine phosphoribosyltransferase
    DOI:  https://doi.org/10.1093/stcltm/szaf065
  13. Nephron. 2025 Dec 19. 1-18
    Mitochondria to the rescue: organelle trafficking in renal health and disease.
    Luca Perico, Giuseppe Remuzzi, Ariela Benigni.
       BACKGROUND: Mitochondria are central regulators of cellular metabolism, redox signaling, and apoptosis. Their dysfunction plays a pivotal role in the pathogenesis of kidney diseases, including acute kidney injury and diabetic nephropathy.
    SUMMARY: Recent advances have unveiled horizontal mitochondrial transfer as a novel intercellular communication by which renal cells exchange mitochondria to promote tissue repair through the modulation of metabolic processes, oxidative stress, apoptosis, and fibrosis.
    KEY FINDINGS: Horizontal mitochondrial transfer, mediated by tunneling nanotubes and extracellular vesicles, has emerged as a potential homotypic rescue mechanism between injured tubular and glomerular cells. In addition, heterotypic mitochondrial transfer from mesenchymal stromal cells to renal cells has been described. These findings open new perspectives for exploring therapeutic mitochondrial transplantation in both acute and chronic kidney diseases. Nonetheless, significant challenges remain, including elucidating the poorly characterized biological mechanisms underlying mitochondrial transfer, optimizing delivery strategies, and defining the long-term safety and efficacy of mitochondrial-based therapies.
    DOI:  https://doi.org/10.1159/000550092
  14. Forensic Sci Int. 2025 Dec 12. pii: S0379-0738(25)00414-1. [Epub ahead of print]379 112770
    An efficient preprocessing workflow tailored for mitochondrial genome assembly from fragmented DNA.
    Yongheng Zhou, Peng Gao, Shuhui Yang, Yanchun Xu.
      Mitochondrial DNA (mtDNA), characterised by its high copy number, structural stability, and maternal inheritance, is a critical genetic marker in forensic genetics, species identification, and conservation studies. Accurate mtDNA genome assembly is essential for these applications. However, DNA from typical wildlife and historical sources - such as museum specimens, keratinised tissues, environmental samples, and ancient remains - is often highly fragmented and damaged, limiting assembly efficiency and accuracy. Here, we developed a preprocessing workflow (MTAK) specifically designed to improve mtDNA assembly from degraded DNA. MTAK integrates two core steps: (1) extraction of homologous reads via reference-sequence alignment and (2) targeted processing of severely damaged 5' and 3' terminal bases. The workflow was evaluated on 24 degraded samples of varying quality. MTAK substantially enhanced assembly completeness and accuracy, particularly in samples with extensive DNA damage, while reducing computational time by over tenfold and minimising resource consumption. An interaction model was implemented to guide optimal sequencing depth for efficient assembly. This approach is compatible with most existing assembly tools and significantly improves mtDNA recovery from challenging historical and wildlife samples.
    Keywords:  DNA damage; Fragmented DNA; Mitochondrial assembly; Pre-processing workflow
    DOI:  https://doi.org/10.1016/j.forsciint.2025.112770
  15. Pediatr Neurol. 2025 Nov 27. pii: S0887-8994(25)00370-4. [Epub ahead of print]175 223-228
    Counseling and Prognostic Challenges in Survivorship and Mortality in Primary Mitochondrial Disease: Reshaping a Once Bleak Landscape.
    Ibrahim Elsharkawi, Amy Goldstein, Rebecca D Ganetzky, Eva Morava.
      Primary mitochondrial diseases comprise a clinically, genetically, and biochemically heterogenous group of disorders associated with multisystemic involvement and significant morbidity and mortality of various etiologies. To date, no disease modifying therapies have been FDA approved, and treatment is largely symptomatic and supportive. Because of the rarity of mitochondrial specialists, most patients with mitochondrial diseases are cared for by clinicians without mitochondrial-specific expertise. Therefore, these clinicians by necessity rely on existing literature or older prognostic approaches which may be discordant with modern clinical practice and evolving therapeutic strategies and outcomes. Furthermore, existing literature may be skewed to the more severe end of the spectrum as publications may disproportionately focus on the most severe or unusual cases. Prognostic, therapeutic, and palliative discussions should ideally take place in a multidisciplinary setting where shared decision making can take place between the patient, family, and clinician team. Prognosis is increasingly shaped by the unprecedented development of various therapeutic modalities and personalized medicine. We aim to highlight the multipronged challenges and considerations faced in counseling patients and caregivers and draw from our own patient cohorts and observations in contemporary mitochondrial medicine to offer additional insights and future considerations for approaching patient counseling and prognostication.
    Keywords:  Leigh syndrome; MELAS; Mitochondrial disease prognosis; Mitochondrial dysfunction; Primary mitochondrial disease; Survivorship
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2025.11.019
  16. BMJ Open Respir Res. 2025 Dec 14. pii: e003364. [Epub ahead of print]12(1):
    Patients' research priorities and participation in primary ciliary dyskinesia research.
    Yin Ting Lam, Laura Behan, Katie Dexter, Lucy Dixon, Claudia E Kuehni, Leonie Daria Schreck, Jane S Lucas, Myrofora Goutaki.
       INTRODUCTION: People living with chronic diseases can provide a unique perspective for research that often differs from that of healthcare professionals. This is particularly important in rare diseases like primary ciliary dyskinesia (PCD), with many knowledge gaps and limited research resources. We aimed to assess participation of patients and caregivers in PCD research and identify their research priorities in a mixed-method study.
    METHODS: We conducted in-depth, semistructured interviews with adults and adolescents with PCD, and caregivers of children with PCD. After verbatim transcription and thematic analysis, we developed an anonymous online survey, translated it into eight languages and circulated it widely in collaboration with PCD support groups worldwide and the European Lung Foundation.
    RESULTS: The findings from the interviews identified key areas to be explored further through the survey including: developing treatments for PCD and increasing knowledge about different topics such as mental health, fertility, upper airway problems, treatment burden and impact of environment and lifestyle. 399 participants completed the online survey from 29 countries with median age 41 (IQR 33-49), 74% were female. 180 participants (45%) had participated in research before. For the remaining, the main reason for no participation was not being informed about studies (65%). 172 (43%) preferred regular research updates during a study. The top three ranked research priorities were (1) finding a cure to restore ciliary function; (2) developing treatments to improve lung function and reduce infections and mucus production; (3) finding the best way to manage the disease using existing medication. Other priorities were: involving more doctors and people with PCD in research, raising awareness of the condition and increasing knowledge about mental health and fertility.
    CONCLUSION: We found that people with PCD are motivated to participate in research when they are informed appropriately and invited. Their main research priorities relate to developing new treatments or improving the evidence base for existing treatments. Our findings will help the PCD research community to improve patient engagement in research and to draw common priorities together with the people who live with PCD and their families.
    Keywords:  Patient Outcome Assessment; Rare lung diseases; Surveys and Questionnaires; Systemic disease and lungs
    DOI:  https://doi.org/10.1136/bmjresp-2025-003364
  17. Cell Death Dis. 2025 Dec 19. 16(1): 893
    Stochasticity contributes to explaining minority and majority MOMP during apoptosis.
    Jenny Geiger, Fabian Klötzer, Nadine Pollak, Gavin Fullstone, Markus Rehm.
      Apoptosis dysfunction is linked to diseases like cancer and neurodegenerative disorders. A key event during apoptosis is mitochondrial outer membrane permeabilization (MOMP), which typically proceeds in a rapid all-or-none fashion. If MOMP occurs only in a subset of mitochondria (minority MOMP), it can be sublethal and contribute to tumorigenesis and cancer progression. Similarly, individual mitochondria escaping widespread MOMP (majority MOMP) can allow cancer cells to recover if apoptosis execution fails. How such heterogeneities in mitochondrial MOMP responsiveness arise within cells is incompletely understood. In particular, whether stochasticity in subcellular protein distributions and interactions across cytosol and mitochondria can realistically contribute to mitochondrial MOMP heterogeneity has not yet been studied. To assess this, we sequentially built and experimentally parameterized a particle-based, cell-sized model including cytosolic and mitochondrial compartments, and that featured a reduced interactome of MCL-1, BAK and tBID. High-performance computing enabled cell-scale simulations of protein distributions and interactions to understand how and under which conditions stochasticity could contribute to heterogeneity in MOMP susceptibility. Our results show that stochastic effects strongly predispose sub-pools of fragmented mitochondria to MOMP under low apoptotic stress. At higher apoptotic stress, fractions of small mitochondria were more likely to escape MOMP than large mitochondria. Retrospective quantification of mitochondrial sizes in experimental scenarios of minority and majority MOMP confirmed these findings. We therefore conclude that stochasticity substantially contributes to enabling small or fragmented mitochondria to undergo MOMP in minority MOMP scenarios and to escape MOMP in majority MOMP scenarios.
    DOI:  https://doi.org/10.1038/s41419-025-08258-9
  18. Genet Med. 2025 Dec 17. pii: S1098-3600(25)00314-4. [Epub ahead of print] 101667
    Equity-focused implementation to enhance access to rare disease genomic research and understand diverse perspectives.
    Eva Martinez, Jillian Serrano, Siwaar Abouhala, Ashana Neale, Grace VanNoy, Heidi L Rehm, Melanie O'Leary, Anne O'Donnell-Luria, Monica H Wojcik.
       PURPOSE: Rare disease genomic research suffers from a lack of diverse participation. We therefore implemented and evaluated a multi-faceted intervention to support recruitment of populations previously-underrepresented by race, ethnicity, primary language, household income, education level, or rural residence to the Rare Genomes Project (RGP).
    METHODS: For a prospective cohort, we tracked completion of our enrollment processes supported by interventions including clinician engagement, language support, proactive and flexible participant contact, and use of mobile phlebotomy. Participants were offered a survey upon enrollment to assess values and priorities.
    RESULTS: 161/195 (83%) participants completed enrollment. High-yield interventions included clinician referral forms and increased staff assistance. Genome sequencing data has been generated for 133 participants, with a diagnosis found for 17 (13%) and candidate for 23 (17%) thus far. Most diagnosed participants (13/17, 76%) benefited from clinician rather than self-referral. Perceived importance of a genetic diagnosis was ranked very/extremely high for 81/96 (84%) of participants. Spanish primary language was associated with higher perceived importance and high income with lower perceived importance, although only income remained significant in a multivariable model.
    CONCLUSION: Overall, our equity-focused initiative enabled enrollment of participants from populations previously underrepresented in rare disease genomic research and offers insight into potential motivators.
    Keywords:  equity; genetics; genomics; rare disease; research
    DOI:  https://doi.org/10.1016/j.gim.2025.101667
  19. Cold Spring Harb Perspect Biol. 2025 Dec 19. pii: a041773. [Epub ahead of print]
    Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.
    David R Eberhardt, Dipayan Chaudhuri.
      Calcium (Ca2+) is vital in hepatocyte metabolism and plays a dual role in liver mitochondrial function: Physiological Ca2+ stimulates respiration and mitochondrial dynamics-processes crucial for proper metabolic functioning. However, Ca2+ overload can be catastrophic, leading to mitochondrial dysfunction and the halt of metabolic processes. This dichotomy plays out in liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic liver disease (ALD), where excess lipid and alcohol, respectively, result in pathological changes in this precarious Ca2+ balance, impairing liver function and contributing to liver failure. In this review, we discuss the complex processes of Ca2+ signaling in hepatic mitochondria and how these processes are altered or fail in liver disease states.
    DOI:  https://doi.org/10.1101/cshperspect.a041773
  20. Nat Commun. 2025 Dec 15. 16(1): 10992
    Mitochondrial RNA cytosolic leakage drives the SASP.
    Stella Victorelli, Madeline Eppard, Hélène Martini, Seung-Hwa Woo, Stacia P A Everts, Gung Lee, Nicholas Pirius, Nuan Han, Eugene Y Liang, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Eva Nóvoa, Rubén Nogueiras, Patrick L Splinter, Steven P O'Hara, Olivia Morgenthaler, Lucía Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas F LaRusso, Petra Hirsova, João F Passos.
      Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK play a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction-Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-66159-z
  21. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  22. Cell Biochem Funct. 2025 Dec;43(12): e70151
    Mitochondrial Dysfunction Drives Oxidative Stress and Energy Imbalance in a Murine Model of Spondyloarthritis.
    Rodrigo Prieto-Carrasco, Susana Aideé González-Chávez, Eduardo Chaparro-Barrera, Mario Loya-Rivera, Belén Cuevas-López, Fernando E García-Arroyo, Omar Emiliano Aparicio-Trejo, César Pacheco-Tena.
      Joint inflammation and structural damage in spondyloarthritis (SpA) are not fully explained by known immune mechanisms. While mitochondrial dysfunction has been implicated in other rheumatic diseases, such as rheumatoid arthritis and lupus, its role in SpA remains poorly understood. Male DBA/1 mice with spontaneous arthritis (SpAD) and healthy BALB/c mice were compared to assess mitochondrial alterations in joint tissues, isolated mitochondria and cultured fibroblast-like synoviocytes (FLS). Analyses focused on mitochondrial dynamics (fission and fusion) and turnover (biogenesis and mitophagy), bioenergetic function, oxidative stress, and transcriptomic changes associated with mitochondrial function. SpAD induced a coordinated mitochondrial dysfunction in joint tissues characterized by increased fission (Drp1), reduced fusion (Mfn2), and dysregulated turnover processes with elevated mitophagy (PINK1) and biogenesis (PGC-1α). This imbalance led to dysregulation mitochondrial complexes activity, reduced ATP production, and a pronounced increase in oxidative stress. The latter was evidenced by decreased catalase and glutathione peroxidase (Gpx) activity, elevated superoxide dismutase (SOD) activity, and accumulation of 4 hydroxynonenal (4-HNE), highlighting a shift toward a chronic pro-oxidative environment. Similar gene expression changes were observed in cultured FLS. Transcriptomic analysis identified 6,673 differentially expressed genes, including 139 related to mitochondrial function, which reinforces the central role of mitochondrial dysregulation in SpAD pathophysiology. This study is the first to comprehensively characterize mitochondrial dysfunction in a murine model of SpA, identifying it as a potential driver of joint damage. Targeting mitochondrial pathways may offer novel strategies for disease modification in spondyloarthritis.
    Keywords:  DBA/1 mice; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial turnover; oxidative stress; spondyloarthritis
    DOI:  https://doi.org/10.1002/cbf.70151
  23. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00943-8. [Epub ahead of print]85(24): 4483-4484
    Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
    Erdem M Terzi, Richard Possemato.
      Iron is a critical nutrient, especially to power mitochondrial iron-sulfur cofactor synthesis. In this issue of Molecular Cell, Liu et al.1 engineer a fluorescent iron sensor, enabling them to define a critical function of the mitochondrial translocase, TIM22, in powering mitochondrial iron use by proper targeting of the mitochondrial iron importers, the mitoferrins.
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.026
  24. Front Med (Lausanne). 2025 ;12 1716485
    Multidimensional study on mitochondrial dysfunction in pulmonary hypertension.
    Xuntao Yuan, Yutao Zhang, Yuyan Liu, Xiao Guo, Shuying Jia, Xingquan Xiong, Xiuying Sun, Zian Jin.
      Pulmonary hypertension (PH), as a complex clinical syndrome, can be caused by multiple pathophysiological factors. Its characteristics are similar to hemodynamic abnormalities, significant increase of pulmonary artery pressure, contraction and remodeling of blood vessels, which eventually lead to serious complications such as increased pulmonary vascular resistance, hypertrophy of the right ventricle, and heart failure. The etiology of PH is multifaceted and highly variable, with a common pathological basis primarily characterized by mitochondrial dysfunction. Endothelial cell dysfunction, which directly impacts metabolism and function, is closely associated with PH and other lung diseases, making mitochondrial dysfunction the cornerstone of this condition. The therapy for PH primarily focuses on relaxing pulmonary blood vessels. However, existing vasodilation approaches struggle to effectively reverse the observed vascular remodeling process, which limits further therapeutic enhancement. Moreover, mitochondrial dysfunction represents a promising new direction of significant research in the treatment of PH. This review systematically combs the key molecular mechanisms of mitochondrial dysfunction in the pathological process of PH. The study focuses on multi-channel pathogenic mechanisms, including mitochondrial DNA (mtDNA) damage, electron transfer chain (ETC) dysfunction, protein homeostasis imbalance, defects in mitochondrial biogenesis, dynamic abnormality, and autophagy defect. Furthermore, this review summarizes recent research advancements targeting mitochondrial dysfunction as a potential intervention strategy for clinical treatment of PH. By integrating updated findings on molecular mechanisms with insights from existing literature, the study provides a comprehensive understanding of mitochondrial dysfunction's role in PH pathogenesis and offers actionable evidence for developing novel therapeutic approaches.
    Keywords:  mitochondrial dysfunction; oxidative stress; pulmonary hypertension; pulmonaryvascular remodeling; research progress
    DOI:  https://doi.org/10.3389/fmed.2025.1716485
  25. Neurol Genet. 2026 Feb;12(1): e200330
    Identification of Intronic Variants in NDUFA3 as a Cause of Leigh Syndrome by Whole Genome Sequencing and RNA Sequencing.
    Kohta Nakamura, Yoshihito Kishita, Ayumu Sugiura, Kokoro Ozaki, Yukiko Yatsuka, Naoyuki Matsumoto, Atsuko Okazaki, Holger Prokisch, Koichi Maruyama, Hiroyasu Iwasa, Kei Murayama, Hiroshi Matsumoto, Akira Ohtake, Yuichi Shiraishi, Yasushi Okazaki.
       Background and Objectives: Leigh syndrome is an important manifestation of childhood-onset primary mitochondrial disease. Panel sequencing and whole exome sequencing are cost-effective for diagnosing mitochondrial diseases; however, more than half of mitochondrial disease cases remain genetically undiagnosed. This study aimed to demonstrate that combining whole genome sequencing (WGS) and RNA sequencing (RNA-seq) analyses can identify disease-causing variants that would otherwise be missed.
    Methods: We performed WGS and RNA-seq on a patient with Leigh syndrome. Chromosomal phasing using Sanger sequencing of parental and patient blood samples was conducted to confirm compound heterozygous variants. RNA-seq data were analyzed for splicing abnormalities. Overexpression studies of wild-type NDUFA3 in patient-derived fibroblasts were performed to assess restoration of mitochondrial function.
    Results: We discovered compound heterozygous intronic variants (c.86-16_86-15del in intron2 and c.164-362G>A in intron3) of the NDUFA3 gene. RNA-seq data analysis revealed intron retention and exonization in NDUFA3. Exonization was related to a variant involving the mobile element Alu that resulted in complex abnormal splicing events. Overexpression of wild-type NDUFA3 restored mitochondrial dysfunction in patient-derived fibroblasts, confirming NDUFA3 as a Leigh syndrome causative gene.
    Discussion: This study highlights the importance of combining WGS and RNA-seq and provides new insights into detecting abnormalities in deep intronic regions, particularly those involving mobile elements, such as Alu. This approach can play a crucial role in identifying genetic variations and elucidating transcriptional control mechanisms that are not readily achieved by conventional methods, especially in the context of mobile element-induced complexities.
    DOI:  https://doi.org/10.1212/NXG.0000000000200330
  26. Nat Commun. 2025 Dec 16.
    VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
    Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.
      Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.
    DOI:  https://doi.org/10.1038/s41467-025-67445-6
  27. J Clin Lab Anal. 2025 Dec 15. e70147
    Functional Screening of NDUFAF6 Variants in Knockout Cells and Complementary Computational Analysis.
    Feng Jiang, Ayumu Sugiura, Yoshihito Kishita, Kohta Nakamura, Xinju Qi, Yuxin Liu, Kei Murayama, Yasushi Okazaki.
       BACKGROUND: NDUFAF6 (NADH:ubiquinone oxidoreductase complex assembly factor 6) is a nuclear-encoded gene essential for the assembly of mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase), the largest and most intricate component of the oxidative phosphorylation system, and its mutations are associated with mitochondrial diseases. However, the functional consequences of many NDUFAF6 variants remain unclear.
    METHODS: We selected 24 NDUFAF6 variants from published studies and our internal sequencing database. Using CRISPR-Cas9, we generated NDUFAF6 knockout HEK293FT cells and transfected them with wild-type or mutant expression vectors. Functional validation was performed using a luminescence-based ATP assay under mitochondrial stress. In silico predictions were conducted using multiple tools, and ColabFold, MitoFates, and ProtScale were used for structural modeling, mitochondrial targeting analysis, and hydrophobicity profiling.
    RESULTS: Six variants (p.Pro26fs, p.Asp69Val, p.Arg113Ter, p.Leu193Ter, p.Arg303Ter, and p.Lys331Arg) failed to restore ATP levels in knockout cells, indicating a significant loss of function. Among these, p.Asp69Val and p.Arg113Ter were consistent with ClinVar classifications. However, other variants such as p.Arg303Ter and p.Lys331Arg also showed functional impairment, highlighting discrepancies between database annotations and experimental results. Most variants retained mitochondrial targeting features, though p.Pro26fs exhibited a shifted MPP cleavage site. Hydrophobicity analysis indicated structural instability in several variants.
    CONCLUSIONS: Our study highlights the importance of experimental validation in improving the classification of NDUFAF6 variants. The ATP-based functional assay provides a useful and quantitative approach for assessing mitochondrial variant effects, which may complement in silico predictions and contribute to future efforts in mitochondrial disease diagnostics.
    Keywords:   NDUFAF6 ; ATP assay; mitochondrial diseases; mitochondrial dysfunction; variants of uncertain significance
    DOI:  https://doi.org/10.1002/jcla.70147
  28. Biol Chem. 2025 Dec 18.
    There and back again: a cell biologist's journey from organelles to molecules.
    Emma J Fenech, Yury S Bykov.
      Eukaryotic life is defined by the presence of organelles. Organelles, in turn, were classically defined as specialized membrane-bound compartments composed of a unique set of macromolecules which support specific functions. Over the last few decades, a concerted effort into uncovering which components are present in each organelle has shaped our view of cell biology. However, despite some organelles already being visualized over 100 years ago, we are still discovering new organelle residents. Furthermore, our concept of both 'organelles' and 'compartmentalization' has evolved together with our deepening understanding in a number of fields. These include: organelle substructure and organization; the network of contact sites which interconnects all organelles; and membraneless organelles and phase-separated condensates. This review explores how image- and mass spectrometry-based methods can be used to understand the spectrum of where components are localized: from complexes, to subdomains, and whole organelles. The components we mainly focus on are proteins of the mitochondria and secretory pathway organelles.
    Keywords:  contact sites; mass spectrometry; microscopy; organelle subdomains; organelles; protein complexes
    DOI:  https://doi.org/10.1515/hsz-2025-0185
  29. CNS Neurosci Ther. 2025 Dec;31(12): e70703
    The Blood-Brain Barrier as an Integration Hub in Alzheimer's Disease: How Microbiota Metabolites Modulate Central Signal Processing.
    O Giangiulio, R Maccarone.
       BACKGROUND: While both gut-brain axis dysfunction and blood-brain barrier (BBB) breakdown are documented in Alzheimer's disease (AD), current research treats these as separate phenomena. However, emerging evidence suggests that the BBB may function as an active integration interface that processes microbiota-derived metabolites and thereby potentially modulates how peripheral signals influence cognitive health.
    OBJECTIVE: This review synthesizes current evidence on microbiota metabolites as modulators of BBB integration capacity, discussing how such mechanisms may contribute to variability in cognitive outcomes despite similar gut microbiome profiles by demonstrating how BBB signal-integration mechanisms determine gut-brain communication effectiveness in AD.
    METHODS: We analyzed peer-reviewed literature from 2010 to 2025, focusing on BBB dynamic properties, microbiota metabolite effects on BBB function, and their integration patterns, emphasizing functional evidence supporting the BBB's active signal processing capabilities.
    RESULTS: Current evidence suggests that the BBB exhibits integration properties, including dynamic permeability regulation, context-dependent metabolite processing, and coordinated responses to complex signal streams. Short-chain fatty acids enhance integration capacity through HDAC inhibition and coordinated receptor activation, while lipopolysaccharides and trimethylamine N-oxide may overwhelm integration processes through TLR4-mediated disruption. BBB dysfunction precedes classical AD pathology and correlates with altered metabolite processing capacity. Individual variations in BBB integration capacity may help account for why individuals with similar gut microbiome profiles show different cognitive outcomes.
    CONCLUSION: Viewing the BBB as an active integration interface offers a useful perspective for organizing current evidence on gut-brain interactions in AD. This conceptual perspective suggests that therapeutic strategies might benefit from supporting BBB integration capacity and optimizing metabolite-processing mechanisms alongside improving gut health.
    Keywords:  Alzheimer's disease; blood–brain barrier; gut–brain axis; integration hub; lipopolysaccharide; microbiota metabolites; short‐chain fatty acids; signal processing; trimethylamine N‐oxide
    DOI:  https://doi.org/10.1002/cns.70703
  30. Nat Commun. 2025 Dec 15. 16(1): 11049
    Unequal mitochondrial segregation promotes asymmetric fates during neurogenesis.
    Benjamin Bunel, Rémi Leclercq, Rosette Goïame, Arnaud Gautier, Xavier Morin, Evelyne Fischer.
      Asymmetric cell division plays a critical role during vertebrate neurogenesis by generating neuronal cells while maintaining a pool of progenitors. It relies on unequal distribution of cell fate determinants during progenitor division. Here, we use live imaging in the chick embryonic neuroepithelium to demonstrate that mitochondria behave as asymmetric fate determinants during mitosis. We show that the frequency of unequal distribution of mitochondria increases in parallel with the rate of asymmetric divisions during development. Furthermore, fate tracking experiments reveals that following progenitor division, a cell inheriting fewer mitochondria than its sister consistently differentiates into a neuron. We set up a chemogenetic approach to experimentally displace mitochondria specifically during mitosis to force their unequal inheritance and find that this drives premature neuronal differentiation. In this work, we establish a direct causal relationship between unequal mitochondrial inheritance and the asymmetric fate of sister cells in vivo, revealing a pivotal mechanism for neurogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-66932-0
  31. Seizure. 2025 Dec 11. pii: S1059-1311(25)00337-1. [Epub ahead of print]134 173-179
    The phenotype and genotype of KCNMA1 - related disorders in China.
    Qiuhong Wang, Xiaojuan Tian, Jie Deng, Xiaohui Wang, Lifang Dai, Changhong Ding.
       OBJECTIVE: The KCNMA1 gene encodes the BK K⁺ channel, which modulates neuronal and muscular excitability. Variants in this gene are associated with heterogeneous or overlapping clinical features, including movement disorders, epilepsy, and developmental delays. This study aimed to analyze the genotype-phenotype correlations of KCNMA1-related disorders in China.
    METHODS: Clinical and genetic datas were collected from patients diagnosed with KCNMA1-related disoreders at Beijing Children's Hospital between January 2017 and December 2024. Literature reviews were conducted using the China National Knowledge Infrastructure (CNKI) and Wanfang databases with "KCNMA1″ as the keyword (from database establishment to December 2024) to summarize reported Chinese cases. Data on clinical phenotypes, genetic variant types, imaging findings, and prognosis were analyzed.
    RESULTS: Twenty-seven patients (20 males, 7 females) with KCNMA1 variants were included. Six presented with epilepsy and paroxysmal movement disorders, 6 with movement disorders alone, and 12 with epilepsy alone. Movement disorder types included paroxysmal nonkinesigenic dyskinesia (PNKD), ataxia, and episodic limb weakness. Seizure types encompassed generalized tonic-clonic, tonic, epileptic spasms, absence, focal, myoclonic, and atonic seizures. Twenty-six patients exhibited developmental delays, including 3 with delays alone (no seizures or movement disorders). A total of 25 distinct variants were identified, including 19 missense, 2 frameshift, 2 splice-site, 1 nonsense, and 1 deletion variant, of which 16 were novel. About genotype-phenotype correlations, among the 12 epilepsy-only cases, 8 (66.7%, 8/12) had variants located in transmembrane domains (S0-S6). Of the 12 cases with movement disorders (with or without epilepsy; 10 variants), 8 (80%, 8/10) had variants in intracellular domains, predominantly the RCK-2 region.
    CONCLUSIONS: This study summarized the primary clinical features of KCNMA1 variants, including movement disorders, epilepsy, and developmental delays. Additionally, 16 novel variants were reported. Genotype-phenotype correlations analysis suggested that variants in transmembrane domains are more likely to cause epilepsy, while those in intracellular domains, especially RCK-2, are primarily associated with movement disorders, with or without epilepsy. However, further studies with larger sample sizes are needed for validation.
    Keywords:  Epilepsy; Genotype; KCNMA1; Movement disorders; Phenotype
    DOI:  https://doi.org/10.1016/j.seizure.2025.12.006
  32. Mol Neurobiol. 2025 Dec 16. 63(1): 303
    ZLN005 Alleviates the Dopaminergic Degeneration via PGC-1α-Mediated Mitochondrial Homeostasis in Parkinson's Disease.
    Jasleen Kaur, Saba Naqvi.
      Parkinson's disease (PD) is a neurodegenerative condition marked by significant motor impairments, resulting from extensive loss of dopaminergic neurons and abnormal protein aggregation. One of the early features of PD is disrupted mitochondrial dynamics, which arises from imbalances in cellular energy regulation. Therapeutic strategies that mitigate the mitochondrial dysfunction and enhance mitochondrial performance offer neuroprotection in PD. To delve into the role of mitochondrial function, we employed the synthetic PGC-1α activator ZLN005 to improve PD outcomes. In cellular PD model, we performed western blotting and immunofluorescence assays to assess disease-specific markers, including tyrosine hydroxylase and proteins related to mitochondrial biogenesis and regulation. Mitochondrial function was further evaluated using MitoTracker and ROS detection. We further investigated ZLN005 in a sub-acute MPTP mouse model. Motor performance was assessed, and subsequently, molecular analyses were conducted. Our findings revealed that ZLN005 significantly reduced MPP+/MPTP-induced neurotoxicity, improved motor deficits, and maintained the expression of PGC-1α, tyrosine hydroxylase, and other key mitochondrial markers involved in DNA replication and mitophagy. Notably, proteins that enhance PGC-1α transcription, including SIRT1, were also upregulated. In addition, the expression of mitochondrial fusion proteins increased, a pattern supported by elevated levels of other transcriptional regulators. Imaging and flow cytometry further confirmed that PGC-1α activation improved mitochondrial integrity and reduced oxidative stress. These results provide preliminary insights into the potential therapeutic role of PGC-1α activator in PD. ZLN005 has a neuroprotective effect in PD, which is elaborated by PGC-1α activator regulating the mitochondrial quality control system.
    Keywords:  Mitochondrial biogenesis; Mitophagy; PGC-1α activator; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-025-05612-y
  33. J Extracell Vesicles. 2025 Dec;14(12): e70201
    Hybrid Extracellular Vesicles for Efficient Loading and Functional Delivery of mRNA.
    Xiaoqin Wang, Michael J Munson, Kristina Friis, Anna Marzeda, Andreia M Silva, Franziska Kohl, Leif Hultin, Raymond M Schiffelers, Niek Dekker.
      Extracellular vesicles (EVs) are an attractive delivery vehicle with biological activity, intrinsic homing, low immunogenicity, and engineerability; however, challenges remain regarding loading and functional delivery of mRNA. Here, we developed a novel approach to load mRNA through low pH-induced fusion of EVs with lipid nanoparticles (LNPs) to generate hybrid EVs (HEVs). Conventional characterization showed that HEVs preserved classical features of EVs. Single particle analysis revealed successful loading of mRNA and incorporation of LNP components into HEVs. The combined properties from EV and LNP contributed to the excellent cell tolerability of HEV, overcoming dose-limit toxicity, and functional delivery of mRNA by HEV. We further elucidated the mechanism of HEV-mediated intracellular delivery of mRNA. Our results showed that in contrast to source EVs, HEVs were capable of inducing endosomal escape, facilitating intracellular delivery of mRNA. Furthermore, HEVs functionally delivered mRNA in vivo and displayed extrahepatic delivery capacity with predominant functional distribution in spleen. Our results suggest HEVs as a promising EV-based delivery platform for mRNA delivery.
    Keywords:  cell tolerability; endosomal escape; functional biodistribution; functional delivery; hybrid extracellular vesicle; mRNA loading
    DOI:  https://doi.org/10.1002/jev2.70201
  34. Expert Rev Pharmacoecon Outcomes Res. 2025 Dec 16.
    The value of functional genomics: a contingent valuation.
    Francisco Santos-Gonzalez, Ellenore Martin, Madeleine Harris, Sarah Casauria, The Australian Undiagnosed Diseases Network Udn-Aus, John Christodoulou, Ilias Goranitis.
       BACKGROUND: Functional genomics approaches, such as transcriptomics and proteomics, can provide valuable insights into rare diseases when genomic sequencing fails to yield informative findings. This study estimated the monetary value that parents, carers and individuals with undiagnosed rare diseases place on functional genomics testing.
    RESEARCH DESIGN AND METHODS: A triple-bounded dichotomous choice contingent valuation survey was completed by carers and individuals with suspected rare monogenic disorders recruited as part of the Australian Undiagnosed Disease Network. A multilevel interval regression model was used to analyze response data and estimate the monetary value of functional genomics, in terms of willingness to pay (WTP).
    RESULTS: There was a total of 57 respondents (48%), primarily carers (95%). The mean WTP for functional genomics testing was estimated to be $2,522 (95% CI: $817-$4,228) [US $1,568 (95% CI: $508-$2,629)].
    CONCLUSIONS: Our findings indicate that individuals with undiagnosed rare diseases and their parents or caregivers place high value on functional genomics testing. The estimated WTP is comparable to findings from contingent valuation studies of other genomic interventions and exceeds the expected economic cost of proteomics testing. These insights can inform a preference-based evaluation of the diagnostic outcomes and net benefits achieved through functional genomics, thereby guiding decision-making and clinical implementation.
    Keywords:  Functional genomics; contingent valuation; rare diseases; stated preferences; willingness to pay
    DOI:  https://doi.org/10.1080/14737167.2025.2605152
  35. J Mol Med (Berl). 2025 Dec 13. 104(1): 2
    Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.
    Jasmina Isaković, Anna Athanassiadis, Marian Khubeis.
      This review critically evaluates the current state of stem cell therapy (SCT) for treating and modeling of Alzheimer's (AD) and Parkinson's disease (PD). It includes an in-depth analysis of both preclinical and clinical studies, with a particular focus on clinical trials conducted between 2019 and 2024, reflecting recent advancements in the field. Preclinical studies were examined to elucidate the molecular mechanisms underlying SCT and identify developments that could be translated into clinical practice. Within these studies, stem cells, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), have shown high differentiation and proliferation abilities. These properties, along with their capacity to inhibit inflammation, prevent apoptosis, and stimulate angiogenesis, make them promising candidates for treating AD and PD. Over the past 15 years, 76 SCT-based trials have been conducted-27 for AD and 48 for PD-with more than half occurring in the past 5 years. Despite the promise of SCT, the field faces challenges such as ethical concerns regarding the use of ESCs, heterogeneity of isolated cultures, and inconsistent results across preclinical trials. Novel materials and electromagnetic fields (EMFs) offer potential solutions to these issues. While bioengineering approaches can enhance the successful engraftment of transplanted stem cells, EMFs can direct the cells' migration and differentiation. In conclusion, although significant progress has been made in SCT, ongoing efforts are needed to address existing challenges. Nevertheless, SCT holds considerable promise for the future, offering potential breakthroughs in the treatment of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Clinical trials; Neurodegeneration; Parkinson’s disease; Stem cell therapy; Stem cells
    DOI:  https://doi.org/10.1007/s00109-025-02613-1
  36. J Stroke Cerebrovasc Dis. 2025 Dec 17. pii: S1052-3057(25)00305-2. [Epub ahead of print] 108529
    Dl-3-n-butylphthalide Protects against Ischemic Stroke by Enhancing Mitochondrial Function via MT-CO1 Upregulation.
    Yangfang An, Biao Wang, Jiali Zhao, Hui Zhou, Qiong Zhou.
       OBJECTIVE: Mitochondrial dysfunction is a key determinant of neuronal death and a promising therapeutic target in ischemic stroke. Dl-3-n-butylphthalide (NBP), an approved neuroprotective agent in China, has been shown to improve mitochondrial integrity, yet its precise molecular mechanisms remain unclear. This study aimed to determine whether NBP exerts neuroprotection by upregulating mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) and to clarify the contribution of MT-CO1 to mitochondrial function recovery.
    METHODS: MT-CO1 expression was measured in the circulation from acute ischemic stroke participants before and following NBP therapy. In SH-SY5Y cells under OGD/R treatment, the action of NBP on mitochondrial bioenergetics, oxidative stress, and apoptosis were assessed. MT-CO1 knockdown was used to determine mechanistic involvement.
    RESULTS: NBP significantly increased MT-CO1 expression both in vivo and in vitro, improved mitochondrial membrane voltage and ATP production, reduced ROS generation, and decreased apoptosis. MT-CO1 silencing markedly attenuated these protective effects.
    CONCLUSION: NBP protects against ischemia-induced mitochondrial dysfunction partly through MT-CO1 upregulation, supporting MT-CO1 as a potential therapeutic target for mitochondrial function protection in ischemic stroke.
    Keywords:  3P medicine; MT-CO1; NBP; ischemic stroke; mitochondrial function; mitochondrial medicine; oxidative stress
    DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108529
  37. Aging Dis. 2025 Dec 14.
    Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
    Sen Huang, Ang Li, Yixia Ling, Xinyu Yang, Jiayu Wang, Jing Yuan, Dajiang Qin, Xiaoli Yao.
      Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1G93A, TDP43A315T, and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1G93A transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1G93A transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.
    DOI:  https://doi.org/10.14336/AD.2025.1224
  38. Front Pediatr. 2025 ;13 1686738
    Rapid whole genome sequencing in newborn screening for metabolic diseases.
    Jun Zheng, Xin Yang.
       Background and purpose: Metabolic disorders, which are estimated to include approximately 1,500 distinct conditions such as urea cycle disorders, lysosomal storage diseases, and mitochondrial dysfunctions, pose a significant clinical challenge due to their genetic heterogeneity and rapid onset of symptoms in newborns. Delays in diagnosis often lead to irreversible damage or mortality. Rapid whole genome sequencing (rWGS) has emerged as a transformative diagnostic tool, offering comprehensive genetic insights within 24-72 h.
    Materials and methods: This study reviews the application of rWGS in the early detection and management of metabolic diseases, emphasizing its role in overcoming limitations of traditional diagnostic methods.
    Results: The integration of rWGS into clinical workflows offers a high diagnostic yield, exceeding 50% in neonatal intensive care units (NICUs), where timely interventions are critical. Utilizing advanced sequencing platforms, such as Illumina NovaSeq and Oxford Nanopore, coupled with optimized bioinformatics pipelines, rWGS enables precise variant identification and prioritization. Key findings highlight its capacity to accelerate diagnosis, inform therapeutic decisions, and reduce diagnostic odysseys. For instance, identifying pathogenic variants in genes allows early initiation of targeted therapies, significantly improving outcomes.
    Conclusions: Despite its transformative potential, challenges remain, including cost, data interpretation, and equitable access. Addressing these barriers through investments in infrastructure, training, and policy frameworks will be crucial for broader implementation. This review underscores the critical role of rWGS in neonatal care and highlights its promise as a cornerstone of precision medicine, paving the way for improved diagnostic accuracy and patient outcomes in metabolic diseases.
    Keywords:  NICU diagnostics; metabolic diseases; newborn screening; precisionmedicine; rapid whole genome sequencing
    DOI:  https://doi.org/10.3389/fped.2025.1686738
  39. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00939-6. [Epub ahead of print]85(24): 4587-4601.e7
    The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
    Shuai Liu, Qingyu Li, Mengye Cao, Zefang Bimo Zhao, Cong Liu, Zhuoran Zhen, Jiankun Ren, Chengyang Liu, Danyang Ruan, Luna Zhang, Wenjuan Zhang, Hao Gong, Xiaolong Liu, Xuejie Zhang, Deng Pan, Weijun Pan, Jiajun Zhu.
      Mitochondria host a number of reductive biosynthetic pathways and rely on extensive metabolite exchanges with the cytosol to support cellular anabolic metabolism. Mitochondrial iron-sulfur cluster (Fe-S) biogenesis is essential for multiple cellular functions, and its disruption causes various inborn genetic diseases. How mammalian cells regulate Fe-S biogenesis remains incompletely understood. Here, mitochondria-focused CRISPR screening and DepMap-based gene co-essentiality analysis consistently reveal that components of the carrier translocase of the inner mitochondrial membrane (TIM22) complex, including TIMM29, are selectively required for Fe-S biogenesis. Mechanistically, loss of TIM22 complex function reduced iron transporter presence on mitochondria, thereby impairing iron uptake from the cytosol. Reconstituting mitochondrial iron level was sufficient to restore Fe-S biogenesis and proliferation of TIMM29-deficient cells or rescue the embryonic development of timm29-deficient zebrafish. Thus, a primary function of the TIM22 carrier translocase is to facilitate transporter-mediated iron uptake required for Fe-S biogenesis, underscoring a biosynthetic role of mitochondria in cellular anabolism.
    Keywords:  TIM22 carrier translocase; cellular metabolism; iron-sulfur cluster; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.022
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