bims-polgdi Biomed News
on POLG disease
Issue of 2025–09–14
fifty-five papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial Transplantation Therapy: A Novel Approach in the Era of Organelle-Centered Regenerative Medicine.
  2. Mending a mother's mitochondrial DNA.
  3. Mitochondria-Associated Pathways in Cancer and Precancerous Conditions: Mechanistic Insights.
  4. Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.
  5. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  6. The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
  7. The potential of mitochondrial transfer as the modifying therapy for osteoarthritis.
  8. Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data.
  9. Bacteria-Mitochondria Cross-talk: How Microbes Regulate Mitochondrial Dynamics and Bioenergetics of Host Cells.
  10. Mitochondrial Physiology and Beyond: Mechanistic Insights into Kaempferol Actions.
  11. Therapeutic potentials of mesenchymal stem cells and their extracellular vesicles on liver diseases by modulating mitochondrial function of macrophages.
  12. The Pathophysiological Role of Mitochondrial Oxidative Stress in Rheumatic Diseases.
  13. Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.
  14. LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
  15. Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.
  16. Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
  17. Age-related changes in cardiolipin profile and functional consequences of altered fatty acid supply.
  18. Electrical Vagus Nerve Stimulation Ameliorates Cardiac Ischemia and Reperfusion Injury by Improving Mitochondrial Biogenesis Through the SIRT1/PGC-1α Pathway.
  19. Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.
  20. mtDNA copy number/miR663/AATF axis in invasive ductal carcinoma of the breast.
  21. The Nucleolus and Its Associated Pathologies.
  22. Mitochondrial DNA variants in normal skins: Insights into prevalent pathogenic variants and quality control surveillance.
  23. Clinical Characteristics and Management of Rare Metabolic Bone Diseases: An Audit of the Rare Metabolic Bone Disease Registry of India.
  24. Organoids in Genetic Disorders: from Disease Modeling to Translational Applications.
  25. Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.
  26. Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.
  27. Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
  28. Advancements in Protein-Based Therapeutic Delivery Approaches Targeting the Blood-Brain Barrier and Insights on Computational Strategies.
  29. Mitochondrial DNA driven senescence-associated secretory phenotype facilitates the development of bronchopulmonary dysplasia.
  30. Denisovan mitochondrial DNA from dental calculus of the >146,000-year-old Harbin cranium.
  31. Targeting mitochondrial dysfunction to intervene in liver cancer.
  32. Unraveling the role of mitochondrial dynamics in cancer stem cells: Molecular basis and therapeutic implications.
  33. Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
  34. Recharging the Powerhouse: Mitochondrial Dysfunction and Therapy in Cardiorenal Syndrome Type 4.
  35. The Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease.
  36. Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
  37. Human brain organoids: an innovative model for neurological disorder research and therapy.
  38. Learning from inborn errors of immunity and secondary immune deficiencies about vaccine immunogenicity, efficacy and safety.
  39. Digital speech assessments and machine learning for differentiation of neurodegenerative diseases.
  40. siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review.
  41. Aligning Orphanet Classification to Identify Disease Characteristics among Rare Disease Clusters.
  42. APOE ε4 on immunity.
  43. Lipid-conjugated nucleoside prodrugs for antiviral therapy.
  44. MetabOCT: a clinical trial looking for a metabolomic signature predicting the onset of Leber's hereditary optic neuropathy in healthy MtDNA mutations carriers.
  45. The Essence of Nature Can be the Simplest (6)-Lifespan: Determined by Extracellular Fenton Chemistry.
  46. The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
  47. Tough to treat: What we know about managing PCDH19-related epilepsy - Systematic review.
  48. Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA replication defects.
  49. Incorporating Rare Disease Growth Monitoring Into Routine Practice to Improve Early Recognition and Diagnosis of Genetic Conditions.
  50. DNA polymerase α-primase can function as a translesion DNA polymerase.
  51. Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway.
  52. Drug Delivery Strategies for the Lower GI Tract: A Review.
  53. Alterations of telomere length and mitochondrial DNA copy number in depressive adolescents with non-suicidal self-injury.
  54. Alteration in hippocampal mitochondria ultrastructure and cholesterol accumulation linked to mitochondrial dysfunction in the valproic acid rat model of autism spectrum disorders.
  55. MRI-negative cerebellar syndrome caused by medication-induced magnesium deficiency: a case report.
  1. Front Biosci (Landmark Ed). 2025 Aug 18. 30(8): 37006
    Mitochondrial Transplantation Therapy: A Novel Approach in the Era of Organelle-Centered Regenerative Medicine.
    Ha Rim Shin, Gaheon Lee, Kyung Hwa Kim.
      Mitochondria play crucial roles in maintaining health and influencing disease progression by acting as central regulators of cellular homeostasis and energy production. Dysfunctions in mitochondrial activity are increasingly recognized as key contributors to various pathologies, ultimately impacting healthspan and disease outcomes. However, traditional treatments often do not restore damaged mitochondria to a healthy state. Mitochondrial transplantation, a cellular organelle-based therapy in which mitochondria are introduced into a recipient, has emerged as a novel concept in next-generation therapeutics that overcomes the limitations of current cell-based treatments. This review highlights the unique properties of mitochondria as therapeutic agents, including their ability to restore cellular functions and treat a wide range of diseases. In this review, we focus on the unique role of mitochondria in the regulation of stem cell functions, including stem cell fate, self-renewal, and differentiation. Various perspectives have been explored to better understand mitochondrial transplantation therapy, which harnesses the capacity of mitochondria as living drugs in regenerative medicine, as an innovative strategy to bridge the gap between cell therapy and organelle-based treatments and overcome current clinical barriers.
    Keywords:  mesenchymal stem cell; mitochondrial dysfunction; mitochondrial transplantation; organelle transplantation; regenerative medicine
    DOI:  https://doi.org/10.31083/FBL37006
  2. Nat Med. 2025 Sep 12.
    Mending a mother's mitochondrial DNA.
    Mike May.
      
    DOI:  https://doi.org/10.1038/d41591-025-00056-2
  3. Int J Mol Sci. 2025 Sep 02. pii: 8537. [Epub ahead of print]26(17):
    Mitochondria-Associated Pathways in Cancer and Precancerous Conditions: Mechanistic Insights.
    Ling Li, Dan Pan, Ruixue Ai, Yu Zhou.
      Mitochondria perform critical roles in cellular functions, particularly in metabolism and cell death regulation. Mutations in nuclear and mitochondrial genes can cause mitochondrial dysfunction, leading to classical mitochondrial diseases. Emerging evidence suggests that mitochondrial adaptations in cancer support the high energy demands of proliferating cells and contribute to tumor progression through anti-apoptotic mechanisms, dysregulated mitochondrial quality control (mtQC), and altered mitochondrial DNA (mtDNA) copy numbers. Interestingly, several mitochondrial pathways involved in cancer progression resemble those implicated in mitochondrial diseases. From this perspective, although cancer is not a classical mitochondrial disease, its progression involves mitochondria-associated pathways similar to those in mitochondrial disorders, suggesting that cancer may be considered a mitochondria-related disease in a broader sense. Understanding these shared mechanisms could provide new insights into precision treatment strategies. Furthermore, mitochondrial dysfunction is increasingly recognized in precancerous conditions, suggesting its potential as a target for early intervention. Oral potentially malignant disorders (OPMDs) serve as a valuable model for studying these mitochondria-associated mechanisms, offering a promising avenue for both therapeutic advancements and preventive approaches.
    Keywords:  cancer; gene mutation; mitochondria disease; mitochondrial dysfunction; precancerous condition
    DOI:  https://doi.org/10.3390/ijms26178537
  4. FASEB J. 2025 Sep 15. 39(17): e70986
    Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.
    Miki Shavit, Marie Vancová, Jan Jedlicka, Tomáš Bílý, Mushrek Mahrouk, Jan Cendelin, Kateřina Grygarova, Kristýna Popelková, Zdeněk Tůma, Gabriela Pribanova, Jitka Kuncová, Jan Nevoral.
      Mitochondria in the egg are suggested to be crucial for the onset of new life. However, there is ambiguous knowledge about the necessity for fertilization and early embryonic development. Therefore, we created a conditional Tfam knockout (TfamloxP/loxP; Zp3-Cre) to produce Tfamnull oocytes for investigation of the mitochondrial abundance in oocytes and early embryos. This created mtDNA-depleted eggs, although the abundance of mitochondria did not change. Despite decreased mitochondrial membrane potential, Tfamnull oocytes matured and were fertilized, which led to embryo formation. These Tfamnull eggs were developed into mtDNA-deficient blastocysts. Both TFAM and mtDNA appear to be dispensable for the success of embryo implantation. Tfam expression and mtDNA replication rescue the mtDNA-deficient embryo after implantation, enabling passage through a post-implantation bottleneck, and allowing survivor embryos to develop into healthy individuals. Our findings highlight the uncoupled relationship between mtDNA replication and mitochondrial abundance in the growing oocyte and show the importance of the oocyte bulk mtDNA for successful mitochondrial activation in post-implantation embryos.
    Keywords:  embryo; fertilization; mitochondrial; mitochondrion; oocyte; transcription factor A
    DOI:  https://doi.org/10.1096/fj.202501179R
  5. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  6. Front Biosci (Landmark Ed). 2025 Aug 27. 30(8): 27634
    The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
    Solenn Plouzennec, Juan Manuel Chao de la Barca, Arnaud Chevrollier.
      The bioenergetic machinery of the cell is protected and structured within two layers of mitochondrial membranes. The mitochondrial inner membrane is extremely rich in proteins, including respiratory chain complexes, substrate transport proteins, ion exchangers, and structural fusion proteins. These proteins participate directly or indirectly in shaping the membrane's curvature and facilitating its folding, as well as promoting the formation of nanotubes, and proton-rich pockets known as cristae. Recent fluorescent super-resolution images have demonstrated the strong dynamics of these events, with constant remodeling processes. The mitochondrial outer membrane itself is also highly dynamic, interacting with the endoplasmic reticulum and its environment to ensure a rapid diffusion of surface components throughout the mitochondrial networks. All these movements occur besides migration, fusion, and fission of the mitochondria themselves. These dynamic events at the level of mitochondrial membranes are primarily dependent on their unique lipid composition. In this review, we discuss the latest advances in phospholipid research, focusing on their metabolism and role in mitochondrial dynamics. This process emphasizes the importance of interactions with the endoplasmic reticulum and mitochondrial matrix enzymes, extending its relevance to lipid sources, in particular, cardiolipins and phosphatidylethanolamines at the cellular, tissue and even whole-organism level. Given the expanding array of characterized mitochondrial functions, ranging from calcium homeostasis to inflammation and cellular senescence, research in the field of mitochondrial lipids is particularly significant. As mitochondria play a central role in various pathological processes, including cancer and neurodegenerative disorders, lipid metabolism may offer promising therapeutic approaches.
    Keywords:  dynamic; lipids; membrane; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.31083/FBL27634
  7. Front Cell Dev Biol. 2025 ;13 1643141
    The potential of mitochondrial transfer as the modifying therapy for osteoarthritis.
    Yuanpei He, Xinge Wang, Boya Xu, Shichao Chen, Hongcai Li, Bei Chang, Chao Hu, Xiaorong Lan, Shiting Li, Guangwen Li.
      Mitochondrial transfer is defined the process through which specific cell types release their mitochondria and subsequently transfer them to unrelated cell types in response to various physiological or pathological stimuli. This process enhances cellular function and alters disease states. Recent research has begun to explore the potential of intercellular mitochondrial transfer as a therapeutic strategy for human diseases. Mitochondrial dysfunction represents a significant pathological alteration in osteoarthritis, and studies indicate that mitochondrial transfer may serve as an effective modulatory treatment approach for osteoarthritis. Mitochondrial transfer, as an innovative subcellular therapeutic technique, presents the advantages of diverse acquisition methods and multiple transmission pathways. This paper aims to summarize the current understanding of the mechanisms of mitochondrial transfer in relation to osteoarthritis, emphasizing the existing research on mitochondrial transfer in osteoarthritis and its potential as a disease-modifying therapy.
    Keywords:  artificial mitochondrial transfer; disease-modifying; mitochondrial transfer; osteoarthritis; therapymitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fcell.2025.1643141
  8. Ann Clin Transl Neurol. 2025 Sep 12.
    Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data.
    Ian W McKeague, Kristin Engelstad, Yue Ge, Amber Tucker, Shufang Li, Jasim Uddin, Ziwei Zhao, John L P Thompson, Michio Hirano.
       OBJECTIVE: Therapeutic development for mitochondrial diseases, rare genetic disorders with pathogenic defects of oxidative phosphorylation, is hindered by unsatisfactory outcome measures. To address this problem, we provide the first clinical application of a novel, bias-adjusted outcome measure of acceleration across a range of subjects' activities to assess nucleoside therapy for thymidine kinase 2 deficiency, an ultra-rare autosomal recessive mitochondrial disease.
    METHODS: Data were collected from treated patients in an ongoing phase 2 clinical trial who served as their own controls. If there is a treatment effect, time-in-activity curves for these patients will increase over successive clinic visits. We used a combination of functional data analysis and longitudinal mixed-effects linear regression, adjusted for age and gender, to test for the effect of treatment length on time-in-activity.
    RESULTS: For 14 patients with at least two assessments 6 months apart, we found a significant overall improvement of time-in-activity due to treatment. Improvement was especially significant at two individual activity levels within the range (0.14 and 2 g). In longitudinal analyses, using data on time-in-activity at these two levels for all clinic visits of 19 subjects, the effect of treatment length on time-in-activity was highly significant at both 0.14 g (0.04, CI 0.01-0.08, p = 0.023) and 2 g (0.01, 0.00-0.02, p = 0.013).
    INTERPRETATION: This small-N exploratory analysis using a new accelerometer-based activity measure featuring powerful data reduction and adjustment for circadian rhythms and other biases finds that nucleoside therapy may increase activity levels in thymidine kinase 2 deficiency patients.
    Keywords:  accelerometer; mitochondrial disease; outcome measure; thymidine kinase 2 deficiency
    DOI:  https://doi.org/10.1002/acn3.70180
  9. Infect Disord Drug Targets. 2025 Aug 19.
    Bacteria-Mitochondria Cross-talk: How Microbes Regulate Mitochondrial Dynamics and Bioenergetics of Host Cells.
    Tasbir Amin, Md Asaduzzaman Shishir, Mohammad Mamun Alam, Mohammad Badrul Anam, Nayeema Bulbul, Jinath Sultana Jime, Md Fakruddin.
      Mitochondria are the cellular powerhouses and are considered to be central to energy metabolism, dynamics, and homeostasis. There is growing evidence that the gut microbiome regulates mitochondrial biogenesis, dynamics (fission, fusion, mitoph-agy), and bioenergetics, and that it does so by connecting bacterial metabolites and signaling molecules. This review discusses the molecular mechanisms that underlie the interplay between bacteria and mitochondria, with a particular focus on the modulation of mitochondrial activities by microbial products, including bile acids, immunological mediators, and short-chain fatty acids (SCFAs). The evolutionary relationship between bacteria and mitochondria is explored, along with the implications of microbial dysbio-sis on mitochondrial dysfunction, which is linked to a variety of inflammatory, meta-bolic, and neurodegenerative disorders. Additionally, we emphasised the therapeutic potential of focusing on the microbiota to treat illnesses associated with the mitochon-dria and to restore mitochondrial health. A better understanding of the complex rela-tionship between bacteria and mitochondria can open up new avenues for disease man-agement and novel treatment possibilities.
    Keywords:  Mitochondria; bacteria-mitochondria cross-talk; bioenergetics; dysbiosis.; gut microbi-ota; microbial metabolites; microbiome; mitochondrial biogenesis; mitochondrial dynamics; short-chain fatty acids (SCFAs)
    DOI:  https://doi.org/10.2174/0118715265362556250717063603
  10. Chem Biol Interact. 2025 Sep 10. pii: S0009-2797(25)00373-4. [Epub ahead of print] 111743
    Mitochondrial Physiology and Beyond: Mechanistic Insights into Kaempferol Actions.
    Marcos Roberto de Oliveira.
      Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse in vitro and in vivo models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/ peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.
    Keywords:  kaempferol; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial function; mitophagy; redox signaling
    DOI:  https://doi.org/10.1016/j.cbi.2025.111743
  11. Int Immunopharmacol. 2025 Sep 08. pii: S1567-5769(25)01477-8. [Epub ahead of print]165 115486
    Therapeutic potentials of mesenchymal stem cells and their extracellular vesicles on liver diseases by modulating mitochondrial function of macrophages.
    Shouhan Yao, Yelei Cen, Guohua Lou, Yanning Liu.
      Macrophages play crucial roles in the progression of liver diseases. Increasing studies have shown that mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) could reshape the liver immune microenvironment by regulating the function and phenotype of macrophages, thereby exerting a therapeutic effect on liver diseases. Mitochondria, apart from being the central hub of energy metabolism, also finely regulate macrophage-mediated innate immune responses by modulating reactive oxygen species levels, cell polarization, and cell death. Mitochondrial dysfunction-associated abnormal macrophage function and phenotype is attracting increasing attention. In this review, we summarize the multiple types of mitochondrial damage in macrophages across various liver diseases and comprehensively discuss how MSCs can modulate macrophage mitochondrial function, including mitochondrial biogenesis and dynamics, mitophagy, and metabolic remodeling, or directly donate healthy mitochondria to alleviate liver diseases. A complete understanding of MSCs and MSC-EVs in the context of restoring mitochondrial function in macrophages may provide new insights for developing novel interventions targeting the immune microenvironment and innovative immunotherapeutic strategies for liver diseases.
    Keywords:  Extracellular vesicles; Innate immunity; Liver disease; Macrophages; Mesenchymal stem cells; Mitochondria
    DOI:  https://doi.org/10.1016/j.intimp.2025.115486
  12. J Inflamm Res. 2025 ;18 12021-12044
    The Pathophysiological Role of Mitochondrial Oxidative Stress in Rheumatic Diseases.
    Zhao Ma, Qiaoping Xu, Xinchang Xu.
      Mitochondria play a crucial role in reactive oxygen species (ROS)-dependent rheumatic diseases, including ankylosing spondylitis, osteoarthritis (OA), systemic lupus erythematosus (SLE) and scleroderma. Mitochondrial DNA (mtDNA), which encodes mitochondrial proteins, is more vulnerable to oxidants compared to nuclear DNA. When mtDNA gets damaged, it leads to mitochondrial dysfunction, such as electron transport chain impairment and loss of mitochondrial membrane potential. Moreover, the damaged mtDNA functions as a damage-associated molecular pattern (DAMP), triggering inflammatory and immune responses. In this review, ROS-related transcription factors and downstream cell signaling pathways are investigated. It also explains the mechanism of mitochondrial dysfunction and the clinical significance of major rheumatic diseases, as well as the clinical transformation status of key antioxidants, the risks/reasons for promoting mitochondrial ROS research in rheumatic diseases, and antioxidant therapy. We conclude that targeting oxidative stress with antioxidant agents,such as polyphenols, garlic, pomegranate, Coenzyme Q10, probiotic, α-lipoic acid, N-acetylcysteine (NAC), selenium, microalgae, fucoidan, resveratrol, quercetin, and curcumin should be considered as promising new strategies for treating rheumatic diseases lacking effective treatments.
    Keywords:  ROS; antioxidant agents; inflammatory; mtDNA; rheumatic diseases
    DOI:  https://doi.org/10.2147/JIR.S534574
  13. Int J Mol Sci. 2025 Sep 06. pii: 8693. [Epub ahead of print]26(17):
    Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.
    Agnieszka Dominiak, Elżbieta Gawinek, Agnieszka Anna Banaszek, Anna Wilkaniec.
      Mitochondrial quality control (MQC) mechanisms, including proteostasis, mitophagy, mitochondrial dynamics, and biogenesis, are essential for maintaining mitochondrial function and overall cellular health. Dysregulation of these systems is a common feature of both neurodegenerative diseases and cancer, but the outcomes differ. Neurons depend strongly on healthy mitochondria and are easily damaged when MQC fails, resulting in organellar dysfunction and oxidative stress. By contrast, cancer cells often adapt by using MQC pathways to sustain survival and resist cell death. The mitochondrial unfolded protein response (mtUPR) and mitophagy are central to these processes, yet their roles are context-dependent. In neurodegeneration, activation of these pathways may help neurons survive, yet persistent stimulation can shift towards harmful effects. In cancer, these same pathways enhance metabolic flexibility, promote resistance to treatment, and support tumor progression. Although therapeutic strategies targeting MQC are being explored, their translation to the clinic is difficult, partly due to opposite effects in different diseases. The observed inverse epidemiological link between cancer and neurodegeneration may also reflect the distinct regulation of MQC pathways. A clearer understanding of these mechanisms is needed to identify new treatment strategies for disorders that are clinically distinct but share common mitochondrial defects.
    Keywords:  cancer; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms26178693
  14. Clin Genet. 2025 Sep 10.
    LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
    Undiagnosed Diseases Network
      LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.
    Keywords:  CODAS; LONP1; congenital diaphragmatic hernia; mitochondrial encephalopathy; neurodevelopmental disorder
    DOI:  https://doi.org/10.1111/cge.70057
  15. Exp Eye Res. 2025 Sep 08. pii: S0014-4835(25)00403-8. [Epub ahead of print] 110632
    Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.
    Hetong Sun, Bin Li, Yu Gu, Fei Li, Guohu Di, Peng Chen.
      Mitochondria play a crucial role in energy production and are intimately associated with ocular function. Mitochondrial dysfunction can trigger oxidative stress and inflammation, adversely affecting key ocular structures such as the lacrimal gland, lens, retina, and trabecular meshwork. This dysfunction may compromise the barrier properties of the trabecular meshwork, impeding aqueous humour outflow, elevating intraocular pressure, and resulting in optic nerve damage and primary open-angle glaucoma. Additionally, impaired mitochondrial homeostasis can contribute to dry eye, cataracts, and age-related macular degeneration (AMD) by disrupting the function of the lacrimal gland, lens, and macula. Imbalanced mitochondrial homeostasis primarily involves four pathological features: disruption of mitochondrial quality control, mitochondrial damage (inducing inflammation), excessive production of mitochondrial reactive oxygen species (ROS) (initiating oxidative stress), and disturbances in mitochondrial calcium (Ca2+) homeostasis. Oxidative stress and inflammation are central mechanisms of cellular injury. Pharmacological strategies aimed at reducing excessive ROS, restoring redox balance, and mitigating oxidative and inflammatory damage show therapeutic promise. Moreover, enhancing mitochondrial function through pharmacological agents, replacing damaged mitochondria, and promoting mitochondrial rejuvenation represent emerging treatment avenues. This review explores the relationship between mitochondrial dysfunction and ocular diseases such as dry eye, glaucoma, cataracts, and AMD, with a focus on associated mechanisms and potential therapeutic interventions.
    Keywords:  AMD; Cataracts; Dry eye; Glaucoma; Mitochondrial Dysfunction; Oxidative Stress; Targeted Therapy
    DOI:  https://doi.org/10.1016/j.exer.2025.110632
  16. Cell Signal. 2025 Sep 08. pii: S0898-6568(25)00536-4. [Epub ahead of print]136 112121
    Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
    Chao Hu, Tianhong Su, Ying Zhang, Jing Yang, Xun Su, Zhikang Zhang, Xin Wang, Weiwei Zou, Dan Liang, Yajing Liu, Dongmei Ji, Yunxia Cao.
      Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G > A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing OPA1-mediated fusion and enhancing DRP1-dependent fission, resulting in decreased expression of ND1, ND5, NDUFB8, SDHB and COX2, impaired mitochondrial bioenergetic function, and cell proliferation. Additionally, the m.3635G > A mutation promoted intrinsic apoptosis, altered autophagic flux, evidenced by elevating levels in apoptotic proteins PARP1, caspase-3, and 9, reduced levels of autophagy protein LC3-II, and increased levels of substrate P62. Moreover, the m.3635G > A mutation inhibited PINK1-Parkin-dependent mitophagy. Based on sex-specific differences in hormone metabolism, we proposed that estrogen plays a protective role in women and showed that estrogen receptor α and β were downregulated in LHON. We demonstrated that estradiol improved cell viability by reducing apoptosis, inducing mitochondrial biogenesis through the PGC1α-NRF1/2-TFAM axis, and vigorously promoting PINK1-Parkin-dependent mitophagy in LHON iPSCs and iPSC-derived RPE cells. Our findings have highlighted the critical role of the m.3635G > A mutation in the pathogenetic process of LHON, and our observations support the hypothesis that estrogen is helpful in the preventive treatment of LHON.
    Keywords:  Autophagy; Induced pluripotent stem cell; Leber's hereditary optic neuropathy (LHON); Mitochondrial disease; Mitophagy; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112121
  17. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Sep 07. pii: S1388-1981(25)00095-2. [Epub ahead of print] 159687
    Age-related changes in cardiolipin profile and functional consequences of altered fatty acid supply.
    Philipp W Weiß, Philip P Kaltenborn, Christiane Frahm, Ulrike Schulze-Späte, Estelle Heyne, Marten Szibor, Sandor Nietzsche, Ralf A Claus, Markus H Gräler.
      Cardiolipins (CLs) are primarily expressed in the inner mitochondrial membrane where they play essential roles in membrane architecture and mitochondrial functions. CLs have a unique structure characterized by four acyl chains with different stoichiometries such as chain length and degree of saturation. CL composition changes with disease and age, but it is largely unknown how dynamic changes affect mitochondrial function. Here, we compared CL profiles in different mouse tissues across different age groups using liquid chromatography and triple quadrupole mass spectrometry. A key finding was that CLs in the brain differ significantly from those in peripheral organs, with a tendency towards longer-chain variants. We hypothesized that these differences may be influenced by the availability of fatty acids (FA), which in the brain could be affected by the blood-brain barrier. In support of this notion, we found that FA concentrations varied in the different compartments. In addition, we found that CL profiles changed during aging. In cultivated macrophages supplemented with different FAs, we tested how altered CL profiles may affect both, mitochondrial morphology and function such as cristae density, and mitochondrial membrane potential and respiration, respectively. Finally, we validated our in vitro results in vivo by altering the CL profile in mice by using palmitic acid and oleic acid enriched diets. Our study highlights a dynamic adaptation of CL profiles in response to FA availability and aging and emphasizes its functional importance for mitochondrial function. Furthermore, FA supplementation may be a promising therapeutic strategy to address disease- and age-related mitochondrial malfunctions.
    Keywords:  Aging; Dietary fat; Lipid saturation; Mass spectrometry; Mitochondria; Phospholipid
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159687
  18. Appl Biochem Biotechnol. 2025 Sep 11.
    Electrical Vagus Nerve Stimulation Ameliorates Cardiac Ischemia and Reperfusion Injury by Improving Mitochondrial Biogenesis Through the SIRT1/PGC-1α Pathway.
    Yingqiang Guo, Yu Zhang, Jinzhou Zhang, Xingwan Bai, Wei Kang, Yujie Guo, Xianming Zeng.
      Vagus nerve stimulation (VNS) has demonstrated cardioprotective effects in a variety of cardiovascular diseases, including cardiac ischemia and reperfusion (IR) injury. However, the mechanisms responsible for these effects have not been completely understood. The present work aimed to uncover the potential mechanisms through which VNS confers protection against cardiac IR injury. Rats subjected to cardiac IR injury received electrical VNS through the right cervical vagus nerve. This intervention led to a notable reduction in cardiac dysfunction and injury, as well as decreased cardiac apoptosis, oxidative stress, and inflammation. Moreover, VNS treatment improved mitochondrial biogenesis by upregulating estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and transcriptional factor A mitochondrial (TFAM). In addition, VNS treatment not only increased the copy number of mitochondrial DNA (mtDNA) and the content of adenosine triphosphate (ATP), but also effectively reduced mitochondrial damage. VNS also upregulated the expression of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in IR-injured hearts. Inhibition of either SIRT1 or PGC-1α significantly reversed the effects of VNS on mitochondrial biogenesis and abolished its cardioprotective benefits. Notably, VNS increased the level of acetylcholine (ACh) in IR-injured hearts. Administration of atropine, a muscarinic ACh receptor (mAChR) antagonist, counteracted the effects of VNS on the SIRT1/PGC-1α pathway, mitochondrial biogenesis, and the associated cardioprotective outcomes. These findings suggest that VNS protects against cardiac I/R injury by enhancing mitochondrial biogenesis. This beneficial effect of VNS on mitochondrial biogenesis is attributed to activation of the SIRT1/PGC-1α pathway through the ACh/mAChR axis. Therefore, this research offers fresh perspectives on the mechanisms underlying the cardioprotective effects of VNS.
    Keywords:  Acetylcholine; Cardiac ischemia and reperfusion injury; Mitochondrial biogenesis; Mitochondrial damage; Vagus nerve stimulation
    DOI:  https://doi.org/10.1007/s12010-025-05359-1
  19. Asian J Psychiatr. 2025 Sep 05. pii: S1876-2018(25)00337-5. [Epub ahead of print]112 104694
    Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.
    Xue Xia, Kaiqing Li, Baiyi Jiang, Wei Zou, Long Wang.
      Major depressive disorder (MDD) is a severe mental illness with complex pathophysiology. Growing evidence highlights mitochondrial dysfunction as a key player in MDD, influencing neuroinflammation, synaptic plasticity, and energy metabolism. This review summarizes recent advances in understanding how mitochondrial defects-including mtDNA mutations, impaired mitophagy, disrupted dynamics, altered biogenesis, and metabolic dysregulation-contribute to depressive pathogenesis. We also evaluate mitochondria-targeted therapeutic strategies, encompassing both pharmacological agents (e.g., antioxidants, CoQ10, NAD+ precursors, SSRIs, and natural compounds) and non-pharmacological interventions (e.g., exercise, ketogenic diet, photobiomodulation, and electroacupuncture). Importantly, we emphasize the interplay between mitochondrial processes and the need to balance anabolic and catabolic functions. While preclinical results are promising, further clinical translation is essential. This review underscores mitochondrial health as a central theme in MDD research and therapy development.
    Keywords:  Major depressive disorder; Mitochondria-targeted therapy; Mitochondrial DNA; Mitochondrial dysfunction; Neuroplasticity
    DOI:  https://doi.org/10.1016/j.ajp.2025.104694
  20. Bioimpacts. 2025 ;15 30792
    mtDNA copy number/miR663/AATF axis in invasive ductal carcinoma of the breast.
    Farzaneh Dahi, Shirin Shahbazi, Loabat Geranpayeh.
      
    Introduction: Mitochondrial DNA (mtDNA) copy number variations have been reported in multiple human cancers. Previous studies indicate that mitochondrial retrograde signaling regulates miR663, which plays a key role in tumorigenesis, including regulating apoptosis antagonizing transcription factor (AATF). This study investigates the expression of miR663 and AATF in relation to mtDNA copy number in invasive ductal carcinoma (IDC) of the breast.
    Methods: Paired primary tumors and adjacent non-tumor tissues were analyzed to assess changes in miR663 and AATF expression using fold-change analysis. The mtDNA copy number was quantified using COX1 as the mitochondrial gene and COX4 as the nuclear control gene. To validate the findings, publicly available data from The Cancer Genome Atlas (TCGA) were also analyzed.
    Results: A significant reduction in tumor miR663 expression was observed (fold change=0.139), with a strong correlation between miR663 and AATF expression. A significant Z-score difference was also detected between miR663 and mtDNA copy number. miR663 was predominantly expressed in grade I tumors but significantly downregulated in higher-grade tumors, whereas AATF expression increased with tumor grade. In silico analysis of TCGA data confirmed elevated AATF expression, with notable variations across breast cancer subtypes.
    Conclusion: We observed reduced expression of miR663 and mtDNA copy number in breast tumors, along with variations in AATF levels across subtypes. The decrease in miR663 could be associated with lower mtDNA copy numbers and impaired retrograde signaling, impacting AATF expression and function. Our findings underscore the therapeutic promise of targeting the mtDNA/miR-663/AATF axis, which could lead to advancements in breast cancer treatment.
    Keywords:  Breast cancer; Tumorigenesis; miRNAs
    DOI:  https://doi.org/10.34172/bi.30792
  21. WIREs Mech Dis. 2025 Sep-Oct;17(5):17(5): e70003
    The Nucleolus and Its Associated Pathologies.
    Marvin J Menjivar-Vallecillo, Nadia V Padilla-Claros, Pilar Gavarrete-Garrido, Sherlyn A León-Castañeda, Héctor M Ramos-Zaldívar.
      The nucleolus, traditionally known for its role in ribosome biogenesis, is now recognized for its broader functions, including cellular stress adaptation and its involvement in various pathological processes, such as ribosomal alterations, viral infections, autoimmune disorders, and age-related diseases. Disruptions in nucleolar function can impair protein synthesis, cellular homeostasis, and immune responses, leading to multisystem disorders and increased susceptibility to neoplasms. This review classifies nucleolus-associated diseases into seven categories: deficiencies in protein synthesis, ribosomal and non-ribosomal alterations, cancer and nucleolar alterations, diseases related to aging and cellular stress, autoimmune diseases, and viral diseases. Understanding the complexity of the nucleolus and its dysfunctions represents a fundamental step toward advancing knowledge of the molecular basis of these pathologies, laying the groundwork for future research addressing its implications in cell biology and the development of human diseases. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.
    Keywords:  cell nucleolus; disease; microRNAs; nucleolin; ribosomes
    DOI:  https://doi.org/10.1002/wsbm.70003
  22. Mitochondrion. 2025 Sep 09. pii: S1567-7249(25)00078-9. [Epub ahead of print] 102081
    Mitochondrial DNA variants in normal skins: Insights into prevalent pathogenic variants and quality control surveillance.
    Kohta Nakamura, Yasunari Sato, Masao Hashimoto, Naoyuki Matsumoto, Sachiko Nitta, Yasushi Okazaki, Yasuo Miyoshi, Hiroki Nagase.
      Mitochondrial genome diversity in normal tissues remains poorly understood due to 100 to 1000 copies of mitochondrial DNA in a cell. This study analyzed mitochondrial DNA variants in two distant sites of normal skin tissues from 119 breast surgery cases using deep sequencing. We identified 1337 variants across the mitochondrial genome (59.1 % in coding region). Intriguingly variants were categorized two groups, homoplasmic (81.1 %) or low heteroplasmy rate group (14.1 %). Even MITOMAP pathogenic variants, two out of eight were homoplasmic, common in several patients, and found in both skin sites of the same individual, while six heteroplasmic pathogenic variants were identified in a single patient with < 5 % heteroplasmy rates, half only detected in a single skin site with < 2 % rates. Pathogenic mutations predicted by AlphaMissense were significantly less common in the homoplasmic group (30/1085) but more common in the heteroplasmic group (216/431). Significant increases of mitochondrial copy number were also repeatedly detected in cases with pathogenic variants. This study provides new insights into the diversity of mitochondrial genome and the complexity of mitochondrial homeostasis in normal skin tissue, including the possibility of evading pathogenic mutations through quality control surveillance and the restoration of mitochondrial function due to increase in copy number.
    Keywords:  Deep sequencing; Heteroplasmy ratio; Mitochondrial DNA; Pathogenic variant; Variant prevalence
    DOI:  https://doi.org/10.1016/j.mito.2025.102081
  23. Calcif Tissue Int. 2025 Sep 07. 116(1): 119
    Clinical Characteristics and Management of Rare Metabolic Bone Diseases: An Audit of the Rare Metabolic Bone Disease Registry of India.
    Mani Sangar, Liza Das, Simran Kaur, Vandana Dhiman, Sanjay Kumar Bhadada.
      Rare diseases, defined by the 2002 Rare Disease Act, affect fewer than 5 in 10,000 individuals. Rare metabolic bone diseases (MBDs), such as osteogenesis imperfecta, hypophosphatasia, osteopetrosis, and other unclassified disorders, can disrupt bone development and remodeling, posing diagnostic and management challenges. This study analyzed data from the rarembd.in registry (2010-2024), a 15-year database documenting only rare MBDs. Clinical presentation and demographic data of patients with rare MBDs were collated. Common MBDs (osteoporosis, primary hyperparathyroidism) were excluded. Genetic testing was performed in a subset of patients. There was a total of 218 patients with an almost equal gender distribution (male-to-female ratio of 1:1.07) and a mean age of 29.1 ± 18.9 years. The registry identified 29 rare MBDs with three main disease categories: demineralization disorders (50.4%), disorders of bone matrix and cartilage formation (32.5%), and sclerotic disorders (13.7%); with a smaller proportion categorized as unclassified bone disorders (2.7%). Rickets/osteomalacia (27.1%) was the most common, followed by osteogenesis imperfecta (23.4%) and fibrous dysplasia/McCune-Albright syndrome (18.8%). Fractures affected 57.7% of patients, with 24.5% experiencing multiple fractures, while 31.1% exhibited skeletal deformities. Mutation analysis in our registry identified pathogenic variants in the SOST, TGFβ1, SLC34A3, ALPL, and VCP genes, confirming the genetic basis of sclerosteosis, Camurati-Engelmann disease, hypophosphatemic rickets, hypophosphatasia, and IBMPFD, respectively. Different management strategies were used that included teriparatide, bisphosphonates (zoledronate or alendronate) with total contact casting, intralesional zoledronate, denosumab, calcium, active vitamin D, and recombinant human growth hormone. Total parathyroidectomy was performed in specific cases. The registry classified RMBDs into four categories, with demineralization disorders being the most common, followed by bone matrix/cartilage formation disorders, sclerotic diseases, and unclassified cases. There were 29 RMBDs, and rickets/osteomalacia was the most prevalent subtype, tumor-induced osteomalacia followed by familial hypophosphatemic osteomalacia. Among the unclassified bone disorders, fragility fractures emerged as the most common presentation.
    Keywords:  Fibrous dysplasia/McCune-Albright Syndrome; Osteogenesis imperfecta; Rare metabolic bone disorders; Rickets/osteomalacia
    DOI:  https://doi.org/10.1007/s00223-025-01423-4
  24. Stem Cell Rev Rep. 2025 Sep 11.
    Organoids in Genetic Disorders: from Disease Modeling to Translational Applications.
    Yuanhang Zhu, Nanshan Lin, Juan Li, Haoqian Zhang, Ping Zhang, Xin Cheng, Qian Yang, Ling Liu.
      The emergence of organoid models has significantly bridged the gap between traditional cell cultures/animal models and authentic human disease states, particularly for genetic disorders, where their inherent genetic fidelity enables more biologically relevant research directions and enhances translational validity. This review systematically analyzes established organoid models of genetic diseases across organs (e.g., brain, eye, kidney, lung, and heart), highlighting their pivotal roles in identifying novel pathogenic genes, elucidating disease mechanisms, and advancing therapeutic strategies such as drug screening platforms, gene-editing therapies, and organ transplantation strategies. Furthermore, we critically address current limitations-including challenges in recapitulating complex pathologies and scaling production-while underscoring their potential for personalized medicine through multi-omics integration and bioengineering innovations. Although the scope of "genetic diseases" is broad, this synthesis focuses on disorders with well-defined inheritance patterns, such as monogenic disorders, copy number variations (CNVs), and aneuploidies. Despite covering only a subset of these conditions, this review aims to provide researchers with a comprehensive overview of the field, emphasizing how organoid-based approaches could accelerate both mechanistic discoveries and clinical translation in genetic disease research.
    Keywords:  Drug screening; Gene-editing therapies; Genetic diseases; Genetic variation; Organoids
    DOI:  https://doi.org/10.1007/s12015-025-10973-x
  25. Trends Immunol. 2025 Sep 09. pii: S1471-4906(25)00201-7. [Epub ahead of print]
    Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.
    Chun-Ting J Kwong, Mariana J Kaplan.
      Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.
    Keywords:  autoimmune diseases; mitochondrial dysfunction; myeloid cells
    DOI:  https://doi.org/10.1016/j.it.2025.08.003
  26. Methods Cell Biol. 2025 ;pii: S0091-679X(25)00130-X. [Epub ahead of print]197 275-290
    Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.
    Eleni Tsakiri, Giorgos Niforos-Garcia, Brian D Ackley, Konstantinos Palikaras.
      Mitochondrial dysfunction is a shared hallmark of neurodegenerative disorders, including Alzheimer's disease (AD) and tauopathies among others. Pathological alterations of the microtubule-associated protein Tau can disrupt mitochondrial dynamics, transport, and function, ultimately leading to neuronal toxicity and synaptic deficits. Understanding these processes is crucial for developing therapeutic interventions. The nematode Caenorhabditis elegans serves as a powerful model to study mitochondrial morphology and Tau-induced neurotoxicity due to its well-characterized nervous system and genetic tractability. Here, we describe a robust methodology for assessing mitochondrial morphology, Tau aggregation, and neuronal integrity in a nematode model of tauopathy. By combining confocal laser scanning microscopy and motility assays, we provide a comprehensive framework for investigating mitochondrial deficits. This approach offers valuable insights into the interplay between Tau pathology and mitochondrial dysfunction, thereby advancing our understanding of neurodegenerative mechanisms and potential therapeutic targets.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Mitochondria; Motility; Neurodegeneration; Neurons; Tauopathy
    DOI:  https://doi.org/10.1016/bs.mcb.2025.05.002
  27. Autophagy. 2025 Sep 13.
    Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
    Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.
    Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2025.2561073
  28. Crit Rev Ther Drug Carrier Syst. 2025 ;42(6): 45-81
    Advancements in Protein-Based Therapeutic Delivery Approaches Targeting the Blood-Brain Barrier and Insights on Computational Strategies.
    Radhakrishnan Nithya, Muthiah Ramanathan.
      Treating neurological disorders is challenging due to the blood-brain barrier (BBB), which limits therapeutic agents, including proteins and peptides, from entering the central nervous system. Despite their potential, the BBB's selective permeability is a significant obstacle. This review explores recent advancements in protein therapeutics for BBB-targeted delivery and highlights computational tools. Strategies such as nanoparticulate-mediated delivery, nose-to-brain delivery, lipid-based approaches, exosomes, cell-penetrating peptides (CPPs), and BBB shuttle peptides have been developed to overcome this barrier. Nanoparticulate systems deliver protein therapeutics across the BBB and can be surface-functionalized to target therapeutic agents into the brain parenchyma. Nose-to-brain delivery is a minimally invasive approach to bypass the BBB. Lipid-based strategies like liposomal systems and nanostructured lipid carriers enhance protein therapies by overcoming BBB restrictions. Exosomes, with unique lipid and surface protein compositions, and CPPs provide versatile drug delivery across the BBB. BBB shuttle peptides, designed for targeted brain delivery, show enhanced stability, efficiency, and cargo transport. Computational tools, notably molecular dynamics simulations, are essential in optimizing protein therapeutics for BBB penetration. These tools offer insights into molecular interactions, guiding the design and optimization of protein therapeutics for better brain penetration. Despite accuracy, limitations due to the BBB's complexity, integrating realistic models and experimental data can improve predictions.
    DOI:  https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2025054214
  29. Am J Physiol Cell Physiol. 2025 Sep 12.
    Mitochondrial DNA driven senescence-associated secretory phenotype facilitates the development of bronchopulmonary dysplasia.
    Yang Meng, Hui Shi, Hui Xu, Yazhou Sun, Xingyun Wang, Rui Wang, Yongjun Zhang.
      Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and disrupted vascular growth in preterm infants. While cellular senescence has been well established in age-related diseases, such as chronic lung diseases, its role in developmental lung diseases originating in the neonatal period remains largely unknown. Here, we investigated the role and underlying mechanisms of the senescence-associated secretory phenotype (SASP) in BPD using targeted inhibitor treatments and rescue strategies. Key SASP factors, including IL-6, IL-1β, MMP-12, and TGF-β1, were significantly elevated after hyperoxia exposure, indicating their involvement in BPD pathogenesis. Confocal imaging revealed that hyperoxia-induced partial mitochondrial outer membrane permeabilization triggered mitochondrial DNA (mtDNA) leakage, establishing mitochondrial dysfunction as a key driver of BPD progression. Further experiments demonstrated the role of the voltage-dependent anion channel 1 (VDAC1) oligomerization and the cGAS-STING pathway in mediating mtDNA release and SASP, respectively. Collectively, these findings define a molecular cascade where VDAC1 oligomerization causes mtDNA leakage, activating cGAS-STING to drive SASP during BPD progression. Targeting the cGAS-STING pathway holds therapeutic potential for alleviating the chronic impact of BPD.
    Keywords:  Bronchopulmonary dysplasia; Incomplete mitochondrial outer membrane permeabilization; Lung development; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1152/ajpcell.00040.2025
  30. Cell. 2025 Jul 24. pii: S0092-8674(25)00627-0. [Epub ahead of print]188(15): 3919-3926.e9
    Denisovan mitochondrial DNA from dental calculus of the >146,000-year-old Harbin cranium.
    Qiaomei Fu, Peng Cao, Qingyan Dai, E Andrew Bennett, Xiaotian Feng, Melinda A Yang, Wanjing Ping, Svante Pääbo, Qiang Ji.
      Denisovans have yet to be directly associated with a hominin cranium, limiting our understanding of their morphology and geographical distribution. We have attempted to retrieve DNA from a nearly complete Middle Pleistocene cranium from Harbin (>146 ka), northeastern China. Although no DNA could be retrieved from a tooth or the petrous bone, mitochondrial DNA (mtDNA) could be isolated from dental calculus. The mtDNA falls within Denisovan mtDNA variation and is related to an mtDNA branch carried by early Denisovan individuals in southern Siberia, previously observed in Denisova Cave. This suggests that Denisovans inhabited a large geographical range in Asia in the Middle Pleistocene. The association of Denisovan mtDNA with the Harbin cranium allows a better understanding of the morphological relationships between Denisovans and other East Asian Middle Pleistocene fossils. Furthermore, the retrieval of host DNA from dental calculus opens new possibilities for genetic research on Middle Pleistocene hominins.
    Keywords:  Denisovan mtDNA; Harbin hominin; dental calculus; host DNA; nearly complete cranium
    DOI:  https://doi.org/10.1016/j.cell.2025.05.040
  31. Cancer Biol Med. 2025 Sep 08. pii: j.issn.2095-3941.2025.0180. [Epub ahead of print]
    Targeting mitochondrial dysfunction to intervene in liver cancer.
    Maomao Li, Siyao Liang, Le Chang, Bingyan Lu, Jiahua Cheng, Tian Yang, Ying Wu, Yuhong Lyu, Xiaochan He, Changwu Yue.
      The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction. Mitochondria exhibit characteristics, such as decreased oxidative phosphorylation efficiency, abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect, as the core of energy metabolism and apoptosis regulation. Mutations in mitochondrial DNA (mtDNA) and dysregulation of mitochondrial autophagy (mitophagy) further enhance the invasive and metastatic capabilities of liver cancer. Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes, regulating calcium homeostasis, repairing mtDNA, and activating mitochondrial apoptotic pathways. Although these approaches have shown therapeutic effects, challenges persist, such as tumor heterogeneity, insufficient drug specificity, and drug resistance. Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction, development of targeted delivery systems, optimization of combination therapy regimens, and screening of biomarkers to provide new pathways for individualized treatment. With advances in technology, targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.
    Keywords:  Mitochondrial targeting; clinical translation; liver cancer therapy; mitochondrial metabolic reprogramming; mtDNA mutations; reactive oxygen species
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0180
  32. Biochim Biophys Acta Rev Cancer. 2025 Sep 10. pii: S0304-419X(25)00192-1. [Epub ahead of print] 189450
    Unraveling the role of mitochondrial dynamics in cancer stem cells: Molecular basis and therapeutic implications.
    Gaia Giannitti, Sara Marchesi, Riccardo Garavaglia, Ivan Preosto, Fabrizio Fontana.
      Many tumors consist of heterogeneous cell populations derived from a minority of cancer stem cells (CSCs), which possess distinct metabolic profiles that contribute to resistance against conventional anticancer therapy and increase the risk of tumor relapse. These unique CSC phenotypes are largely supported by altered mitochondrial function and turnover, regulated through continuous cycles of mitochondrial biogenesis, fission, fusion, and mitophagy. Consequently, understanding mitochondrial regulatory mechanisms in CSCs could reveal novel targets for cancer therapy. This article explores how mitochondrial dynamics contribute to CSC metabolic adaptation and drug resistance, alongside recent advances in the development of mitochondria-targeted drugs and their therapeutic usage.
    Keywords:  Cancer stem cells; Cancer therapy; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial fission and fusion; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189450
  33. Redox Biol. 2025 Sep 04. pii: S2213-2317(25)00372-6. [Epub ahead of print]86 103859
    Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
    Nada Ahmed Selim, Andrew P Wojtovich.
      Mitochondria are central to cellular function, acting as metabolic hubs that regulate energy transduction to communicate cellular status. A key component of this energetic regulation is the mitochondrial membrane potential (MMP), a charge separation across the inner mitochondrial membrane generated by the electron transport chain. Beyond MMP's canonical role in driving ATP synthesis, MMP acts as a dynamic signaling hub. MMP rapidly adjusts to acute changes in cellular energy demand and undergoes sustained modifications during developmental processes, such as neuronal remodeling. Changes in MMP influence reactive oxygen species (ROS) production, calcium handling, and mitochondrial quality control, enabling localized and time-sensitive regulation of cellular function. In neurons, changes in MMP coordinate synaptic plasticity by linking metabolic state to structural changes at synapses. This review highlights the non-canonical roles of MMP in signal integration, spatial organization, and stress adaptation, providing a broader framework for understanding mitochondrial contributions to health and disease.
    Keywords:  Bioenergetics; Metabolic specialization; Mitochondria; Mitophagy; Neuron plasticity
    DOI:  https://doi.org/10.1016/j.redox.2025.103859
  34. Curr Heart Fail Rep. 2025 Sep 13. 22(1): 24
    Recharging the Powerhouse: Mitochondrial Dysfunction and Therapy in Cardiorenal Syndrome Type 4.
    Edouard Long, Joshua M Heihre.
       PURPOSE OF REVIEW: Cardiorenal syndrome type 4 (CRS-4) is characterised by the development of cardiac dysfunction secondary to chronic kidney disease (CKD). This review outlines the pathophysiology of CRS-4, with a focus on the emerging role of mitochondrial dysfunction, and evaluates novel mitochondria-targeting therapeutics for CRS-4.
    RECENT FINDINGS: Current research has positioned mitochondrial dysfunction in cardiomyocytes as a key driver of CRS-4 pathophysiology, characterised by impaired adenosine triphosphate production, increased reactive oxygen species (ROS) generation, dysregulated mitophagy, altered mitochondrial biogenesis and dynamics, and bioenergetic malfunction. Currently licensed drugs, such as dapagliflozin and sacubitril/valsartan, have demonstrated mitoprotective effects in CRS-4, and numerous other therapies targeting mitochondria have proven efficacious in preclinical studies. However, real-world clinical trials are required to determine whether mitochondria represent a viable therapeutic target that offers meaningful clinical benefits to patients with CKD. There is increasing evidence that mitochondrial dysfunction is a key pathomechanism in the development of CRS-4. Mitochondrial-targeting therapies offer a novel mechanism-driven approach, with numerous showing preclinical promise. However, real-world clinical trials are required to determine their therapeutic potential.
    Keywords:  Cardiorenal syndrome; Chronic kidney disease; Heart failure; Inflammation; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1007/s11897-025-00713-0
  35. Immunology. 2025 Sep 12.
    The Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease.
    Marc Ayoub, Chris Abou Jaoude, Mohamad Ayoub, Aline Hamade, Mohamad Rima.
      Immunosenescence is the process of immune dysfunction and gradual deterioration of the immune system associated with aging, while cellular senescence is the stable cell cycle arrest that can occur in non-immune or immune cells in response to stress or damage. Immunosenescence significantly impacts both the innate and adaptive immune responses and is characterised by physical changes in lymphoid organs, as well as dysfunctions in cellular and molecular mechanisms. Key features of immunosenescence include T-cell dysfunction, thymic involution, B cell aging, an imbalance in the ratio of naïve to memory cells, chronic inflammation known as inflammaging and metabolic dysregulation. This decline in immune cell diversity and functionality contributes to various age-related diseases. Therefore, restoring a more 'juvenile' immune function in aging populations, through interventions targeting immunosenescence, holds promise for alleviating many age-related diseases and promoting healthier aging. In this review, we provide a comprehensive understanding of the interplay between the immune system and senescent cells in both healthy and disease contexts. We then dissect the immune dysfunction that occurs with aging, known as immunosenescence, and explore its impact on the health of elderly individuals. Finally, we discuss recent advances in targeting immune system aging to promote healthier longevity, with a special focus on Programmed Death-Ligand 1 (PD-L1), an emerging and promising target for therapeutic intervention.
    Keywords:  aging; chronic diseases; immune system; immunosenescence; inflammation; longevity
    DOI:  https://doi.org/10.1111/imm.70036
  36. RSC Med Chem. 2025 Aug 01.
    Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
    Pradeep Kodam, Vaishali Kumar, Paramita Pattanayak, Praharsh Vitta, Tanmay Chatterjee, Shuvadeep Maity.
      Mitochondrial dysfunction is one of the primary cellular conditions involved in developing Huntington's disease (HD) pathophysiology. The accumulation of mutant huntingtin protein with abnormal PolyQ repeats resulted in the death of striatal neurons with enhanced mitochondrial fragmentation. In search of neuroprotective molecules against HD conditions, we synthesized a set of isoxazole-based small molecules to screen their suitability as beneficial chemicals improving mitochondrial health. Systematic characterization of one of these isoxazole derivatives, C-5, demonstrated improved mitochondrial health with reduced apoptosis via rebalancing fission-fusion dynamics in HD condition. Gene and protein expression analysis confirmed that C-5 treatment enhanced the expression of mitochondrial fusion regulators (MFN1/2) via transcriptional upregulation of PGC-1α, a transcriptional co-activator controlling mitochondrial biogenesis. Collectively, this novel fusion agonist can potentially become a new therapeutic alternative for treating PolyQ-mediated mitochondrial dysfunction, a hallmark of HD pathology.
    DOI:  https://doi.org/10.1039/d5md00345h
  37. Front Cell Neurosci. 2025 ;19 1658074
    Human brain organoids: an innovative model for neurological disorder research and therapy.
    Hancheng Li, Junxiao Zhu, Jieyu Li, Yangkai Wu, Chaohua Luo, Yuting Huang, Jieru Wu, Wenhua Liu, Hongwu Wang, Zhixian Mo.
      The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D in vitro neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.
    Keywords:  disease modeling; human brain organoids; induced pluripotent stem cells; neurological disorders; therapeutic innovation
    DOI:  https://doi.org/10.3389/fncel.2025.1658074
  38. Clin Exp Immunol. 2025 Sep 02. pii: uxaf059. [Epub ahead of print]
    Learning from inborn errors of immunity and secondary immune deficiencies about vaccine immunogenicity, efficacy and safety.
    Nicholas E Peters, Adrian M Shields, Sophie Hambleton, Alex G Richter.
      Since its discovery in the late 18th Century, the role of vaccination in preventing death and disease has expanded across many infectious diseases and cancer. Key to our understanding of vaccine immunogenicity and efficacy is knowledge of the immune system itself. Inborn Errors of Immunity (IEI) represent a heterogeneous group of disorders characterised by impaired function of the immune system. Patients with IEI can have variable responses to vaccinations, depending on the nature and extent of the defect. Studies performed during the recent COVID-19 pandemic have brought unique insight into vaccine immunogenicity in individuals with IEI, knowledge that can be extended to the growing number of patients with secondary immunodeficiency arising from malignancy, organ transplantation, autoimmune conditions and their treatments. In this review, we describe vaccine immunogenicity in IEI alongside their equivalent secondary immunodeficiencies and discuss what lessons can be learned about immunisation strategies more broadly.
    Keywords:  Immunodeficiency Diseases; Infection; Vaccine
    DOI:  https://doi.org/10.1093/cei/uxaf059
  39. Clin Park Relat Disord. 2025 ;13 100389
    Digital speech assessments and machine learning for differentiation of neurodegenerative diseases.
    Kyurim Kang, Adonay S Nunes, Ilkay Yildiz Potter, Ram Kinker Mishra, Andrew Geronimo, Jamie L Adams, Catherine Isroff, Jesse E Wang, Ashkan Vaziri, Anne-Marie Wills, Alexander Pantelyat.
       Introduction: Speech impairment is a prevalent symptom of neurological disorders, including Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), with mechanisms and severity varying across and within conditions. Scalable digital health tools and machine learning (ML) are essential for diagnosing and tracking neurodegenerative disease.
    Methods: A total of 92 individuals were included in this study (21 PSP, 21 PD, 18 HD, 15 ALS, and 16 healthy elderly controls (CTR)). The Rainbow Passage was collected on a digital device and analyzed to extract 12 speech features representing speech production. A set of Elastic Net ML models was trained on these speech features to differentiate between diagnostic classes. A specialized Support Vector Machine ML model was then developed to differentiate PSP from PD.
    Results: Elastic Net models achieved a balanced accuracy of 77% over 5 diagnostic classes (group-specific sensitivities of 76% for PSP, 67% for PD, 83% for HD, 73% for ALS, and 88% for CTR) and 83% over 4 diagnostic classes (group-specific sensitivities of 83% for PSP-PD, 83% for HD, 73% for ALS, and 94% for CTR). The PSP vs. PD classification model demonstrated a balanced accuracy of 85%, with sensitivity of 88% for PSP and 82% for PD. Key speech features differentiated clinical conditions, with Total Voiced Time being the strongest positive feature for combined PSP-PD. In HD, ALS, and CTR, Ratio Extra Words, Pauses per Second, and Intelligibility were the most strongly differentiating features, respectively. Articulatory Rate emerged as the most distinguishing feature between PD and PSP.
    Conclusion: Our findings highlight the potential of digital health technology and ML in identifying and monitoring speech features in neurodegenerative diseases.
    Keywords:  Amyotrophic lateral sclerosis; Digital health; Huntington’s disease; Machine learning.; Parkinsons disease; Progressive supranuclear palsy; Speech analysis
    DOI:  https://doi.org/10.1016/j.prdoa.2025.100389
  40. Int J Mol Sci. 2025 Sep 05. pii: 8651. [Epub ahead of print]26(17):
    siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review.
    Alexei Shevelev, Natalia Pozdniakova, Evgenii Generalov, Olga Tarasova.
      RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of genetic defects. RNA-based drugs hold significant potential for treating a range of diseases. However, the transition of these therapies from laboratory research to clinical applications has encountered hurdles. This review explores the composition and outcomes of clinical trials for various modified short RNA drugs. We detail their mechanisms of action, delivery systems-with a focus on lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates-and clinical efficacy in treating conditions such as transthyretin (TTR) amyloidosis. Our analysis reveals that while several RNAi-based drugs have achieved clinical approval, a critical unmet need remains: advanced delivery systems capable of precisely targeting diverse tissues, particularly outside the liver. We also underscore the importance of rigorous target validation utilising sophisticated bioinformatics tools and in vitro/in vivo assays to minimise off-target effects and ensure robust therapeutic efficacy. This review proposes a novel framework for optimising RNA drug development, emphasising the crucial interplay between delivery strategies, target specificity, and understanding disease-specific target biology.
    Keywords:  GalNAc conjugates; LNPs; RNA interference; RNA therapy; gene therapy; siRNA
    DOI:  https://doi.org/10.3390/ijms26178651
  41. Proceedings (IEEE Int Conf Bioinformatics Biomed). 2024 Dec;2024 4561-4563
    Aligning Orphanet Classification to Identify Disease Characteristics among Rare Disease Clusters.
    Sungrim Moon, Jessica Maine, Ewy Mathe, Qian Zhu.
      Understanding the underlying etiologies of rare diseases may facilitate research across multiple conditions, enabling basket trail design and drug repurposing. In this study, we aligned clusters of rare diseases with Orphanet classifications to represent their shared etiologies and establish a foundation for further investigation on underly biological mechanism discovery. By utilizing the linearized Orphanet categories, we connected 35 clusters of rare diseases into 18 classifications. Significant associations were found between the categories "Rare Developmental Defects During Embryogenesis" and "Rare Inborn Errors of Metabolism" and the clusters in this study, suggesting that many rare diseases originating in the prenatal period or related to metabolism may present a substantial opportunity for success in future investigation.
    Keywords:  Orphanet classification; disease cluster; rare disease; rare disease characteristics
    DOI:  https://doi.org/10.1109/bibm62325.2024.10822379
  42. Sci Signal. 2025 Sep 09. 18(903): eaec0130
    APOE ε4 on immunity.
    Leslie K Ferrarelli.
      APOE ε4 dysregulates systemic immunity, creating vulnerability for neurodegenerative disease.
    DOI:  https://doi.org/10.1126/scisignal.aec0130
  43. Bioorg Chem. 2025 Aug 29. pii: S0045-2068(25)00815-6. [Epub ahead of print]165 108935
    Lipid-conjugated nucleoside prodrugs for antiviral therapy.
    Hyesu Oh, Hyeonhwa Lee, Jinha Yu.
      Nucleoside analogs have served as the cornerstone of antiviral therapy by acting as antimetabolites that disrupt viral DNA or RNA synthesis, thereby effectively inhibiting viral replication. Despite their clinical success, many nucleoside-based antivirals suffer from intrinsic limitations such as poor lipophilicity, low membrane permeability, and rapid metabolic degradation, all of which compromise oral bioavailability and therapeutic efficacy. To address these challenges, lipid conjugation has emerged as a promising prodrug strategy that enhances pharmacokinetic properties, improves cellular uptake, and enables targeted delivery. This approach not only improves drug absorption and stability but also offers the potential to reduce toxicity and broaden antiviral indications. In this review, we summarize the design strategies, pharmacological benefits, and antiviral performance of lipid-conjugated nucleoside prodrugs, with a focus on FDA-approved agents. By analyzing recent developments in this field, we aim to provide insights that may inform the rational design of next-generation lipid-based antiviral therapeutics.
    Keywords:  Antiviral; Lipid conjugate; Nucleoside
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108935
  44. Metabolomics. 2025 Sep 09. 21(5): 134
    MetabOCT: a clinical trial looking for a metabolomic signature predicting the onset of Leber's hereditary optic neuropathy in healthy MtDNA mutations carriers.
    Christophe Orssaud, Pascal Reynier.
       INTRODUCTION: The definition of Leber's hereditary optic neuropathy (LHON) does not take into account a preclinical phase during which the thickness of retinal nerve fiber layer (RNFL) is increased, prior to optic nerve atrophy, reducing the chances of visual recovery.
    OBJECTIVES: Search for a metabolomic signature characterizing this preclinical phase and identify biomarkers predicting the risk of LHON onset.
    METHODS AND RESULTS: The blood and tear metabolomic profiles of 90 asymptomatic LHON mutation carriers followed for one year will be explored as a function of RNFL thickness and compared to those of a healthy control.
    CONCLUSION: Identifying pre-clinical biomarkers would open a window for clinical trials.
    Keywords:  Clinical trial; Disease onset and progression; Leber hereditary optic neuropathy (LHON); Metabolomics; Retinal nerve fiber layer (RNFL)
    DOI:  https://doi.org/10.1007/s11306-025-02328-x
  45. Chem Biodivers. 2025 Sep 09. e02369
    The Essence of Nature Can be the Simplest (6)-Lifespan: Determined by Extracellular Fenton Chemistry.
    Xuemei Niu.
      Understanding the determinants of lifespan is a central objective in biology. Lifespan is shaped by dynamic, stage-specific changes in metabolism, energy allocation, and genome integrity. Heart rate serves as a physiological marker that reflects both life stage and metabolic state. Recent studies suggest that all cells perform extracellular Fenton chemistry for holistic energy to power the heartbeat and maintain body temperature, and nucleotides are a source of the reaction substrates in this process. This article synthesizes current evidence on the dynamic changes in heart rate, metabolic rate, and metabolic pathways across key developmental and aging stages. We propose that human lifecycle can be conceptualized as a progressive decline in extracellular Fenton chemistry: beginning with the rapid fetal heartbeat driven by glycolysis-mediated extracellular Fenton activity, transitioning through a developmental shift toward increased intracellular ATP production and declining heart rate, and culminating in the cessation of cardiac activity during aging. The Fenton reactions mediated by DNA in cells lead to mitochondrial formation as a thermochemical restructuring product, analogue to charcoal production. Hutchinson-Gilford progeria syndrome (HGPS) represents an extreme case of persistently elevated extracellular Fenton chemistry. This study highlights the energetic and chemical mechanisms underlying the unifying theme of irreversible properties of life.
    Keywords:  Hutchinson‐Gilford progeria syndrome; extracellular Fenton chemistry; genome size; life stage; lifespan; mitochondrial formation
    DOI:  https://doi.org/10.1002/cbdv.202502369
  46. Neurobiol Dis. 2025 Sep 04. pii: S0969-9961(25)00301-8. [Epub ahead of print]215 107084
    The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
    L Daniel Estrella, Xiaoke Xu, Collin White, Jane E Manganaro, Lexi Sheldon, Trey Farmer, Kelly L Stauch.
      Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (ParkinW402A, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while ParkinW402A surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, ParkinW402A did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of ParkinW402A led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing ParkinW402A. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.
    Keywords:  Alzheimer's disease; Mitophagy; Parkin; ParkinW402A; Phosphorylated Tau; Synapse; Synaptic mitochondria; Tauopathy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107084
  47. Seizure. 2025 Aug 26. pii: S1059-1311(25)00225-0. [Epub ahead of print]132 98-109
    Tough to treat: What we know about managing PCDH19-related epilepsy - Systematic review.
    Aleksandra Tobiasz, Monika Hager, Julia Dębowska, Agata Jaunich, Justyna Paprocka.
       BACKGROUND: PCDH19-related epilepsy is a rare, X-linked developmental and epileptic encephalopathy that primarily affects heterozygous females. It is caused by pathogenic variants in the PCDH19 gene, encoding protocadherin-19, a calcium-dependent adhesion protein involved in neurodevelopment. The disorder's hallmark is cellular interference, leading to brain mosaicism and clinical features including early-onset clustered focal seizures, cognitive impairment, and frequent comorbidity with autism.
    OBJECTIVE: This review synthesizes current evidence on treatment approaches for PCDH19-related epilepsy, covering conventional anti-seizure medications, adjunctive therapies, and non-pharmacological interventions, while highlighting emerging strategies and research gaps.
    METHODS: A systematic literature search was conducted in PubMed and Scopus (January 2008 - April 2025).
    RESULTS: 27 studies were included, involving patients with genetically or clinically confirmed PCDH19-related epilepsy and reported treatment outcomes. The condition is often pharmacoresistant, with highly variable responses. Levetiracetam, especially when initiated early, showed the most consistent seizure reduction, followed by clobazam and potassium bromide. Topiramate and stiripentol showed potential in isolated reports. Carbamazepine was often ineffective or worsened seizures. Adjunctive agents - including corticosteroids, ganaxolone - had variable efficacy; ganaxolone showed promise in recent trials. Non-pharmacological interventions, like vagus nerve stimulation, ketogenic diet, and temporal lobectomy, reduced seizures in some cases but lacked standardized evidence.
    CONCLUSIONS: Treatment remains challenging due to clinical heterogeneity and limited high-quality data. Early, individualized, multimodal approaches appear most beneficial. There is a need for genotype-informed, multicenter trials and standardized outcome measures to guide evidence-based care.
    Keywords:  Anakinra; Anti-seizure medications; Ganaxolone; Genetic epilepsy syndromes; PCDH19-related epilepsy; X-linked epilepsy
    DOI:  https://doi.org/10.1016/j.seizure.2025.08.030
  48. Hum Genet. 2025 Sep 08.
    Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA replication defects.
    Xue Gao, Ying Ma, Wei-Qian Wang, Guo-Jian Wang, Kun Yang, Jin-Cao Xu, Sha-Sha Huang, Xiang Wang, Li-Min Hu, Xi Wang, Qiu-Quan Wang, Zhen-Dong Wang, Ming-Yu Han, Pu Dai, Yong-Yi Yuan.
      Recessive variants in TWNK cause syndromes arising from mitochondrial DNA (mtDNA) depletion. Hearing loss is the most prevalent manifestation in individuals with these disorders. However, the clinical and pathophysiological features have not been fully elucidated. In this study, we collected five cases of hearing loss carrying bi-allelic TWNK variants from three unrelated Chinese families and identified two cases with isolated auditory neuropathy (AN) and three cases segregating with Perrault syndrome, characterized by AN, global developmental delay, and ovarian dysgenesis in females. All patients with cochlear implantation (CI) show poor speech discrimination outcomes, suggesting that the defect involves post-synaptic sites. In the mouse inner ear, Twinkle was immunolocalized to inner phalangeal cells and spiral ganglion neurons. Additionally, the broad expression pattern of Twinkle was observed in the auditory cortex, which to some extent explains the poor rehabilitation outcomes following CI. At the cellular level, Twinkle is localized at the mtDNA membrane, and the p.(Arg609AlaTer6) variant prevents the protein from reaching the mtDNA while the p.(Arg65Trp) variant exhibits a similar localization to the wild type, indicating a second mechanism of action. RT-PCR results indicated that the canonical transcript was abundant in the inner ear, while the shorter transcript was more abundant in the brain. Our findings revealed that bi-allelic TWNK variants lead to AN, which can be either syndromic or non-syndromic, with the molecular pathogenesis involving defects in mtDNA replication at post-synaptic sites. Patients with TWNK-associated conditions are not ideal candidates for CI and gene therapy may offer a solution for hearingrehabilitation.
    DOI:  https://doi.org/10.1007/s00439-025-02774-6
  49. Pediatr Ann. 2025 Sep;54(9): e330-e335
    Incorporating Rare Disease Growth Monitoring Into Routine Practice to Improve Early Recognition and Diagnosis of Genetic Conditions.
    Natasha Shur, Seth Berger, Andrew Dauber, Carrie Daymont.
      Routine growth monitoring includes plotting children on World Health Organization or Centers for Disease Control and Prevention charts that have primarily been developed on typical, healthy populations. However, it is advisable to plot children with known genetic conditions on specialized growth curves (SGCs) when they are available. In this review, we highlight the most common genetic conditions for which SGCs are available, clinical reasons to use SGCs based on specific rare diseases, and how these SGCs can be found. In addition, we raise awareness of the limitations of SGCs and future directions to improve rare disease growth curve accessibility and ease of use into general pediatric practice.
    DOI:  https://doi.org/10.3928/19382359-20250707-05
  50. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2517556122
    DNA polymerase α-primase can function as a translesion DNA polymerase.
    Ryan Mayle, Roxana Georgescu, Michael E O'Donnell.
      Replication of cellular chromosomes requires a primase to generate short RNA primers to initiate genomic replication. While bacterial and archaeal primase generate short RNA primers, the eukaryotic primase, Polα-primase, contains both RNA primase and DNA polymerase (Pol) subunits that function together to form a >20 base hybrid RNA-DNA primer. Interestingly, the DNA Pol1 subunit of Polα lacks a 3'-5' proofreading exonuclease, contrary to the high-fidelity normally associated with DNA replication. However, Polδ and Polε synthesize the majority of the eukaryotic genome, and both contain 3'-5' exonuclease activity for high fidelity. Nonetheless, even the small amount of DNA produced by Pol1 in each of the many RNA/DNA primers during chromosome replication adds up to tens of millions of nucleotides in a human genome. Thus, it has been a longstanding question why Pol1 lacks a proofreading exonuclease. We show here that Polα is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Polα evolved to bypass these common template lesions when they are encountered during chromosome replication. Additionally, we show a unique ability of replication factor C (RFC) to stimulate Polδ lesion bypass, independent of its sliding clamp. This suggests that there may be a coordination between Polδ and RFC that does not involve RFC loading of PCNA.
    Keywords:  DNA polymerase alpha; DNA repair; DNA replication; DNA translesion bypass; primase
    DOI:  https://doi.org/10.1073/pnas.2517556122
  51. Behav Brain Res. 2025 Sep 05. pii: S0166-4328(25)00392-4. [Epub ahead of print]495 115805
    Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway.
    Weigang Luo, Wei Bu, Guisong Zhang, Yujuan Dong, Yuling Wang, Jinyang Wang, Cuicui Liu, Xiaokai Hu, Yanan Jia, Huiling Ren.
       BACKGROUND: Mitochondrial dysfunction is considered to be an important pathogenesis of cognitive impairment in Alzheimer's disease(AD). Activation of Nrf2 can improve cognitive impairment in AD mice, but the underlying mechanism remains to be elucidated. This research aims to investigate the intrinsic molecular mechanism of Nrf2 in mitochondrial biogenesis related to cognitive impairment of AD mice.
    METHODS: APP/PS1 mice were used as AD model mice, and Nrf2 down-regulated mouse model was established by injecting lentivirus into hippocampus. Morris water maze test was used to evaluate the learning and memory ability of mice. The biochemical assays were used to detect the expression of Nrf2, mitochondrial biogenesis-related genes, and Aβ protein.Transmission electron microscopy was used to observe the number of mitochondria and synaptic structure in neurons. Chromatin immunoprecipitation was used to observe the binding of Nrf2 protein to the PGC1α promoter; Co-Immunoprecipitation was used to observe the interaction between PPARγ protein and PGC1α protein.
    RESULTS: Downregulation of Nrf2 reduced mitochondrial biogenesis, aggravated Aβ protein deposition and synaptic damage, and in turn aggravated cognitive impairment in mice. Compared with control mice, AD model mice had reduced levels of Nrf2, PPARγ, PGC1α, NRF1, TFAM protein, mitochondrial number and MAP2, increased Aβ protein deposition, and worsened synaptic damage and cognitive impairment. Lentivirus-induced Nrf2 downregulation downregulates PPARγ, PGC1α, NRF1, and TFAM protein expression, reduces mitochondrial number and MAP2 levels, and aggravates Aβ protein deposition, synaptic damage, and cognitive impairment. Nrf2 protein bound to the PGC1α gene promoter, and PPARγ protein interacted with PGC1α protein.
    CONCLUSION: Nrf2 can directly regulate PGC1α transcription, and can also regulate PPARγ followed by binding to the PGC1α protein, thereby modulating mitochondrial biogenesis.Nrf2 downregulation reduces the expression of PPARγ and PGC1α proteins, thereby reducing their interaction. This suppression impairs mitochondrial biogenesis, exacerbates mitochondrial dysfunction, intensifies Aβ deposition and synaptic damage, and ultimately worsens cognitive impairment in AD mice.
    Keywords:  Alzheimer's disease; Cognitive impairment; Mitochondrial biogenesis; Nrf2; PGC1α; PPARγ
    DOI:  https://doi.org/10.1016/j.bbr.2025.115805
  52. Adv Healthc Mater. 2025 Sep 07. e01540
    Drug Delivery Strategies for the Lower GI Tract: A Review.
    Britt De Munter, Jef Brebels, Arn Mignon.
      The lower gastrointestinal (GI) tract is affected by a range of diseases, including colorectal cancer and inflammatory bowel disease, among others. Effective treatment of these conditions requires drug delivery systems (DDSs) capable of precise targeting. While pH- and enzyme-sensitive DDSs are the most used, they often suffer from premature drug release and target specificity, limiting their efficacy. To address this challenge, researchers are exploring alternative triggers, such as reactive oxygen species (ROS), reduction-oxidation (redox) and modified enzyme- and pH-responsive systems, to enhance specificity and performance. This review highlights the latest advancements and current limitations in targeted drug delivery strategies for the lower GI tract, aiming to improve therapeutic outcomes and the quality of life for patients with intestinal disorders.
    Keywords:  colorectal cancer; lower GI tract; physical drug delivery; smart drug delivery; stimuli responsive
    DOI:  https://doi.org/10.1002/adhm.202501540
  53. J Affect Disord. 2025 Sep 08. pii: S0165-0327(25)01710-0. [Epub ahead of print] 120268
    Alterations of telomere length and mitochondrial DNA copy number in depressive adolescents with non-suicidal self-injury.
    Dong-Ni Wen, Jia-Hui Hu, Ting Ji, Xing-Yu Xiao, Chengcheng Xin Huang, Ji-Fan Zhang, Wei-Biao Feng, Shuo Zheng, Zi-Yi Xiong, Cai-Lan Hou.
       BACKGROUND: NSSI among adolescents is highly prevalent and serves as a significant indicator of subsequent suicidal ideation and behaviors. Recent studies have demonstrated a connection between accelerated cellular aging and a range of psychiatric conditions. The present study explored whether depressive adolescents with NSSI exhibited alterations in telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), both critical markers of cellular aging.
    METHODS: The study comprised 70 depressive adolescents with NSSI (84.3 % female) and 34 depressive adolescents without NSSI (61.8 % female). The TL and mtDNAcn were determined by calculating the ratio of telomere repeats to the single-copy gene β-globin, or by measuring the relative quantity of mtDNA compared to β-globin.
    RESULTS: In this study, the NSSI group demonstrated significantly shorter TL than the non-NSSI group (P < 0.01). This difference persisted after controlling for age, family history, sex, suicidality, childhood maltreatment, depressive symptoms, and psychotic symptoms (P = 0.005). Furthermore, regression analysis showed that TL was considerably shorter in the female NSSI group than in the non-NSSI group after adjusting for age, family history, suicidality, childhood maltreatment, depressive symptoms, and psychotic symptoms (P < 0.001). After controlling for these variables, mtDNAcn was markedly reduced in the male NSSI group compared to the non-NSSI group (P < 0.001).
    CONCLUSIONS: This work is, to our knowledge, the first to demonstrate that NSSI correlates with alterations in TL and mtDNAcn. These findings suggest that molecular pathways associated with aging may play a crucial role in the pathogenesis of NSSI.
    Keywords:  Adolescent depression; Mitochondrial DNA copy number; NSSI; Telomere length
    DOI:  https://doi.org/10.1016/j.jad.2025.120268
  54. Psychopharmacology (Berl). 2025 Sep 10.
    Alteration in hippocampal mitochondria ultrastructure and cholesterol accumulation linked to mitochondrial dysfunction in the valproic acid rat model of autism spectrum disorders.
    Paula D Prince, Martín G Codagnone, Javier A W Opezzo, Juan S Adán Areán, Christian Höcht, Nathalie Arnal, Silvia Alvarez, Sandra Zárate, Analía Reinés.
       RATIONALE: Autism spectrum disorders (ASD) are a group of neurodevelopmental and multifactorial conditions with cognitive manifestations. The valproic acid (VPA) rat model is a well-validated model that successfully reproduces the behavioral and neuroanatomical alterations of ASD. Previous studies found atypical brain connectivity and metabolic patterns in VPA animals: local glucose hypermetabolism in the prefrontal cortex, with no metabolic changes in the hippocampus.
    AIM: This study aimed to explore mitochondrial structural features, lipid content, and functionality in the hippocampus and cerebral cortex in the VPA model.
    METHODS: On embryonic day 10.5, pregnant Wistar rats were injected with VPA (450 mg/kg) or saline solution. In the hippocampus and cerebral cortex of male offspring (postnatal day 35), the mitochondrial structure was evaluated by transmission electron microscopy, oxidized/reduced glutathione was determined by high-performance liquid chromatography, mitochondrial membrane cholesterol, and phospholipids were determined by thin-layer chromatography, and oxygen consumption and ATP synthesis were measured in isolated mitochondria.
    RESULTS: Mitochondrial increased oxygen consumption and decreased ATP production, increased oxidized/reduced glutathione, cholesterol accumulation in mitochondrial membrane and altered mitochondrial structure were found in the hippocampus of VPA animals. All parameters were preserved in the cerebral cortex of VPA rats.
    CONCLUSIONS: These findings reveal brain region-specific mitochondrial structural and functional alterations in VPA-treated animals, with preserved mitochondria in regions with high glucose demand and impaired mitochondria in metabolically normal areas. Moreover, cholesterol accumulation in hippocampal mitochondrial membranes is a potential cause of mitochondrial dysfunction, contributing to a prooxidant state.
    Keywords:  Autism spectrum disorders; Brain connectivity; Hippocampus; Mitochondria; Mitochondrial lipid profile; Prefrontal cortex; Valproic acid
    DOI:  https://doi.org/10.1007/s00213-025-06899-4
  55. BMC Neurol. 2025 Sep 09. 25(1): 380
    MRI-negative cerebellar syndrome caused by medication-induced magnesium deficiency: a case report.
    Marvin Jüchtern.
       BACKGROUND: Cerebellar pathologies in adults can have a wide range of hereditary, acquired and sporadic-degenerative causes. Due to the frequency in daily hospital, especially intensive care, settings, electrolyte imbalances are an important, yet rare differential diagnosis. The hypomagnesemia-induced cerebellar syndrome (HiCS) constitutes a relevant disease entity with clinical and morphological variability due to a potential progression of symptoms and a promising causal treatment. Cases of HiCS without imaging abnormalities are scarcely reported and pose a particular challenge to practitioners.
    CASE PRESENTATION: A 68-year-old female patient presented with subacute onset gait impairment and concomitant vertigo. Gaze induced nystagmus, ataxia and limb dysmetria became objectifiable. A broad diagnostic workup, including liquor puncture, whole-body positron emission tomography, antibody serology and most notably thin-layer magnetic resonance imaging remained unconclusive. Only a more detailed examination of chronic hypokalemia with the detection of severe magnesium deficiency under the intake of proton pump inhibitors and a recent gastrointestinal infection found a causal treatment through electrolyte substitution.
    CONCLUSIONS: Electrolyte disorders as a reason for central nervous pathologies remain underdiagnosed and underestimated, as a heterogeneous clinical appearance, the growing number of defined cerebellar diseases and, like in our case, lacking imaging abnormality aggravatingly contrast with a high intake prevalence of triggering medication. The presence of diarrhea or vomiting, electrolyte shortage, cardiac arrhythmia, alcoholism and particularly the intake of proton pump inhibitors in patients with cerebellar symptoms should result in thorough electrolyte diagnostics. Early recognition of this causally treatable cerebellar syndrome and prompt discontinuation of triggering medication are crucial to improve the often poor prognosis.
    Keywords:  Cerebellar syndrome; Hypomagnesemia; MRI; Nystagmus; Proton pump inhibitors
    DOI:  https://doi.org/10.1186/s12883-025-04399-8
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