bims-polgdi Biomed News
on POLG disease
Issue of 2026–02–01
43 papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.
  2. Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease.
  3. Mitochondrial DNA damage in HIV infection: a mechanistic driver of immunometabolic dysfunction and chronic inflammation.
  4. [Super-refractory status epilepticus caused by hereditary mitochondrial disease].
  5. Mitochondrial epigenetic mechanisms in cancer: an updated overview.
  6. HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.
  7. Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
  8. Mitochondrial Myopathy, Lactic Acidosis, and Stroke-Like Episodes Combined with Diabetes: A Case Report.
  9. Mitochondria as sources and targets of cellular signaling.
  10. Mitochondrial DAMPs as a critical driver in the development of acute graft versus host disease and emerging mitochondria targeted therapeutic strategies.
  11. No Association Between Autism Spectrum Disorder and Mitochondrial DNA Variants: A Comprehensive Genetic Study in Trakya Population.
  12. Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.
  13. Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
  14. Systematic evaluation of mitochondrial morphology regulators for amelioration of neuronal α-synucleinopathy.
  15. Meiotic purification of dysfunctional mitochondria in mouse oocytes.
  16. ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
  17. ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.
  18. Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Aging: Current Insights and Therapeutic Advances.
  19. Bioactive Peptide C248 of PRDX4 Ameliorates the Function of Testicular Leydig Cells via Mitochondrial Protection.
  20. Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
  21. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
  22. Mitochondrial and Antioxidant Activity as the Basis of the Neuroprotective Effect of Potential Multitarget Drugs for the Treatment of Neurodegenerative Diseases.
  23. Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
  24. Mitochondrial dysfunction-induced PANoptosis: Mechanisms, triggers, and disease implications.
  25. Unveiling a Novel MT-TS1 m.7479G>A in Mitochondrial Diabetes: The Critical Role of mtDNA Sequencing in Atypical Cases.
  26. SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
  27. Taurine intake ameliorates lactic acidosis and hyperferritinemia occurring after mRNA SARS-CoV-2 vaccination in a patient with β-thalassemia trait: a case report and review of literature.
  28. Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
  29. Strategies for blood-brain barrier rejuvenation and repair.
  30. Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
  31. The language of cytokines: Decoding immune signals with information theory.
  32. Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.
  33. Blood-Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism.
  34. Mitochondrial Adaptations Underlying Tetraploidization in Human Cancer, Fungal, and Yeast Models.
  35. Bidirectional Regulation of NLRP3 Inflammasome and Mitochondrial Quality Control in Sepsis: Mechanisms and Therapeutic Implications.
  36. Aptamer-Based Delivery of Genes and Drugs Across the Blood-Brain Barrier.
  37. Pleiotropic regulation of mitochondrial translational factors in governing proliferation, apoptosis and metastasis during cancer progression.
  38. Chitosan nanoparticles for brain targeted nose-to-brain drug delivery in neurodegenerative disease: a comprehensive exploration of advances, limitations and future prospects.
  39. Incomplete penetrance in inborn errors of immunity: A skeleton in the closet-The sequel.
  40. Novel Clinical Insights From a Swedish RFC1 Spectrum Disorder Cohort.
  41. Measuring the health benefits of genome and exome sequencing: a systematic review of economic evaluations.
  42. Generating cerebellar organoids from pluripotent stem cells.
  43. A novel amide-quinoline salt-based mitochondrial-targeted fluorescent probe for detecting pH in cells and water samples.
  1. Genes (Basel). 2026 Jan 13. pii: 82. [Epub ahead of print]17(1):
    Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.
    Magan N Pittman, Mary Beth Nelsen, Marlo K Thompson, Aishwarya Prakash.
      Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP production by OXPHOS generates reactive oxygen species (ROS) that pose a significant threat to the nearby mtDNA. To counter these insults, neurons rely on base excision repair (BER), the principal mechanism for removing oxidative and other small, non-bulky base lesions in nuclear and mtDNA. BER involves a coordinated enzymatic pathway that excises damaged bases and restores DNA integrity, helping maintain mitochondrial genome stability, which is vital for neuronal bioenergetics and survival. When mitochondrial BER is impaired, mtDNA becomes unstable, leading to ETC dysfunction and a self-perpetuating cycle of bioenergetic failure, elevated ROS levels, and continued mtDNA damage. Damaged mtDNA fragments can escape into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways and inflammasome complexes. Chronic activation of these pathways drives sustained neuroinflammation, exacerbating mitochondrial dysfunction and neuronal loss, and functionally links genome instability to innate immune signaling in neurodegenerative diseases. This review summarizes recent advancements in understanding how BER preserves mitochondrial genome stability, affects neuronal health when dysfunctional, and contributes to damage-driven neuroinflammation and neurodegenerative disease progression. We also explore emerging therapeutic strategies to enhance mtDNA repair, optimize its mitochondrial environment, and modulate neuroimmune pathways to counteract neurodegeneration.
    Keywords:  base excision repair; damage associated molecular patterns; mitochondrial DNA; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3390/genes17010082
  2. Cells. 2026 Jan 10. pii: 127. [Epub ahead of print]15(2):
    Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease.
    Beatrisa Rimskaya, Ekaterina Kropocheva, Elza Shchukina, Egor Ulashchik, Daria Gelfenbein, Lidiya Lisitskaya, Vadim Shmanai, Svetlana Smirnikhina, Andrey Kulbachinskiy, Ilya Mazunin.
      Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report the first successful mitochondrial import of a catalytically active RNA-guided prokaryotic Argonaute protein from the mesophilic bacterium Alteromonas macleodii (AmAgo). By guiding AmAgo to the single-stranded D- or R-loop region of mtDNA using synthetic RNA guides, we observed a nearly threefold reduction in mtDNA copy number in human cell lines. This proof of concept study demonstrates that a bacterial Argonaute can remain active within the mitochondrial environment and influence mtDNA levels. These findings establish a foundational framework for further development of programmable systems for mitochondrial genome manipulation.
    Keywords:  DNA editing; mitochondria; mtDNA copy number; prokaryotic Argonaute proteins
    DOI:  https://doi.org/10.3390/cells15020127
  3. Front Immunol. 2025 ;16 1722463
    Mitochondrial DNA damage in HIV infection: a mechanistic driver of immunometabolic dysfunction and chronic inflammation.
    Li Ma, Xiaolei Wang, Huanbin Xu.
      Mitochondria are central regulators of cellular metabolism and immunity. Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with metabolic complications and chronic inflammation, yet the underlying mechanisms remain incompletely understood. Increasing evidence implicates mitochondrial dysfunction-particularly mitochondrial DNA (mtDNA) damage-as a key contributor. HIV/SIV infection and ART both compromise mtDNA integrity through direct and indirect mechanisms, leading to impaired oxidative phosphorylation, dysregulated reactive oxygen species, and altered mitochondrial dynamics. These changes contribute to immune cell bioenergetic failure, T cell exhaustion, and cytosolic release of mtDNA, which can activate cGAS-STING and NLRP3 pathways to sustain chronic inflammation. In addition, certain ART drugs, especially early nucleoside reverse transcriptase inhibitors, inhibit polymerase γ, driving mtDNA depletion and mutation accumulation that underlie toxicities such as lipodystrophy, neuropathy, and accelerated aging. Monitoring mtDNA copy number and mutational burden may offer useful biomarkers of immune recovery and treatment-related complications. Targeting mitochondrial protection and repair represents a promising strategy to improve long-term outcomes in people living with HIV.
    Keywords:  HIV; antiretroviral therapy; cGAS-STING; immunometabolism; inflammaging; mtDNA; oxidative stress
    DOI:  https://doi.org/10.3389/fimmu.2025.1722463
  4. Ugeskr Laeger. 2026 Jan 26. pii: V07250609. [Epub ahead of print]188(5):
    [Super-refractory status epilepticus caused by hereditary mitochondrial disease].
    Niels Bach Sørensen, Kristina Stamenkovic, Ellen Hollands Steffensen, Inge Ring Kofoed.
      In this case report, we present an 11-year-old girl who developed super-refractory status epilepticus (SRSE) after focal seizures. Initial investigations, including MRI, CSF analysis, and autoimmune panels, were normal. Despite extensive treatment with several anti-seizure medications, immunotherapy, attempt of treatment with ketogenic diet and anesthetic infusions targeting burst-suppression, no improvement occurred. Trio whole genome sequencing revealed compound heterozygous pathogenic variants in POLG, confirming mitochondrial disease. Due to poor prognosis and deterioration, treatment was withdrawn, and she died in ICU.
    DOI:  https://doi.org/10.61409/V07250609
  5. Front Cell Dev Biol. 2025 ;13 1720652
    Mitochondrial epigenetic mechanisms in cancer: an updated overview.
    Andrea Stoccoro, Fabio Coppedè.
      Mitochondria are central organelles in regulating apoptosis, cellular metabolism, metabolite biosynthesis, energy production, and overall cellular homeostasis. Over the past years, abundant evidence has shown that mitochondrial dysfunction and the resulting metabolic reprogramming profoundly influence key hallmarks of tumor development, including initiation, progression, angiogenesis, and metastasis, playing a role also in therapeutic resistance. Consequently, mitochondria have emerged as a promising target for anticancer therapy. Beyond well-known mutational abnormalities in the mitochondrial genome, recent studies indicate that altered mitochondrial epigenetic mechanisms could also contribute to cancer etiology. In the current review, we present a brief, up-to-date overview of the literature on mitochondrial epigenetic regulation in cancer. We will focus on the main characterized mitoepigenetic mechanisms, namely mitochondrial DNA (mtDNA) methylation and activity of mtDNA-encoded non-coding RNAs. We also consider bidirectional epigenetic crosstalk between the nucleus and mitochondria, whereby metabolites and signaling pathways coordinate chromatin states and mitochondrial function. Collectively, available evidence links mitoepigenetic alterations to tumor progression and pharmacoresistance, nominating these pathways as tractable targets for pharmacological intervention.
    Keywords:  cancer; epigenetics; histone modifications; mitoepigenetics; mtDNA methylation; non-coding RNA
    DOI:  https://doi.org/10.3389/fcell.2025.1720652
  6. Front Pharmacol. 2026 ;17 1705666
    HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.
    Liting Xu, Min Zeng.
      High temperature requirement protein A2 (HtrA2/Omi), a key regulator of mitochondrial quality control, plays a pivotal role in determining cell fate through its subcellular localization, whether mitochondrial or cytosolic. Growing evidence links the absence or dysfunction of HtrA2 to the pathogenesis of neurodegenerative diseases. This review examines the structure and function of HtrA2, highlights its transcriptional regulators, explores its involvement in neurodegeneration, and outlines the currently identified agonists and inhibitors, offering new insights for developing HtrA2/Omi as a potential therapeutic target for neurodegenerative disorders.
    Keywords:  HtrA2; UCF-101; apoptosis; mitochondria; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fphar.2026.1705666
  7. Mol Cancer. 2026 Jan 27.
    Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
    Hongling Zhong, Renjie Pan, Yuzhen Ouyang, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Hucheng Li, Tianfang Peng, Pan Chen.
      Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.
    Keywords:  Cancer Metabolism Reprograming; Mitochondrial DNA (mtDNA) Damage; Mitochondrial Homeostasis; Mitochondrial-Targeted Therapies; Tumor Microenvironment
    DOI:  https://doi.org/10.1186/s12943-026-02571-3
  8. Endocr Metab Immune Disord Drug Targets. 2026 Jan 15.
    Mitochondrial Myopathy, Lactic Acidosis, and Stroke-Like Episodes Combined with Diabetes: A Case Report.
    Shumin Zhou, Yongjun Tian, Fengying Liu, EnZhu Wu, Xiaodan Feng.
       INTRODUCTION: Mitochondrial diseases refer to a group of hereditary disorders involving damage to high-energy-consuming tissues, such as muscles, nerves, and the heart. Mitochondrial DNA (mtDNA) mutations account for most cases, but the timely identification and treatment of these conditions remain challenging.
    CASE PRESENTATION: This report describes a case of a 36-year-old male patient who was diagnosed with diabetes in 2017 and subsequently experienced recurrent diabetic ketoacidosis and seizures. On May 20, 2022, he presented with cognitive impairment, unsteady gait, and an elevated blood lactate level. Brain MRI and mitochondrial gene sequencing on peripheral blood cells revealed destructive neuronal lesions and a mutation of m.3243A>G in the MT-TL1 gene with a ratio of 6.04%, which supported the diagnosis of mitochondrial encephalomyopathy associated with lactic acidosis and stroke-like episodes (MELAS) and mitochondrial diabetes mellitus (MDM). Treatment with insulin, fluid replacement, ketoacidosis correction, diazepam, and phenobarbital relieved most symptoms. However, his blood glucose was poorly controlled. Four months after discharge, the patient suffered a relapse. Although therapies to combat infection, reduce blood glucose, and correct ketoacidosis improved his condition, the patient died in 2023 due to cerebral infarction.
    CONCLUSION: This case embodies the typical manifestations of mitochondrial diseases, emphasizing the urgency of prompt diagnosis and symptom management, which largely depends on effective genetic screening.
    Keywords:  Mitochondrial diabetes; mitochondrial DNA.; mitochondrial encephalomyopathy associated with lactic acidosis and stroke-like episodes (MELAS)
    DOI:  https://doi.org/10.2174/0118715303419754251125093050
  9. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]
    Mitochondria as sources and targets of cellular signaling.
    Anna Meichsner, Verian Bader, Konstanze F Winklhofer.
      Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
    Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
  10. Front Immunol. 2025 ;16 1740433
    Mitochondrial DAMPs as a critical driver in the development of acute graft versus host disease and emerging mitochondria targeted therapeutic strategies.
    Vasantharaja Raguraman, Yogamaya Divakar Prabhu, Gopal Viswanathan Velmurugan, Gerhard C Hildebrandt, Senthilnathan Palaniyandi.
      Mitochondrial fusion and fission regulate mitochondrial morphology and homeostasis, both of which are essential for maintaining cellular health. Free mitochondria and mitochondrial-containing extracellular vesicles have emerged as key mediators of pathological processes. Conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) damage and lead to impaired mitochondrial function, including biogenesis and respiration, as well as elevated reactive oxygen species (ROS), which contribute to the development of inflammatory conditions as well as activation of antigen presenting cells, the latter being key players in acute graft versus host pathophysiology (GVHD). This leads to increased T-cell activation and proliferation, which increases alloreactivity and drives GVHD. Dysregulated mitochondrial dynamics lead to the release of mitochondrial DNA and formylated peptides, which act as Damage-Associated Molecular Patterns (DAMPs) and trigger cellular homeostatic imbalances, ultimately leading to more inflammation. The understanding that mitochondrial dysfunction contributes to GVHD offers novel therapeutic strategies, including blocking DAMP signaling and modulating immune cell metabolism to restore mitochondrial health. This review aims to understand mitochondrial homeostasis in both recipient and donor cells. This is crucial for understanding GVHD pathophysiology and developing mitochondria-targeted therapies or mitochondrial transfer strategies as potential therapeutic interventions for GVHD.
    Keywords:  DAMP (Damage Associated Molecular Pattern); Graft versus host disease (GVHD); hematopoietic cell transplantation (HCT); mitochondria transfer; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fimmu.2025.1740433
  11. Int J Dev Neurosci. 2026 Feb;86(1): e70100
    No Association Between Autism Spectrum Disorder and Mitochondrial DNA Variants: A Comprehensive Genetic Study in Trakya Population.
    Hasan Cem Aykutlu, Engin Atlı, Leyla Bozatlı, Hazal Sezginer Güler, Cansu Çınar, Ayhan Kütükçü, Hakan Gürkan, Işık Görker.
       BACKGROUND: Autism spectrum disorder (ASD) has a strong genetic basis, yet specific etiological factors remain unidentified in the majority of cases. Mitochondrial DNA (mtDNA) variations have been hypothesized as potential contributors to ASD development. However, the precise role of mtDNA remains unclear due to inconsistent findings across studies, which often suffer from methodological limitations.
    AIMS: This study aimed to comprehensively investigate the association between mtDNA variants, gene-level variant burden and haplogroup distributions in a Turkish paediatric ASD cohort.
    STUDY DESIGN: Case control study.
    METHODS: Whole mtDNA analysis of peripheral blood samples from 95 children with ASD and 95 healthy controls was performed using next-generation sequencing. Identified variations were evaluated for pathogenicity via genomic databases and in silico analyses. Potentially pathogenic variations underwent segregation analysis. Additionally, mtDNA haplogroup distributions were compared between the groups.
    RESULTS: The overall frequency of mtDNA variants was significantly higher in the ASD group than in the control group (p = 0.033). The ASD cohort harboured 23 distinct variants (initially classified as three pathogenic/likely pathogenic (P/LP) and 20 variants of uncertain significance [VUS]); while the control group had 13 VUS and no P/LP variants. Gene-based burden analysis identified a significantly higher variant load in the MT-CYB gene within the ASD cohort (FDR = 0.048). However, segregation analysis of the P/LP variants (including m.827A > C, m.9804G > A and a novel MT-CYB variant) revealed maternal inheritance from asymptomatic mothers. Consequently, all P/LP variants were reclassified as VUS. No significant difference was found in mtDNA haplogroup distribution between groups.
    CONCLUSION: Through comprehensive mtDNA scanning and rigorous pathogenicity assessment, our findings suggest that mtDNA variations are not implicated in the pathogenesis of ASD. However, given the complex nature of ASD, future research is needed with larger sample sizes, standardized pathogenicity assessment criteria and detailed phenotypic analyses to further elucidate the relationship between mtDNA variants and ASD.
    Keywords:  autism spectrum disorder; genetic variation; haplotypes; high‐throughput nucleotide sequencing; mitochondrial DNA; segregation analysis
    DOI:  https://doi.org/10.1002/jdn.70100
  12. Curr Issues Mol Biol. 2025 Dec 14. pii: 1042. [Epub ahead of print]47(12):
    Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.
    Mi Eun Kim, Yeeun Lim, Jun Sik Lee.
      Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2-KEAP1 antioxidant system, the cGAS-STING innate immune pathway, and the PINK1-Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD+ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases.
    Keywords:  chronic inflammation; immuno-metabolism; metabolic reprogramming; mitochondrial dysfunction; therapeutic targeting
    DOI:  https://doi.org/10.3390/cimb47121042
  13. Biology (Basel). 2026 Jan 13. pii: 139. [Epub ahead of print]15(2):
    Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
    Jessica Ábalos-Martínez, Francisco Visiedo, María Victoria Cascajo-Almenara, Celeste Santos-Rosendo, Victoria Melero-Jiménez, Carlos Santos-Ocaña, Luis Vázquez-Fonseca, Fernando Bugatto.
      Preeclampsia is a serious pregnancy disorder of unknown etiology. One of its cellular hallmarks is increased mitochondrial dysfunction in placental tissue. Further investigation into this aspect may help elucidate the molecular basis of preeclampsia. A total of 24 pregnant women who delivered by cesarean section participated in the study: n = 13 controls and n = 11 diagnosed with preeclampsia. Maternal blood samples were collected to assess the biochemical profile, and demographic and clinical data were recorded. Placental trophoblast samples were processed to isolate mitochondria and perform molecular biology assays. Women with preeclampsia exhibited the characteristic clinical features of the disease, along with biochemical alterations consistent with an inflammatory process. A significant decrease (73%) in mitochondrial DNA (mtDNA) copy number in trophoblastic tissue and a reduction in citrate synthase (CS) activity (-51%) in cytotrophoblast mitochondria-enriched fractions were observed in preeclampsia, indicating mitochondrial dysfunction accompanied by a loss of functional mitochondrial mass. In addition, we detected a marked decrease in MnSOD levels (-32%), together with an increase in the LC3II/LC3I ratio (47%) in cytotrophoblast mitochondria-enriched fractions, supporting the presence of mitochondrial alterations and suggesting the possible activation of mitophagy specifically in this cell type. Moreover, coenzyme Q10 (CoQ10) levels were elevated by 31% in trophoblastic villi. A pronounced 2.5-fold increase in CoQ10 normalized to CS activity (CoQ10/CS) was detected specifically in cytotrophoblasts from preeclamptic placentas. Importantly, we did not observe these alterations in the syncytiotrophoblast. In conclusion, preeclampsia is associated with mitochondrial dysfunction and increased CoQ10 levels normalized to CS activity, specifically in cytotrophoblast mitochondria, with findings being consistent with a possible involvement of mitophagy in this cell type. These findings suggest that cytotrophoblast mitochondrial metabolism may be more affected in preeclampsia compared with syncytiotrophoblasts, and that CoQ10 accumulation together with the possible activation of mitophagy may represent cellular defense mechanisms. Due to the limitations of the study, it should be considered exploratory and hypothesis-generating, and its results should be regarded as preliminary.
    Keywords:  coenzyme Q10; cytotrophoblast; mitochondria; mitophagy; preeclampsia
    DOI:  https://doi.org/10.3390/biology15020139
  14. NPJ Parkinsons Dis. 2026 Jan 27.
    Systematic evaluation of mitochondrial morphology regulators for amelioration of neuronal α-synucleinopathy.
    Su Yeon Kim, JunYoung Choi, Dong Cheol Jang, Pa Reum Lee, Gyu-Sang Hong, Jinkuk Kim, Won-Ki Jeong, Kihoon Han, Seok-Kyu Kwon.
      Neuronal mitochondria display distinct morphologies across compartments, with dendritic mitochondria being elongated and axonal ones shorter, and their morphologies are dynamically changed via fusion and fission machineries. Mitochondrial structural abnormalities are common in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, yet systematic evaluation of therapeutic targets remains limited. Here, we tested key mitochondrial shape regulators, mitofusin 1/2 for fusion and Mff/Fis1 for fission, in an α-synucleinopathy model. Using MitoVis, a deep learning-based neuronal mitochondrial image analysis tool, we achieved rapid, compartment-specific analysis of mitochondrial morphologies. Among all interventions, Fis1 knockdown most effectively protected mitochondrial structure to control levels without inducing over-elongation of axonal mitochondria, which was linked to abnormal Ca2+ dynamics. While all manipulations preserved dendritic spine loss, Fis1 optimally maintained axonal mitochondrial function. These findings demonstrate a high-throughput screening approach for mitochondrial regulators and highlight Fis1 as a promising preventive/therapeutic target. Our results support targeting mitochondrial morphology as a viable strategy for treating α-synucleinopathy and potentially other mitochondria-related neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41531-026-01277-z
  15. Reproduction. 2026 Jan 06. pii: xaaf008. [Epub ahead of print]171(1):
    Meiotic purification of dysfunctional mitochondria in mouse oocytes.
    Sanbao Shi, Zhunyuan Min, Yongqi Li, Jianxin Pan, Hongying Sha.
      Mitochondrial purification, including mitophagy, during oogenesis is critical for ensuring accurate mitochondrial DNA transmission, but it remains unclear whether meiosis plays a role in eliminating defective mitochondria. Here, we show that mitochondria in the first polar body (PB1) exhibit reduced membrane potential compared with those retained in oocytes. TUNEL and cytochrome c assays suggest that mitochondrial dysfunction in PB1 precedes nuclear fragmentation. Notably, the second polar body (PB2) exhibits heterogeneous membrane potentials, with both functional and dysfunctional populations present. By injecting dysfunctional and functional mitochondria, isolated respectively from the cytoplasts of the PB1and the oocyte, into germinal vesicle-stage mouse oocytes, we found that dysfunctional mitochondria were preferentially extruded into PB1, while functional mitochondria were retained after meiosis I. Interestingly, mitochondria from PB1 exhibit low membrane potential even after being transferred into a new, healthy oocyte, whereas oocyte-derived mitochondria maintain normal membrane potential following the same procedure. Immunofluorescence analysis further shows that PB1-derived mitochondria lack colocalization with motor protein Rho T1, in contrast to their oocyte-derived counterparts. Furthermore, PB1 transfer combined with mitochondrial probe and fast-NGS demonstrated that meiosis II also contributes to the extrusion of dysfunctional mitochondria into PB2. By comparison, spindle transfer revealed that most functional mitochondria were retained in the oocyte, with only minimal amounts detected in PB2. Predictably, PB2 and pronuclear transfer failed to extrude foreign mitochondria. Collectively, these findings identify meiosis as a distinctive safeguard for mitochondrial quality during oogenesis, with implications that warrant further investigation in humans.
    Keywords:  Cytochrome C; Meiosis; Mitochondria; oocyte; polar body
    DOI:  https://doi.org/10.1093/reprod/xaaf008
  16. Nat Commun. 2026 Jan 29.
    ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
    Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.
      Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.
    DOI:  https://doi.org/10.1038/s41467-026-68813-6
  17. FEBS J. 2026 Jan 29.
    ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.
    Giorgia Maria Renna, Alessandro Cherubini, Ersilia Varone, Serena Germani, Alice Marrazza, Ester Zito.
      Proteostasis maintains the balance between protein synthesis, folding, and degradation within the endoplasmic reticulum (ER). This quality-control system ensures that proteins undergo proper post-translational modifications-such as PDI-ERO1-mediated oxidative folding and STT3-dependent N-glycosylation-so that only correctly folded proteins proceed through the secretory pathway. Impairment of protein load, folding capacity, or degradation via the ER-associated degradation (ERAD) pathway leads to the accumulation of unfolded proteins, triggering ER stress and activating the unfolded protein response (UPR), which, in the first instance, is an adaptive signaling network designed to restore homeostasis by adjusting protein synthesis, enhancing folding capacity, and promoting the clearance of misfolded proteins. During ER stress, the ER undergoes morphological and functional remodeling to manage the increased folding burden, including an increase of ER-mitochondria contact sites (ERMCs). These nanometric junctions (~10-100 nm) facilitate lipid and metabolite exchange and mediate calcium and reactive oxygen species signaling to support cellular metabolism. However, chronic ER stress can further tighten ERMCs, leading to calcium overload, mitochondrial dysfunction, and apoptosis. This review examines the core mechanisms underlying ER proteostasis in the context of ER stress and explores how ER stress first boosts mitochondrial activity and later impairs it through ERMCs, contributing to cell death and disease. Finally, emerging therapeutic strategies aimed at restoring proteostasis and modulating the dynamics of ERMCs are highlighted as promising interventions for conditions, such as cancer and congenital myopathies, where ER and mitochondrial dysfunction play central roles in pathogenesis.
    Keywords:  ERMC; cancer; mitochondria metabolism; neuromuscular diseases; proteostasis
    DOI:  https://doi.org/10.1111/febs.70431
  18. Biomedicines. 2026 Jan 03. pii: 100. [Epub ahead of print]14(1):
    Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Aging: Current Insights and Therapeutic Advances.
    Nabila Izzati Nur Azan, Norwahidah Abdul Karim, Nadiah Sulaiman, Min Hwei Ng, Asyraff Md Najib, Haniza Hassan, Ekram Alias.
      Mitochondrial dysfunction plays a central role in cardiac aging. Damaged mitochondria release excessive free radicals from the electron transport chain (ETC), leading to an increased production of reactive oxygen species (ROS). The accumulation of ROS, together with impaired ROS clearance mechanisms, results in oxidative stress, further disrupts mitochondrial dynamics, and diminishes bioenergetic capacity. Furthermore, the dysfunctional mitochondria exhibit an impaired endogenous antioxidant system, exacerbating this imbalance. These alterations drive the structural and functional deterioration of the aging heart, positioning mitochondria at the center of mechanisms underlying age-associated cardiovascular decline. In this review, we summarize the current evidence on how mitochondrial oxidative stress, mutations on mitochondrial DNA (mtDNA), and disruptions in the fission-fusion balance contribute to cardiomyocyte aging. This review also explores ways to mitigate oxidative stress, particularly with mitochondria-targeted antioxidants, and discusses the emerging potential of mitochondrial transplantation to replace dysfunctional mitochondria.
    Keywords:  ROS; cardiovascular aging; mitochondria dynamics; mitochondria-targeted antioxidants; mitochondrial dysfunction; mitochondrial transplantation; oxidative stress
    DOI:  https://doi.org/10.3390/biomedicines14010100
  19. Antioxidants (Basel). 2025 Dec 22. pii: 21. [Epub ahead of print]15(1):
    Bioactive Peptide C248 of PRDX4 Ameliorates the Function of Testicular Leydig Cells via Mitochondrial Protection.
    Nini Wei, Shuning Yuan, Li Gao, Bei Zhang, Zhengjie Yan, Chao Gao, Yan Meng, Yugui Cui.
       BACKGROUND: The senescence of testicular Leydig cells (LCs) is a key cause of age-related testosterone deficiency, in which oxidative stress (OS) and mitochondrial dysfunction are critical driving mechanisms. We explore whether the bioactive peptide C248 of PRDX4, an intracellular antioxidant, exerts mitochondrial protection to ameliorate LCs' function.
    METHODS: Based on the antioxidant domains of the PRDX4 protein, small molecular peptides were designed, and bioactive peptide C248 stood out from the crowd. An OS-induced senescence model of LCs was constructed by treating the MLTC-1 cell line with hydrogen peroxide (H2O2). C248 peptide or nicotinamide mononucleotide (NMN), as the positive control, was administered in the culture medium. The cellular function-related indicators, including DPPH free radical scavenging rate, cell viability, testosterone level, hydrogen peroxide (H2O2) content, senescence-associated β-galactosidase (SA-β-gal) activity, 8-hydroxy-2'-deoxyguanosine (8-OHDG) level, and 4-hydroxynonenal (4-HNE) level, were evaluated. The mitochondrial function and structural indicators, such as mitochondrial membrane potential, ATP production, mitochondrial morphology, and mitochondrial DNA (mtDNA) copy number, were subsequently tested.
    RESULTS: In vitro experiments confirmed that C248 could scavenge DPPH free radicals in a dose-dependent manner, reduce the levels of reactive oxygen species, and increase antioxidant enzyme activity in LCs (p < 0.01). Both C248 and NMN increased testosterone secretion and improved cell viability (p < 0.01). Both C248 and NMN increased mitochondrial morphology and quantity, mitochondrial membrane potential (p < 0.01), ATP production (p < 0.01), and mitochondrial DNA (mtDNA) copy number (p < 0.01).
    CONCLUSION: This study reveals that the small molecular C248, a bioactive peptide of PRDX4, is a new candidate molecule for intervening in LC senescence and confirms that mitochondrial protection is a key strategy for improving age-related testicular dysfunction.
    Keywords:  LCs senescence; antioxidant peptide; mitochondrial protection; nicotinamide mononucleotide; peroxiredoxin 4
    DOI:  https://doi.org/10.3390/antiox15010021
  20. Int J Mol Sci. 2026 Jan 08. pii: 630. [Epub ahead of print]27(2):
    Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
    Francesco Bellomo, Domenico De Rasmo.
      Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.
    Keywords:  bioenergetics; cAMP; cysteamine; cystinosis; flavonoids; ketogenic diet; lysosomal storage diseases; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms27020630
  21. Nat Aging. 2026 Jan 29.
    Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
    Masahiro Wakita, Koyu Ito, Kaho Fujii, Dai Sakamoto, Takumi Mikawa, Sho Sugawara, Xiangyu Zhou, Jeong Hoon Park, Hideka Miyagawa, Daisuke Motooka, Emi Ogasawara, Naotada Ishihara, Akiko Takahashi, Hiroshi Kondoh, Eiji Hara.
      Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.
    DOI:  https://doi.org/10.1038/s43587-025-01057-z
  22. Curr Neuropharmacol. 2026 Jan 19.
    Mitochondrial and Antioxidant Activity as the Basis of the Neuroprotective Effect of Potential Multitarget Drugs for the Treatment of Neurodegenerative Diseases.
    Elena Feofanovna Shevtsova, Alexey Yuryevich Aksinenko, Alla Vadimovna Stavrovskaya, Vladimir Petrovich Fisenko, Sergey Olegovich Bachurin.
       BACKGROUND: The mechanisms of neurodegeneration common to many neurodegenerative diseases include oxidative stress, mitochondrial dysfunctions, excitotoxicity, and others. Beyond the broad spectrum of strategies for developing neuroprotective agents that target stagespecific mechanisms in each neurodegenerative disease, considerable attention is also being given to approaches aimed at developing compounds that can effectively modulate general pathogenic mechanisms and enhance the overall resilience of neuronal cells to cell death induction.
    OBJECTIVE: This review discusses some of the results on new multitarget multipharmacophore agents with neuroprotective effects, particularly through their influence on mitochondrial permeability transition and antioxidant properties. We conducted comprehensive online searches on PubMed to gather the latest data on multitarget multipharmacophore agents consisting of pre-defined pharmacophores that have already demonstrated neuroprotective properties.
    RESULTS AND DISCUSSION: To create compounds with a desirable spectrum of biological activity, an approach based on the conjugation of specific structural fragments of pharmacologically active substances into a single molecular entity could be used. Core fragments of compounds that have already demonstrated neuroprotective properties due to mitochondrial and antioxidant mechanisms of action can be used as neuroactive scaffolds.
    CONCLUSION: The combination of several pharmacophores in one molecule may not only result in the mere addition of the useful properties of each component, but may also give rise to new types of biological activity. The examples of the appearance of new properties in such multipharmacophore compounds, not inherent in the reference agents, discussed in our review, may be considered a prospective approach for creating a novel generation of neuroprotective agents.
    Keywords:  Neurodegenerative diseases; antioxidant activity; mitochondria; mitochondrial permeability transition; multitarget drugs.; neuroprotectors
    DOI:  https://doi.org/10.2174/011570159X409525251027064739
  23. Immunology. 2026 Jan 29.
    Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
    Woo Hyun Park.
      Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin-1β (IL-1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K+) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox-mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)-mediated mtDNA synthesis. The profound involvement of the mtDNA-inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.
    Keywords:  immunogenic cell death; inflammasome; innate immunity; mitochondrial DNA; pyroptosis; sterile inflammation
    DOI:  https://doi.org/10.1111/imm.70111
  24. Mitochondrion. 2026 Jan 25. pii: S1567-7249(26)00005-X. [Epub ahead of print] 102115
    Mitochondrial dysfunction-induced PANoptosis: Mechanisms, triggers, and disease implications.
    Liyang Pan, Shijie Fang, Fanhua Kong, Shaojun Ye, Yan Xiong.
      In recent years, PANoptosis, as a novel form of cell death that integrates multiple cell death pathways, has progressively emerged as a cutting-edge research field in the study of cell death and immune regulation. PANoptosis, a recently proposed form of inflammatory programmed cell death, integrates features of pyroptosis, apoptosis, and necroptosis, while emphasizing their interplay. It is mediated by the PANoptosome and plays a pivotal role in infections, inflammation, tumors, and degenerative diseases. Recent studies have demonstrated that ROS serve as critical signaling molecules for PANoptosome assembly. Given that mitochondria constitute the primary intracellular source of ROS, this establishes a crucial link between mitochondrial and PANoptosis activation. Mitochondria sustain energy production, calcium homeostasis, and signaling but also contribute to immune responses and cell death. Oxidative stress, obesity, and environmental pollutants can induce mitochondrial dysfunction, manifested through impaired mitochondrial dynamics, which subsequently leads to excessive ROS production and mtDNA leakage. These pathological changes ultimately trigger PANoptosis activation. This review systematically summarizes how mitochondrial dysfunction triggers PANoptosis through mechanisms such as ROS accumulation, aberrant mitochondrial dynamics, and mtDNA leakage. Furthermore, it explores the implications of this process in traumatic brain injury, inflammatory diseases, ischemic disorders, and diseases induced by environmental toxins (e.g., microplastics and heavy metals). Understanding the interplay between mitochondria and PANoptosis may provide critical insights into the pathogenesis of inflammation-related diseases and offer novel mitochondria-targeted therapeutic strategies.
    Keywords:  Mitochondrial DNA; Mitochondrial dynamics; Mitochondrial dysfunction; PANoptosis; PANoptosome; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.mito.2026.102115
  25. JCEM Case Rep. 2026 Feb;4(2): luaf341
    Unveiling a Novel MT-TS1 m.7479G>A in Mitochondrial Diabetes: The Critical Role of mtDNA Sequencing in Atypical Cases.
    Eleanor Danek, Felicity Pyrlis, Aleena Shujaat Ali, Elif I Ekinci.
      Mitochondrial diabetes is a rare form of diabetes mellitus caused by mitochondrial DNA (mtDNA) mutations, often presenting with atypical features and maternal inheritance. We report a 71-year-old white female presenting with diabetes diagnosed at age 50, managed with oral therapy, who exhibited significant weight loss and a strong maternal family history of diabetes. Glutamic acid decarboxylase and insulinoma-associated-2 antibodies were negative with normal C-peptide, and genetic testing revealed a heteroplasmic MT-TS1 m.7479G>A variant (13.90%). Glycemic management was achieved with metformin and gliclazide, and at 21 years post diagnosis, the patient maintained stable glycemic control with a glycated hemoglobin A1c of 6.5% (SI: 48 mmol/mol) (reference range, 4.0%-6.0% [SI 20-42 mmol/mol]) without insulin. The MT-TS1 m.7479G>A variant is implicated as a pathogenic cause of mitochondrial diabetes, highlighting the importance of mtDNA sequencing in atypical cases with maternal inheritance, the potential for milder phenotypes with low-heteroplasmy variants, and the critical role of genetic counseling.
    Keywords:  MT-TS1; atypical diabetes; genetic testing; m.7479G>A; maternal inheritance; mitochondrial diabetes
    DOI:  https://doi.org/10.1210/jcemcr/luaf341
  26. Sci Rep. 2026 Jan 27.
    SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Age-related hearing loss is characterized by the progressive degeneration of cochlear hair cells and neurons, with mitochondrial dysfunction and impaired mitophagy implicated as molecular mechanisms. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, plays a critical role in the regulation of mitochondrial quality control and mitophagy. SRT2104, a synthetic SIRT1 activator with improved bioavailability compared to resveratrol, has shown neuroprotective effects in age-related neurodegeneration. However, the role of SIRT1 in auditory cell senescence remains unclear. In this study, we investigated the effects of SRT2104 on cellular senescence and mitophagy in HEI-OC1 auditory cells and organotypic cochlear explants. Senescence was induced using low-dose H₂O₂, and SRT2104 was used as a pre-treatment. SRT2104 significantly enhanced SIRT1 activity, upregulated mitophagy-related proteins (PINK1, Parkin, BNIP3, and LC3-II), and downregulated senescence markers (p53 and p21) in cellular and explant models. β-galactosidase staining confirmed reduced senescence in SRT2104-treated groups. Pre-treatment with SRT2104 preserved mitochondrial function, as indicated by enhanced mitochondrial membrane potential, improved mitochondrial DNA integrity, and increased ATP production. SIRT1 knockdown abolished these protective effects, confirming that SRT2104 mediated its anti-senescence and pro-mitophagy activities via SIRT1. Our findings demonstrated that SRT2104 alleviates premature senescence and promotes mitophagy in auditory cells via SIRT1 activation. The pharmacological activation of SIRT1 may represent a promising therapeutic strategy to counteract age-related degeneration in the auditory system.
    DOI:  https://doi.org/10.1038/s41598-026-37606-8
  27. J Med Case Rep. 2026 Jan 28.
    Taurine intake ameliorates lactic acidosis and hyperferritinemia occurring after mRNA SARS-CoV-2 vaccination in a patient with β-thalassemia trait: a case report and review of literature.
    Anthony M Kyriakopoulos, Peter A McCullough, Stephanie Seneff.
       BACKGROUND: Taurine is a powerful antioxidant necessary for mitochondrial function. Lactic acidosis is a complication encountered in the condition mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), which can be successfully treated with supplemental taurine. Furthermore, taurine regulates the production of iron-dependent proteins such as ferritin that can act as chelating agents to sequester labile iron.
    CASE PRESENTATION: A 38-year-old Greek male with a β-zero thalassemia trait developed multiple severe symptoms soon after his first and only mRNA (Pfizer) SARS-CoV-2 vaccination that included hematological stress to be a candidate for blood transfusion. Amongst the hematological readings, the patient had lactate levels > 4 mmol/ml, indicating lactic acidosis, and ferritin levels > 820 ng/ml, representing hyperferritinemia. Moreover, the patient has organic acid and plasma metabolite levels in the urine that are indicative of mitochondrial dysfunction. Regular taurine intake (500 mg/day) for years helped the patient control lactate and ferritin levels and avoid more serious clinical decompensation.
    CONCLUSION: Regular taurine intake helps to avoid lactic acidosis and reverse hyperferritinemia after mRNA SARS-CoV-2 vaccination in a patient with β-zero thalassemia trait with no obvious genetic trait linked to mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Taurine seemed to be protective for mitochondria.
    Keywords:  Case study; Hyperferritinemia; Lactic acidosis; Mitochondrial dysfunction; SARS-CoV-2 mRNA vaccination injury; Taurine
    DOI:  https://doi.org/10.1186/s13256-026-05844-z
  28. Biology (Basel). 2026 Jan 20. pii: 189. [Epub ahead of print]15(2):
    Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
    Yanyu Bao, Guoying Miao, Nannan He, Xingting Bao, Zheng Shi, Cuilan Hu, Xiongxiong Liu, Bing Wang, Chao Sun.
      Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.
    Keywords:  melatonin; mitochondrial dysfunction; mitochondrial quality control; neurodegenerative diseases; oxidative stress
    DOI:  https://doi.org/10.3390/biology15020189
  29. Nat Rev Drug Discov. 2026 Jan 28.
    Strategies for blood-brain barrier rejuvenation and repair.
    Peter C Searson, William A Banks.
      Blood-brain barrier (BBB) dysfunction is a hallmark of many diseases of the brain, including those that represent the largest healthcare burden (for example, Alzheimer disease and stroke). Despite this, rejuvenation and repair of the BBB is not a mainstream concept. During life, the BBB is subjected to perturbations and stresses from a wide range of endogenous or exogenous sources, which can promote brain health or can lead to brain pathologies. The BBB supports many functions that are critical for central nervous system homeostasis and so there are many mechanisms of dysfunction, and hence many targets for intervention. Furthermore, many mechanisms are shared among diseases and disease subtypes, resulting in the potential for common strategies for BBB repair. In this Review, we consider the BBB as a therapeutic target and discuss approaches to its repair and protection in specific disease states and during normal ageing.
    DOI:  https://doi.org/10.1038/s41573-025-01364-5
  30. Biomolecules. 2026 Jan 20. pii: 171. [Epub ahead of print]16(1):
    Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
    Mariagrazia Mancuso, Federico Mezzalira, Beatrice Vignoli, Elisa Greotti.
      Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca2+ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca2+-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca2+ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca2+-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca2+ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca2+-centered mitochondria-glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer's disease.
    Keywords:  Alzheimer’s disease; astrocyte–neuron communication; excitotoxicity; glutamate homeostasis; glutamatergic synapse; metabolic coupling; mitochondrial Ca2+ signaling; mitochondrial signaling; neuronal hyperexcitability; synaptic vulnerability
    DOI:  https://doi.org/10.3390/biom16010171
  31. Biochim Biophys Acta Mol Cell Res. 2026 Jan 22. pii: S0167-4889(26)00015-7. [Epub ahead of print] 120119
    The language of cytokines: Decoding immune signals with information theory.
    Sophie Streuber, Emelie Rieneck, Fred Schaper, Anna Dittrich.
      Communication between cells is fundamental for maintaining and restoring homeostasis in multicellular organisms under both physiological and pathological conditions. A variety of mechanisms for encoding, transmitting, and decoding information have evolved. Information theory, originally developed in engineering, is increasingly being applied to dissect how cells process and exchange signals. Yet, biological systems exhibit distinctive properties that pose conceptual and quantitative challenges not encountered in technical systems. In this review, we examine how cellular networks manage and often exploit the intrinsic heterogeneity of cell populations. We discuss how individual cells and cell populations sense cytokine stimulus strength and specificity, and how regulatory proteins shape not only signalling dynamics but also the capacity and robustness of information transmission. From an information theoretical perspective, health can be viewed as a state of efficient and reliable cellular communication, whereas disease reflects the loss or distortion of robust cellular communication. We conclude that information theory offers an intuitive framework for biologists seeking to unravel the principles of cytokine signalling.
    Keywords:  Channel capacity; Cytokine; Information theory; Mutual information; Signal transduction; Single cells
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120119
  32. Biomolecules. 2026 Jan 01. pii: 71. [Epub ahead of print]16(1):
    Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.
    Chen Dong, Depeng Lv, Yanyan Dong, Zuohan Zhang, Quancai Li, Zhen Chen.
      Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes recent advances in the analytical techniques employed for CL analysis. The principles and applications of mass spectrometry-based platforms, nuclear magnetic resonance, Fourier-transform infrared spectroscopy, atomic force microscopy-infrared spectroscopy, and fluorescent probes were discussed, with an emphasis on their strengths in revealing the structure, composition, dynamics, and spatial distribution of CL. Furthermore, the evidence of CL abnormalities in various CNS disorders was assessed, often showing decreased CL levels, loss of polyunsaturated species, and increased oxidation associated with mitochondrial dysfunction and neuronal apoptosis. Furthermore, the nutritional interventions for CL modulation were discussed, such as polyunsaturated fatty acids, polyphenols, carotenoids, retinoids, alkaloids, and triterpenoids, which summarize their potential health-beneficial effects in remodeling the CL acyl chain, preventing oxidation, and regulating mitochondrial homeostasis. Overall, this review provided insight into integrating CL analysis and dietary modulation in understanding CL-related pathologies in CNS disorders.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; antioxidants; lipidomics; mass spectrometry; molecular species; nutritional bioactive components; phospholipids; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/biom16010071
  33. Antioxidants (Basel). 2025 Dec 28. pii: 41. [Epub ahead of print]15(1):
    Blood-Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism.
    David Mantle, Neve Cufflin, Mollie Dewsbury, Iain Parry Hargreaves.
      The disparity in outcomes between preclinical and clinical studies supplementing coenzyme Q10 (CoQ10) in neurological disorders may be a reflection of the differences in the ability of supplemental CoQ10 to access the blood-brain barrier (BBB) in rodents and in humans, which is, in turn, a consequence of contrasting structures of the BBB. The applicability of in vivo animal models to study access of CoQ10 across the BBB and subsequent neuronal metabolism has, therefore, been questioned, and there is an argument, perhaps surprisingly, that in vitro model systems (particularly 3D cellular systems) may be more appropriate. In this article, we have, therefore, reviewed the role of model systems to study the access of CoQ10 across the BBB, as well as the role of such systems in studying the role of CoQ10 in aspects of neuronal metabolism, such as mitochondrial and lysosomal function. In addition, the use of such model systems to study the interactions of CoQ10 with vitamin E and selenium has been reviewed. Finally, the practical application of a neuronal model system to investigate the effect of CoQ10 supplementation on CoQ10 status and mitochondrial metabolism in a CoQ10 deficiency state has been described.
    Keywords:  2D and 3D model systems; STARD7; blood–brain barrier; coenzyme Q10; intranasal; selenium; vitamin E
    DOI:  https://doi.org/10.3390/antiox15010041
  34. Biology (Basel). 2026 Jan 19. pii: 181. [Epub ahead of print]15(2):
    Mitochondrial Adaptations Underlying Tetraploidization in Human Cancer, Fungal, and Yeast Models.
    Mohamed Jemaà, Ameni Bedoui, Nihel Ammous, Ali Gargouri, Mohamed Guerfali.
      Whole-genome duplication, or tetraploidization, occurs in cells, tissues, or entire organisms. In human cancers, tetraploidization promotes aneuploidy and genomic instability, accelerating tumor progression, metastasis, and drug resistance. These adaptations demand metabolic rewiring, including mitochondrial plasticity. Here, we investigate the relationship between mitochondrial quantity/activity, including the mitochondrial transmembrane potential, the intracellular calcium, and the oxidative stress in diploid versus tetraploid cancer cells (colon, sarcoma, liver) and fungal and yeast models (C. albicans diploid/tetraploid strains; S. cerevisiae haploid/diploid/tetraploid strains). We demonstrate that tetraploid cells, whether from human carcinomas or yeast, exhibit consistently enlarged cell size, elevated mitochondrial content, and heightened metabolic activity compared to diploids. Our findings underscore mitochondrial adaptation as a hallmark of tetraploidization, offering novel therapeutic targets for chromosomally unstable tumors.
    Keywords:  flow cytometry; mitochondria; mtDNA; polyploidy; size
    DOI:  https://doi.org/10.3390/biology15020181
  35. Mediators Inflamm. 2026 ;2026 3168669
    Bidirectional Regulation of NLRP3 Inflammasome and Mitochondrial Quality Control in Sepsis: Mechanisms and Therapeutic Implications.
    Xiangxin Liao, Yixun Wang, Zhaohui Zhang, Xingguang Qu, Gaosheng Zhou.
      Characterized by its capacity to induce organ failure, sepsis constitutes a life-threatening pathological state with high incidence and mortality rates. Current treatments primarily focus on antimicrobial therapy and organ support, lacking direct interventions targeting the restoration of cellular or organelle function. Among these mechanisms, mitochondrial dysfunction and overactivation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome stand out as key pathological hallmarks. As a classic inflammasome, the NLRP3 inflammasome, upon activation, drives cellular pyroptosis and massive release of inflammatory mediators. Beyond their role as cellular energy generators, mitochondria participate in the modulation of inflammatory responses and oxidative stress control. Mitochondrial quality control (MQC) serves as a prerequisite for the orderly performance of mitochondrial physiological functions. Disruption of MQC invariably results in mitochondrial dysfunction, triggering liberation of mitochondrial reactive oxygen species (mtROS) along with mitochondrial damage-associated molecular patterns (mtDAMPs), which serve as direct triggers for NLRP3 inflammasome formation and stimulation. This process disrupts MQC, exacerbates mitochondrial dysfunction, and forms a mutually reinforcing "MQC imbalance-NLRP3 overactivation" vicious cycle that drives disease progression. This review aims to: (1) systematically elucidate the complex bidirectional regulatory mechanisms between the NLRP3 inflammasome and MQC in the context of sepsis, (2) summarize the latest research progress on targeted intervention strategies based on this vicious cycle, and (3) discuss the challenges in clinical translation and future directions of these strategies.
    Keywords:  NLRP3 inflammasome; mitochondrial dysfunction; mitochondrial quality control; sepsis; targets; treatment
    DOI:  https://doi.org/10.1155/mi/3168669
  36. Pharmaceuticals (Basel). 2026 Jan 16. pii: 164. [Epub ahead of print]19(1):
    Aptamer-Based Delivery of Genes and Drugs Across the Blood-Brain Barrier.
    Luona Yang, Yuan Yin, Xinli Liu, Bin Guo.
      The blood-brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle-aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies.
    Keywords:  aptamers; blood-brain barrier; drug delivery; gene therapy; nanotechnology
    DOI:  https://doi.org/10.3390/ph19010164
  37. World J Clin Oncol. 2026 Jan 24. 17(1): 113600
    Pleiotropic regulation of mitochondrial translational factors in governing proliferation, apoptosis and metastasis during cancer progression.
    Nikita Agarwal, Uttam Sharma, Akshi Shree, Rajiv Ranjan Kumar, Jaya Kanta Gorain, Vaishnavi Vishwas, Farhana Jahan, Archna Singh, Jayanth Kumar Palanichamy, Deepam Pushpam, Radhika Bakhshi, Anita Chopra, Ranjit Kumar Sahoo, Atul Batra, Surender K Sharawat, Sameer Bakhshi.
      Mitochondrial translation relies on the coordinated activity of mitoribosomes, mitochondrial ribosome proteins, mitochondria-specific transfer RNAs, and dedicated translation factors, including mitochondrial initiation factor 2/3, mitochondrial elongation factor Tu, mitochondrial elongation factor Ts, mitochondrial elongation factor G1/G2, mitochondrial elongation factor 4, mitochondrial ribosome recycling factor, and mitochondrial release factor 1A. These components collectively drive the synthesis of 13 essential polypeptides encoded by mitochondrial DNA, all constituting subunits of the oxidative phosphorylation complexes. Although mitochondrial metabolism is increasingly recognized as a key player in cancer, the specific contribution of mitochondrial translation to cancer progression remains poorly explored. This gap in knowledge limits our understanding of how mitochondrial dysfunction contributes to tumor initiation, progression, and therapy resistance. Herein, in this review, we highlight how dysregulation of mitochondrial translation factors can influence major cancer hallmarks such as sustained proliferative signaling, resistance to apoptosis, and increased invasion and metastasis. In addition, we discuss the known molecular mechanisms that link defects in mitochondrial translation to oncogenic features. We also consolidate current insights into the mitochondrial translation machinery and discuss recent evidence of its role in cancer, aiming to emphasize mitochondrial translation as a contributor to malignancy and a potential therapeutic target.
    Keywords:  Cancer; Hallmark; Mitochondrial ribosomal proteins; Mitochondrial translation; Mitochondrial translation factors
    DOI:  https://doi.org/10.5306/wjco.v17.i1.113600
  38. Expert Opin Drug Deliv. 2026 Jan 29. 1-19
    Chitosan nanoparticles for brain targeted nose-to-brain drug delivery in neurodegenerative disease: a comprehensive exploration of advances, limitations and future prospects.
    Mumtaz, Devika Unnithan, Hadiseh Hosseini, Javed Ali, Mohammad Ahmed Khan.
       INTRODUCTION: Neurodegenerative diseases (NDDs), such as Alzheimer's and Parkinson's and epilepsy, cause irreversible nerve cell degradation, resulting in cognitive and motor decline. The blood-brain barrier (BBB) complicates treatment, limiting drug access and causing low bioavailability. Chitosan nanoparticles (CH-NPs) offer a promising solution for improving drug delivery to the brain due to their biocompatibility and ability to enhance intranasal delivery, potentially increasing therapeutic efficacy.
    AREAS OF COVERAGE: The review discusses advancements in chitosan-based nanoparticle drug delivery systems for NDDs, highlighting literature from 2015 to 2025. It indicates that chitosan can improve drug uptake in the brain by up to ten times and emphasizes its potential for targeted central nervous system (CNS) delivery due to its unique properties. Additionally, intranasal delivery is a non-invasive method to bypass the BBB and enhance therapeutic precision.
    EXPERT OPINION: CH-NPs effectively deliver therapeutics to the CNS, leveraging their mucoadhesive properties and biocompatibility to cross the BBB via intranasal delivery. This platform enhances drug uptake and retention in the brain, addressing challenges faced by traditional therapies for NDDs. Optimizing nanoparticle biomaterial properties and delivery methods could improve therapeutic precision and clinical outcomes.
    Keywords:  Neurodegenerative diseases; blood-brain barrier; chitosan nanoparticles; drug delivery; intranasal drug delivery; targeted delivery
    DOI:  https://doi.org/10.1080/17425247.2026.2619090
  39. J Hum Immun. 2025 Nov 03. 1(4): e20250064
    Incomplete penetrance in inborn errors of immunity: A skeleton in the closet-The sequel.
    Dusan Bogunovic.
      Primary immunodeficiencies (PIDs), more recently renamed inborn errors of immunity (IEIs), are a diverse group of over 550 genetic disorders. They cause clinically apparent immune dysregulation, leading to infections, autoinflammation, autoimmunity, and cancer. Initially, most IEIs were described as Mendelian disorders with complete penetrance, but the community has now shown that, in most IEIs, some individuals harboring disease-causing genotypes display only partial clinical disease, or no disease at all. Thus, most IEIs are actually Mendelian disorders with incomplete penetrance. Despite the frequency of incomplete penetrance in IEIs, the conceptual framework for systematically categorizing and explaining these occurrences remains limited. Here, I expand on four recurrent themes of incomplete penetrance that we have recently proposed: genetic variant quality, epigenetic and genetic modification, environment, and mosaicism. For each of these principles, I review what is known and unknown and propose future experimental approaches to fill the gaps in our knowledge. I focus on IEIs, but these concepts can be generalized to all genetic diseases.
    DOI:  https://doi.org/10.70962/jhi.20250064
  40. Eur J Neurol. 2026 Feb;33(2): e70488
    Novel Clinical Insights From a Swedish RFC1 Spectrum Disorder Cohort.
    Victor Alm, Linda Säll, Kristin Samuelsson, Rayomand Press, Snjolaug Arnardottir, Anna Lindstrand, Valter Niemelä, Lilia Terinte, Frida Nordin, Per Svenningsson, Daniel Nilsson, Luca Verrecchia, Martin Paucar.
       BACKGROUND: Biallelic pentanucleotide expansions in RFC1 cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and a growing spectrum of presentations. We aimed to clinically characterize a cohort of patients from Sweden with biallelic expansions in RFC1.
    METHODS: We retrospectively enrolled patients with homozygous expansions in RFC1 from a tertiary center in Sweden, evaluating clinical and genetic data. Assessments included nerve conduction studies (NCS, n = 27), electromyography (n = 7), quantitative sensory testing (n = 18), brain MRI (n = 27), and vestibular/eye motor tests (n = 18-21).
    RESULTS: Of the 30 patients enrolled, 28 were ethnic Swedish; 17/30 from smaller regions, including eight (27%) from Norrbotten. Twenty-two patients met the CANVAS criteria. Mean age of onset was 52 ± 12 years (range 20-70), and disease duration was 14 ± 12 years. Symptoms matched the CANVAS acronym with multisystemic features in 83%, including dysautonomia (77%), dyskinesia (36%), and bradykinesia (17%). Phenotypes overlapped with MSA-C (n = 2) and mitochondrial ataxias (n = 1). Notably, one symptomatic patient lacked neuropathy on NCS. Annual disease progression was slow (0.3 by spinocerebellar degeneration functional score, 1.2 by SARA). At vestibular testing, 47% showed a preserved caloric response and pathologic angular VOR with a nonsignificant trend among younger patients and milder ataxia; otolith function was largely preserved.
    DISCUSSION: Our findings expand the RFC1 spectrum, suggesting a founder effect in Sweden and extensive subclinical involvement. RFC1-spectrum disorder should also be considered in patients with cerebellar and vestibular dysfunction but lacking neuropathy. A discordant VOR pattern may represent an incipient sign of RFC1-spectrum disorder; interestingly, otolith pathways seem to be generally spared.
    Keywords:   RFC1 ; CANVAS; Ganglionopathy; Neuropathy; VEMP; bilateral vestibulopathy; cerebellar ataxia; vHIT; vestibular areflexia; vestibulo‐ocular reflex
    DOI:  https://doi.org/10.1111/ene.70488
  41. Front Public Health. 2025 ;13 1728978
    Measuring the health benefits of genome and exome sequencing: a systematic review of economic evaluations.
    Marianna Riccio, Annalisa Rosso, Leonardo Maria Siena, Valentina Baccolini, Giuseppe Migliara, Antonio Sciurti, Claudia Isonne, Jessica Iera, Francesco Pierri, Carolina Marzuillo, Corrado De Vito, Giuseppe La Torre, Paolo Villari.
       Introduction: Genome sequencing (GS) and exome sequencing (ES) technologies have gained increasing attention in health economics for evaluating their clinical and public health introduction, but their complexity challenges traditional methods. This systematic review aimed to investigate and discuss full economic evaluations (EEs) of GS and ES in relation to health outcomes, with a focus on methodological issues.
    Methods: A systematic search of several databases was carried out (PROSPERO CRD42023430992). Quality was evaluated using the Quality of Health Economic Studies instrument. Key methodological features were investigated, and a narrative synthesis of the findings was performed after grouping studies by testing scope.
    Results: Overall, 12 recently published cost-utility analyses (CUAs) were included, assessing the use of GS/ES for guiding targeted therapy in oncology (N = 4) or major depressive disorder (N = 1), and diagnosing rare genetic diseases (N = 7). The findings suggested that GS/ES may be cost-effective for diagnosing rare diseases and may also be cost-effective for treatment guidance under favorable conditions. Methodological rigor tended to be higher in treatment guidance studies, whereas EEs in pediatric diagnostics faced greater challenges. Utility values were largely derived from a common survey using validated multi-attribute utility instruments, and studied on proxy conditions. Variability in perspectives, target populations, and costs limited comparability. To strengthen future EEs, standardized methodologies and long-term, real-world data on clinical and non-clinical benefits are needed.
    Conclusion: Traditional CUA approaches are essential to guide the implementation of new technologies, but they should be accommodated or complemented by alternative methods, innovative and comprehensive frameworks that capture the broader value of GS/ES and support their integration into clinical and public health practice.
    Keywords:  cost-effectiveness; cost-utility; economic evaluation; exome sequencing (ES); genome sequencing (GS); systematic review
    DOI:  https://doi.org/10.3389/fpubh.2025.1728978
  42. Dis Model Mech. 2026 Jan 01. pii: dmm052478. [Epub ahead of print]19(1):
    Generating cerebellar organoids from pluripotent stem cells.
    Esther B E Becker, Simone Mayer, Lena M Kutscher.
      Cerebellar organoids present promising tools for the modelling of human cerebellar development and diseases. As this young field grows, robust standards and transparent reporting practices are needed to ensure the reproducibility and utility of the generated cerebellar organoid models. Here, we summarize current approaches to generate cerebellar organoids and their applications. We suggest common quality control standards and biological readouts that should be considered in this emerging area.
    Keywords:  Cerebellum; Development; Disease models; Organoid; Quality control
    DOI:  https://doi.org/10.1242/dmm.052478
  43. Spectrochim Acta A Mol Biomol Spectrosc. 2026 Jan 22. pii: S1386-1425(26)00071-5. [Epub ahead of print]351 127500
    A novel amide-quinoline salt-based mitochondrial-targeted fluorescent probe for detecting pH in cells and water samples.
    Feng-Ting Liu, Bang-Zhao Zhou, Jun-Ying Miao, Bao-Xiang Zhao, Zhao-Min Lin.
      Mitochondria is the primary organelle responsible for energy production, and their weakly alkaline microenvironment (pH ≈ 8) is closely linked to cellular metabolism and disease states. Mitochondrial acidification is closely associated with the pathogenesis of a spectrum of disorders, encompassing neurodegenerative syndromes, cardiovascular disorders and cancer. Therefore, monitoring mitochondrial pH fluctuations is crucial for deciphering cellular physiological processes. In this research, we constructed a novel pH fluorescent probe QAA based on amide-quinoline salt, featuring piperazine as the pH recognition site and quinoline salt as the mitochondrial targeting group. QAA exhibited excellent water solubility (PBS buffer) which could be well matched with the cell imaging conditions, appropriate pKa (8.0) and mitochondrial targeting. Fluorescence spectroscopy results indicated that QAA possessed high selectivity and sensitivity, with a linear response in pH range of 6.6 to 9.5. The recognition mechanism was confirmed by density functional theory (DFT) calculations and HNMR spectral. Crucially, QAA not only exhibited excellent photostability, low cytotoxicity and the ability to detect pH in cellular mitochondria, but also could be used for real water sample detection, achieving recovery rates ranging from 98.96% to 104.84%. QAA held practical potential as a mitochondrial pH indicator for studying physiology-related processes involving mitochondria.
    Keywords:  Amide-quinoline salt; Cell imaging; Mitochondrial targeting; Water samples; pH
    DOI:  https://doi.org/10.1016/j.saa.2026.127500
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