bims-polgdi Biomed News
on POLG disease
Issue of 2026–02–15
58 papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.
  2. In and out of the mitochondrial intermembrane space.
  3. Transient replication of bovine mitochondrial DNA and subsequent placental development in mouse embryos.
  4. Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.
  5. Short telomeres in mitochondrial DNA depletion disorders.
  6. Implications of mitochondrial function in embryonic development.
  7. Single-cell mitochondrial lineage tracing: Opportunities and challenges.
  8. Mechanisms and disease relevance of mitochondrial translation in humans.
  9. Case Report: Simultaneous pancreas-kidney transplantation in MELAS: first reported case with 5-year follow-up.
  10. Mitochondria-targeted delivery strategies for age-related diseases.
  11. URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.
  12. ASSOCIATION ANALYSIS OF MITOCHONDRIAL HETEROPLASMIC VARIANTS AND CARDIOMETABOLIC TRAITS.
  13. Mitochondrial presequences are more than just address labels.
  14. Longitudinal Analysis of Mitochondrial D-Loop Methylation and Copy Number in Peripheral Blood: Epigenetic Signatures of Alzheimer's Disease Progression and Aging.
  15. Molecular mechanisms of mitochondrial AAA+ proteases.
  16. Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.
  17. Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review.
  18. Application of knowledge graphs in rare disease research.
  19. Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues.
  20. Peroxisomes in Aging: Guardians of Cellular Resilience and Function.
  21. Mitochondrial Transfer in the Tumor Microenvironment.
  22. Mitochondrial D-loop region methylation differentiates Parkinson's disease from atypical parkinsonism and Parkinson's disease dementia.
  23. The associations between epilepsy, metabolism, and their clinical implications.
  24. MSTO1-related mitochondrial myopathy and ataxia syndrome: Case series and literature review.
  25. Referral route: a determinant of inequity for children with undiagnosed genetic diseases?
  26. p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
  27. Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS.
  28. A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
  29. New Insights on Mitochondria-Targeted Neurological Drugs.
  30. Transcranial Photobiomodulation in Rett Syndrome: A Mechanistic Review and Therapeutic Hypothesis.
  31. Statistical interpretation of mtDNA matches in two uncommon types of forensic cases.
  32. A full-length mtDNA dataset for studying genetic variations across generations and complex family structures.
  33. Gene Therapy Techniques and Delivery Methods (Review).
  34. Mitochondrial Haplogroups and Left Ventricular Diastolic Dysfunction in People Living with and without HIV.
  35. AQP4-IgG-Induced Astrocyte-Derived Small Extracellular Vesicles Carrying Mitochondrial DNA Regulate the TLR9/MyD88/NF-κB Pathway to Drive Microglial Activation and Neuromyelitis Optica.
  36. The importance of mitochondria and mitochondrial calcium signaling in health and disease: an updated outlook on inflammation.
  37. A Roadmap to Neurologic Health Equity: An AAN Position Statement.
  38. MitoTex (Mitochondria Texture Analysis User Interface): Open-Source Framework for Textural Characterization and Classification of Mitochondrial Structures.
  39. Energy Allocation Resilience and Endocrine Integration.
  40. Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.
  41. Old enough to be a model? On the role of maturity in stem cell-based models for neuropsychiatric disorders.
  42. DRP1 in Reproduction and Reproductive Aging.
  43. Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System.
  44. "Tumor-to-endothelium mitochondrial transfer licenses endothelial cells for CD8 + T cell recognition via mitochondrial neoantigen presentation".
  45. Sleep in MELAS syndrome.
  46. Assay for numerical and graphical detection of Native American mitochondrial haplogroup B with real-time PCR.
  47. Analysis of biomarkers in the Human Phenotype Project using disease models from UK Biobank.
  48. Regulation of mitochondrial biogenesis and energy metabolism in the heart.
  49. Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.
  50. Diagnostic Yield of Comprehensive Reanalysis After Nondiagnostic Short-Read Genome Sequencing in Infants With Unexplained Epilepsy.
  51. Ginsenoside Rg5 targets the KAT8-CISD2 axis to maintain mitochondrial homeostasis and antagonize senescence.
  52. RareCollab -- An Agentic System Diagnosing Mendelian Disorders with Integrated Phenotypic and Molecular Evidence.
  53. CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.
  54. Myopathy and ataxia related to impaired mitochondrial function in mevalonate kinase deficiency.
  55. Mitochondrial DNA Analysis Should Be Considered in the Genetic Assessment of Focal Segmental Glomerulosclerosis or Unexplained Chronic Kidney Disease: A Case Report.
  56. Telomerase and chronic inflammation as central molecular links in aging.
  57. Systems Biology of Aging, Metabolism, and Mitochondria.
  58. Case Report: Progressive myoclonus epilepsy as an early manifestation of neuronopathic Gaucher disease.
  1. Transl Neurodegener. 2026 Feb 13. 15(1): 5
    Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.
    Abhishek Jauhari, Tanisha Singh, Diane L Carlisle, Robert M Friedlander.
      Mitochondrial DNA (mtDNA) plays a pivotal role in the regulation of neuroinflammation, acting as a potent trigger of innate immune responses when released into the cytoplasm or extracellular space. mtDNA is structurally similar to bacterial DNA, containing unmethylated CpG motifs that are readily recognized by immune sensors. Under conditions of cellular stress, injury, or mitochondrial dysfunction, mtDNA can escape into the cytoplasm, where it activates the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, or it can be detected extracellularly by Toll-like receptors on immune cells. These signaling events lead to the production of pro-inflammatory cytokines and type I interferons, amplifying neuroinflammatory responses. In the central nervous system, this process contributes to the pathogenesis of various neurodegenerative and inflammatory conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc.. The dual role of mtDNA as both a damage-associated molecular pattern and a signaling molecule underscores its importance as a therapeutic target for modulating neuroinflammation and protecting against progressive neuronal damage. In this review, we will discuss the implications of mtDNA-mediated neuroinflammation in neurodegenerative diseases, including AD, PD, and HD, highlighting its potential as a diagnostic biomarker and therapeutic target.
    Keywords:  Mitochondria; Mitochondrial DNA; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1186/s40035-026-00540-w
  2. Protein Sci. 2026 Mar;35(3): e70493
    In and out of the mitochondrial intermembrane space.
    Fara van der Schans, Kostas Tokatlidis, Daniela G Vitali.
      Mitochondria are essential organelles constituted by two membranes, the outer (OMM) and inner mitochondrial membrane (IMM), and two aqueous compartments, the intermembrane space (IMS) and the matrix. Although mitochondria contain their own genome, which encodes for 13 proteins in humans (8 in budding yeast), the vast majority (99%) of mitochondrial proteins are encoded by the nuclear DNA and imported into the organelle co- or post-translationally. The IMS lies between the cytosol and the matrix, making it a strategic hub for monitoring the mitochondrial proteome. All IMS-resident proteins are nuclear-encoded and play critical roles in cellular pathways, such as redox regulation, calcium signaling, apoptosis, and hypoxia response. Furthermore, most mitochondrial proteins pass through the IMS en route to their final destination within the organelle. During this transit, their targeting and folding states are carefully monitored: properly folded proteins are retained, while misfolded or potentially toxic polypeptides are retrotranslocated and degraded. In this review, we highlight the mechanisms by which proteins are sorted into the IMS and discuss its central role in regulating mitochondrial proteostasis and maintaining mitochondrial function.
    Keywords:  Mia40; intermembrane space; oxidative folding; proteostasis
    DOI:  https://doi.org/10.1002/pro.70493
  3. Biochem Biophys Res Commun. 2026 Feb 09. pii: S0006-291X(26)00195-6. [Epub ahead of print]807 153431
    Transient replication of bovine mitochondrial DNA and subsequent placental development in mouse embryos.
    Masaya Komatsu, Hanako Bai, Masashi Takahashi, Manabu Kawahara.
      Mitochondrial DNA (mtDNA) replication during early development is believed to depend on species-specific coordination between the mitochondrial and nuclear genomes. Here, we examined the fate and developmental consequences of bovine mtDNA introduced into mouse embryos using an interspecies mitochondrial transplantation model. Bovine mtDNA exhibited transient amplification during mouse preimplantation development, but declined at the blastocyst stage. Nevertheless, bovine mtDNA persisted in both embryonic and extraembryonic tissues after implantation. Using tetraploid complementation, we further demonstrated that mtB-M embryos developed enlarged placentas with expansion of the spongiotrophoblast layer, accompanied by upregulation of the Sfmbt2-miR-466 m axis. These findings highlight partial engagement of host replication machinery by heterologous mtDNA and species-specific constraints on mtDNA replication in shaping placental development in vivo.
    Keywords:  Interspecies mitochondrial transplantation; Mito-nuclear incompatibility; Mitochondrial DNA replication; Sfmbt2–miR-466 m axis; Spongiotrophoblast expansion
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153431
  4. Mol Genet Metab. 2026 Feb 08. pii: S1096-7192(26)00050-8. [Epub ahead of print]147(3): 109767
    Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.
    Emanuele Barca, Nuri Jacoby, Ali Naini, Michael L Miller, Valentina Emmanuele, Christopher J Winfree, Saba Tadesse, Kurenai Tanji, Michio Hirano.
      Rhabdomyolysis can be due to mitochondrial myopathy, but mitochondrial DNA (mtDNA) pathogenic variants are often overlooked in standard genetic panels. We report a 41-year-old woman with recurrent rhabdomyolysis due to a novel MT-CO3 variant. Muscle biopsy showed cytochrome c oxidase-negative fibers that segregated with high heteroplasmic load on single-fiber. We additionally review previously reported mtDNA variants associated with rhabdomyolysis, highlighting the diagnostic relevance of mtDNA analysis and tissue-specific testing in unexplained rhabdomyolysis.
    Keywords:  COX stain; Mitochondrial DNA; Rhabdomyolysis; Single-fiber analysis; mtDNA pathogenic variant
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109767
  5. Mitochondrion. 2026 Feb 10. pii: S1567-7249(26)00021-8. [Epub ahead of print]88 102131
    Short telomeres in mitochondrial DNA depletion disorders.
    Yumi Dille, Emmanouil Rampakakis, Geraldine Aubert, Christelle Dassi, William Mannherz, Saoussen Berrahmoune, Myriam Srour, Daniela Buhas, Suneet Agarwal, Kenneth A Myers.
      Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, sometimes leading to catastrophic multisystem failure. In a cohort of patients with MDDs, we measured telomere length in lymphocytes, granulocytes, T cells, and B cells, and compared to healthy controls. Telomere length was shorter overall in patients with MDDs, with the most significant differences observed in granulocytes. The observation that mtDNA depletion is associated with shorter telomeres may provide insight into MDD pathophysiology. Telomere length may have potential as a biomarker in mitochondrial disease, but further study is needed.
    Keywords:  C10orf2; DGUOK; Mitochondrial DNA depletion disorders; POLG; RRM2B; SUCLA2; SUCLG1; TK2; TYMP; Telomere length; Telomeres
    DOI:  https://doi.org/10.1016/j.mito.2026.102131
  6. Biosci Trends. 2026 Feb 09.
    Implications of mitochondrial function in embryonic development.
    Jing Wang, Jing Zhou, Yanying Wang, Yun Li, Ling Wang, Lisha Li.
      Mitochondria are organelles that play a crucial role in various physiological processes. They are particularly important during embryonic development, as their proper function is required for essential processes such as fertilization, implantation, and embryonic growth. In addition to their well-known role in adenosine triphosphate (ATP) synthesis and energy production, mitochondria serve multiple other functions during embryonic development. These include the synthesis of important metabolites, involvement in cell signaling pathways, regulation of reactive oxygen species, and facilitation of interactions between organelles. The mitochondrial genome, known as mitochondrial DNA (mtDNA), also plays a unique role in embryonic development. Dysfunction in mitochondria can lead to failures in fertilization, suboptimal embryo development, post-implantation failures, and mitochondrial-related diseases in adults. Advances in sequencing technology and experimental techniques have greatly improved our understanding of mitochondrial function. This paper reviews the roles of mitochondrial functions in embryonic development and the influence of mitochondrial technologies and it highlights the potential impact of understanding mitochondria's unique genetic and functional characteristics on embryonic development and offspring health.
    Keywords:  embryonic development; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.5582/bst.2026.01002
  7. Quant Biol. 2026 Mar;14(1): e70018
    Single-cell mitochondrial lineage tracing: Opportunities and challenges.
    Siqi Li, Kun Wang, Xin Wang, Zheng Hu.
      Lineage tracing using endogenous mitochondrial DNA (mtDNA) variants holds great promise for reconstructing the lineage histories of individual cells, with broad applications in oncology, developmental biology, and regenerative medicine. Unlike synthetic DNA barcoding techniques, mitochondrial lineage tracing does not require genetic engineering of exogenous genetic markers, and thus is particularly suitable for human clinical samples. Various experimental and computational methods have been developed to profile mtDNA variants from single-cell genomic, transcriptomic, and epigenomic sequencing data. Despite the technical advances, several challenges still limit the robustness of single-cell mitochondrial lineage tracing, such as random genetic drift, genetic bottlenecks, informative variant identification, and low mtDNA coverage. In this review, we systematically examine current experimental and computational approaches for analyzing mtDNA variants in single cells and discuss current challenges and future technical developments aimed at enhancing the robustness and applicability of single-cell mitochondrial lineage tracing.
    Keywords:  lineage tracing; mtDNA variants; phylogenetic reconstruction; single‐cell genomics
    DOI:  https://doi.org/10.1002/qub2.70018
  8. Nat Rev Mol Cell Biol. 2026 Feb 13.
    Mechanisms and disease relevance of mitochondrial translation in humans.
    Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.
      Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41580-026-00948-2
  9. Front Transplant. 2026 ;5 1737352
    Case Report: Simultaneous pancreas-kidney transplantation in MELAS: first reported case with 5-year follow-up.
    Vera Nilsén, Julia Bojstedt, Johan Nordström.
       Background: Mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial DNA disorder that, in severe cases, can result in insulin-dependent diabetes and end-stage renal disease (ESRD). While organ transplantation is a potential treatment, documented cases remain scarce.
    Methods: A 40-year-old patient with dialysis-dependent ESRD and diabetes secondary to MELAS underwent simultaneous pancreas-kidney transplantation. The perioperative and postoperative periods were uncomplicated with only targeted MELAS-specific adaptations to standard protocols.
    Results: During the 5-year follow-up, the patient maintained excellent kidney allograft function and sustained insulin independence, with no need for dialysis or exogenous insulin therapy. At 5 years, creatinine was 77 µmol/L with an estimated GFR above 90 mL/min/1.73 m2, and glycated hemoglobin was 40 mmol/mol.
    Conclusions: SPK transplantation may be feasible in carefully selected patients with MELAS, ESRD, and diabetes, providing durable renal and metabolic graft function at 5 years. To our knowledge, this is the first reported SPK case in MELAS, with extended follow-up.
    Keywords:  MELAS; graft survival; long-term outcomes; mitochondrial disease; mitochondrial disorder; mtDNA-disorder; simultaneous pancreas-kidney transplantation
    DOI:  https://doi.org/10.3389/frtra.2026.1737352
  10. Int J Pharm X. 2026 Jun;11 100494
    Mitochondria-targeted delivery strategies for age-related diseases.
    Zefan Liu, Pei Yang, Guilin Cheng, Xin Kang, Lian Li, Yucheng Xiang.
      Aging is a complex progress accompanied with the progressive deterioration of physiological functions and a marked elevation in mortality risk. Among prominent aging theories, the free radical theory and the mitochondrial dysfunction hypothesis have gained significant attention. Thus, targeted delivery of therapeutic drug to mitochondria might be able to alleviate the mitochondrial dysfunction induced by reactive oxygen species. This review summarizes the possible molecular mechanisms between mitochondrial dysfunction and aging progression. Especially, the recent breakthroughs of mitochondrial-targeted delivery platforms for therapeutics against aging progress. Innovative strategies, including small molecular modification, mitochondrial targeting functional peptide guided delivery and some other strategies are discussed. Their translational potential in anti-aging interventions is evaluated. We anticipate that mitochondria-targeted anti-aging therapeutics will soon enter clinical translation, offering potential solutions to address current age-related challenges.
    Keywords:  Age-Related Diseases; Mitochondrial Dysfunction; Mitochondrial-Targeted Delivery
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100494
  11. Mitochondrion. 2026 Feb 11. pii: S1567-7249(26)00024-3. [Epub ahead of print] 102134
    URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.
    Zeshuo E S Li, Rachel Dunn, Loïc C Caloren, Adam S Ziada, Hailey Chapman, Izabelle Gadawska, Hélène C F Côté.
      The study of mitochondrial genetics has long been limited to polymorphisms and high frequency mutations owing in part to technical and technological limitations in reliably detecting and quantifying rare somatic mutations. Over the past decade or so, the study of rare somatic mitochondrial DNA (mtDNA) variants has expanded and continues to garner increasing interest in a wide range of research fields. Here, we describe Ultra-Rare Mutation Detection-Sequencing (URMD-Seq), a high-throughput method that combines unique molecular identifier (UMI)-based library preparation and Next Generation Sequencing (NGS) for the accurate and scalable detection of ultra-rare mutations in the mtDNA control region. Our method exploits degenerate primers to label individual mtDNA molecules. This is followed by several purification, quantification and amplification steps, to obtain high quality amplicons for sequencing on the Illumina MiSeq platform. Our approach enables the use of total genomic DNA extract as starting point for the assay, overcoming the need for organelle isolation and/or mtDNA enrichment, hence broadening the type of specimen that can be studied, while offering cost and time benefits. The assay described herein has been demonstrated to reliably measure variants present at on average 0.09%, but as low as 0.03%, variant allele frequency in a variety of tissues, including fresh and frozen biobanked specimens. Using this protocol, library preparation of 300 specimens can be completed by a single individual with general nucleic acid handling experience in approximately 20 days. Given its flexibility and scalability, URMD-Seq is particularly well suited for epidemiological studies using a large number of specimens.
    Keywords:  Ultra-rare mutations; mitochondrial DNA (mtDNA); next-generation sequencing (NGS); unique molecular identifiers (UMIs)
    DOI:  https://doi.org/10.1016/j.mito.2026.102134
  12. medRxiv. 2026 Jan 25. pii: 2026.01.23.26344724. [Epub ahead of print]
    ASSOCIATION ANALYSIS OF MITOCHONDRIAL HETEROPLASMIC VARIANTS AND CARDIOMETABOLIC TRAITS.
    TOPMed mtDNA working group
      Mitochondrial heteroplasmic variant has been increasingly recognized as a potential contributor to common complex diseases, yet its relationship with cardiometabolic disorders (CMDs) remains poorly understood. Leveraging deep whole-genome sequencing data from 16,882 participants across six multi-ancestry TOPMed cohorts, we systematically evaluated the associations between rare heteroplasmic variants and eight CMD traits, including body mass index (BMI), obesity, blood pressure, hypertension, blood glucose, diabetes, low-density lipoprotein (LDL), and hyperlipidemia. Using a previously developed statistical framework, we identified heteroplasmic variants according to three coding definitions and performed gene-based burden, SKAT, SKAT-O and ACAT-O tests within sixteen mitochondrial DNA (mtDNA) genes. We identified twelve significant gene-trait associations after Bonferroni correction, with consistent effect directions across coding definitions. The strongest association was observed between hyperlipidemia and heteroplasmic variants in CO1 gene (OR=0.28, 95% CI=(0.17, 0.46), p=3.4E-7) among EA (European Americans). Additional associations were detected for BMI, adjusted SBP (systolic blood pressure), BG (blood glucose), diabetes, and adjusted LDL. These findings highlight the contribution of heteroplasmic variation within mtDNA to cardiometabolic phenotypes and provide new insight into mitochondrial involvement in CMD pathophysiology.
    DOI:  https://doi.org/10.64898/2026.01.23.26344724
  13. Protein Sci. 2026 Mar;35(3): e70491
    Mitochondrial presequences are more than just address labels.
    Erik Marcel Heller, Svenja Lenhard, Doron Rapaport, Johannes Herrmann.
      Most mitochondrial proteins are synthesized in the cytosol as precursor proteins with N-terminal presequences. These presequences serve as targeting signals that facilitate the binding to mitochondrial surface receptors and translocation across the mitochondrial membranes. However, recent studies showed that presequences can be more than address tags. They can contain degradation signals recognized by components of the ubiquitin-proteasome system, and therefore, serve as timers that determine the lifespan of newly synthesized precursor proteins. Moreover, presequences can interact with components of the cytosolic chaperone system to prevent or delay precursor folding. Finally, presequences of some dually localized proteins contain targeting information not only for mitochondria but also for other cellular destinations such as the nuclear lumen or chloroplasts in plant cells. Thus, presequences contain multifaceted information to endow mitochondrial precursor proteins with specific properties that are critical for the early steps of mitochondrial protein biogenesis.
    Keywords:  Presequence; chaperones; mitochondria; proteasome; protein import; ubiquitin ligases
    DOI:  https://doi.org/10.1002/pro.70491
  14. Int J Mol Sci. 2026 Feb 02. pii: 1477. [Epub ahead of print]27(3):
    Longitudinal Analysis of Mitochondrial D-Loop Methylation and Copy Number in Peripheral Blood: Epigenetic Signatures of Alzheimer's Disease Progression and Aging.
    Bartolo Rizzo, Michele Rossi, Riccardo Rocco Ferrari, Elisa Pellegrini, Francesca Dragoni, Rosalinda Di Gerlando, Evelyne Minucchi, Antonio Guaita, Tino Emanuele Poloni, Stella Gagliardi, Annalisa Davin.
      Alzheimer's disease (AD), the leading cause of dementia, is expected to markedly increase in prevalence in the coming decades. Beyond amyloid and tau pathologies, accumulating evidence suggests that mitochondrial dysfunction and impaired protein homeostasis play crucial roles in AD onset and progression. Building on our previous identification of molecular signatures associated with disease progression, this study investigated whether epigenetic alterations of mitochondrial DNA (mtDNA) contribute to cognitive decline. Specifically, we analyzed the methylation status of the mtDNA regulatory D-loop region and mtDNA copy number in blood-derived DNA samples from 75 participants who we followed longitudinally over eight years. Subjects were classified into four groups according to clinical progression from healthy cognition to mild cognitive impairment (MCI) and AD. Using a linear mixed-effects model, we observed significant differences in methylation dynamics and mtDNA copy number across groups and time points. Healthy controls showed a progressive increase in D-loop methylation, whereas individuals converting to AD exhibited a marked decrease in its level. An opposite trend was evidenced for mtDNA copy number. These findings suggest that reduced D-loop methylation and increased mtDNA are associated with mitochondrial dysfunction and disease progression, whereas increased methylation may represent a possible protective mechanism.
    Keywords:  Alzheimer’s disease; aging; cognitive decline; dementia; epigenetic signature; longitudinal study; methylation; mild cognitive impairment; mitochondria; pyrosequencing
    DOI:  https://doi.org/10.3390/ijms27031477
  15. J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00134-1. [Epub ahead of print] 111264
    Molecular mechanisms of mitochondrial AAA+ proteases.
    S Quinn W Currie, Monica M Goncalves, Aaron D Schimmer, Siavash Vahidi.
      Mitochondrial AAA+ proteases, LONP1, ClpXP, YME1L (i-AAA), and the m-AAA complex, maintain protein quality and shape organelle function. Growing interest in these enzymes stems from their association with neurodegeneration, cardiomyopathy, metabolic disease, and cancer. Recent structural and biophysical work clarifies how ATP-driven conformational cycles enable substrate recognition, unfolding, translocation, and proteolysis, and how assembly state, subunit composition, and regulatory inputs tune activity. These insights help interpret patient variants and guide experiments that connect mechanism to phenotype. Here we review shared mechanistic principles across the four proteases, contrast their architectures and regulatory features, and relate these properties to substrate selection and disease mechanisms, with emphasis on evidence from structural, biochemical, and cellular studies. We also survey strategies to modulate function. Small molecules, exemplified by Dordaviprone (ONC201) which activate human ClpP, provide proof of concept, and emerging modalities such as engineered macromolecules, may offer the selectivity and localization required to correct disease mechanisms or exploit disease dependencies. By integrating mechanism, disease links, and modulation strategies, this review provides a framework for translating basic insight on mitochondrial AAA+ proteases into new tools and, ultimately, therapies.
    Keywords:  ClpXP; LONP1; YME1L; i-AAA; m-AAA; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.111264
  16. Arch Toxicol. 2026 Feb 07.
    Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.
    Busra Korkut Celikates, Sinem Ilgin, Melis Umay Yilmaz, Ozlem Atli Eklioglu.
      Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.
    Keywords:  Gentamicin; Mitochondrial dysfunction; Mitochondrial permeability transition pore; Nephrotoxicity; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s00204-026-04310-5
  17. Ann Clin Transl Neurol. 2026 Feb 11.
    Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review.
    Pouria Mohammadi, Lara Basovic, Christopher Michael McGraw.
       OBJECTIVE: Super-Refractory Status Epilepticus (SRSE) is a rare, life-threatening neurological emergency with unclear etiology in many cases. Mitochondrial dysfunction, often due to disease-causing genetic variants, is increasingly recognized as a cause, with each gene producing distinct pathophysiological mechanisms.
    METHODS: We describe the detailed clinical, neurophysiological, neuroimaging, and molecular findings of a 19-year-old female with SRSE associated with compound heterozygous variants in OPA1, a key gene for mitochondrial inner membrane fusion and cristae maintenance. In addition, a literature review was performed, identifying 16 previously published cases reporting one or both of the variants observed in the present case.
    RESULTS: Despite a longstanding history of generalized hypotonia, celiac disease, optic atrophy, cerebellar ataxia, and progressive motor decline, the proband had no prior history of seizures. She developed super-refractory status epilepticus with occipital-predominant epileptiform activity and MRI showing transient diffusion restriction in the right parieto-occipital cortex and cerebellum. Genetic testing revealed a frameshift variant (p.Val903GlyfsTer3) and a missense variant (p.Ile382Met) in the GTPase domain, known to impair mitochondrial fusion. Unlike POLG or MELAS-associated seizures, typically driven by severe mtDNA depletion and respiratory chain failure, OPA1 dysfunction usually spares mtDNA copy number but disrupts mitochondrial dynamics. In severe biallelic loss-of-function, a "second-hit" stressor may trigger a diffuse energy crisis and catastrophic seizures.
    INTERPRETATION: This case of mitochondrial SRSE in a patient with no known infectious, autoimmune, or structural cause emphasizes the possible role of genetic background and mitochondrial disorders in the development of the disease. This case highlights a rare mitochondrial subtype of RSE, emphasizing the need to consider energy metabolism defects in unexplained refractory status epilepticus.
    Keywords:  OPA1; SRSE; mitochondrial disease; mitochondrial dynamics; super‐refractory status epilepticus
    DOI:  https://doi.org/10.1002/acn3.70287
  18. Front Public Health. 2026 ;14 1757612
    Application of knowledge graphs in rare disease research.
    Yiran Fei, Huizhe Ding, Shiyuan Tong, Yibo He, Wenyu Cai.
      Rare disease research faces significant challenges due to data sparsity and heterogeneity, leading to diagnostic delays and limited treatments. Knowledge Graphs (KGs) offer a computational solution by integrating multimodal data into structured semantic networks. This review explores the technical paradigms and applications of KGs throughout the rare disease workflow. We first describe the data foundation, focusing on standardized ontologies (e.g., HPO) and integration strategies. Subsequently, we examine core applications in elucidating pathogenic mechanisms via link prediction, enhancing clinical diagnosis through semantic reasoning, and optimizing drug repositioning using Graph Neural Networks. Notably, the review highlights the emerging integration of KGs with Large Language Models (LLMs), particularly Retrieval-Augmented Generation (RAG), to improve interpretability and precision in medical decision-making. Finally, we discuss challenges such as privacy and dynamic updates, proposing future directions like federated learning to advance the field.
    Keywords:  knowledge graphs; large language models; public health; rare diseases; retrieval-augmented generation
    DOI:  https://doi.org/10.3389/fpubh.2026.1757612
  19. Mol Biol Evol. 2026 Feb 10. pii: msag035. [Epub ahead of print]
    Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues.
    Edmundo Torres-González, Barbara Arbeithuber, Nick Stoler, Marzia A Cremona, Omar Shebl, Thomas Ebner, Irene Tiemann-Boege, Francisco Diaz, Francesca Chiaromonte, Kateryna D Makova.
      Mitochondrial function can be affected by mutations in mitochondrial DNA (mtDNA). However, detecting de novo mutations in mtDNA has been challenging due to its high copy number, particularly in germline cells, and the low accuracy of conventional next-generation sequencing technologies. Using highly accurate duplex sequencing, we study the frequency of de novo insertion and deletion (indel) mtDNA mutations across multiple age groups in somatic and germline tissues of three mammalian species-mouse, macaque, and human. We demonstrate that, similar to de novo nucleotide substitutions, indels accumulate rapidly with age in somatic tissues with high energetic demand (brain and skeletal muscle) or high proliferation (liver). However, in oocytes, indels accumulate slower with age than nucleotide substitutions (or do not accumulate at all). The increases in indel frequency with age are driven mostly by deletions. Short tandem repeats are highly enriched for indels, implicating DNA replication slippage as a major driver of indel formation in mtDNA. For some species and tissues, indels are depleted at protein-coding sequences, however, indels that are multiples of 3 bp are not overrepresented. omfOurs is the most detailed study of de novo small indels in mtDNA to date. It provides parameters for models of mtDNA evolution, informs molecular mechanisms for a multitude of human genetic diseases, and illuminates the accumulation of indel mutations with age. Such accumulation may have functional consequences, as it affects reproduction later in life and drives the decline of mitochondrial function during aging.
    DOI:  https://doi.org/10.1093/molbev/msag035
  20. Cells. 2026 Jan 28. pii: 254. [Epub ahead of print]15(3):
    Peroxisomes in Aging: Guardians of Cellular Resilience and Function.
    Artuur Vercaemst, Mingming Zhao, Ruizhi Chai, Celien Lismont, Marc Fransen.
      Peroxisomes are multifunctional organelles that play essential roles in lipid metabolism, redox regulation, and cellular signaling. An expanding body of evidence implicates peroxisomal dysfunction as a key contributor to aging and age-related diseases. Aging is accompanied by progressive declines in key peroxisomal functions, including catalase activity, fatty acid β-oxidation, plasmalogen biosynthesis, and the metabolism of bile acids and docosahexaenoic acid, resulting in increased oxidative stress, lipid dysregulation, and alterations in membrane composition. Impaired pexophagy further exacerbates these defects by allowing the accumulation of damaged peroxisomes and compromising cellular homeostasis. Through extensive metabolic and signaling crosstalk with mitochondria, the endoplasmic reticulum, and lysosomes, peroxisomal dysfunction can propagate oxidative and metabolic disturbances throughout the cell. In addition, peroxisome-derived signaling molecules, such as hydrogen peroxide and bioactive lipids, link peroxisomal activity to cellular stress responses and organismal metabolic homeostasis. We propose that aging-associated impairments in peroxisomal protein import, redox regulation, and selective turnover progressively shift peroxisomes from adaptive metabolic signaling hubs toward sources of chronic oxidative and lipid stress. In this context, current studies highlight peroxisomal homeostasis as a potential determinant of healthy aging and point to peroxisomal pathways as emerging targets for intervention in age-related disease.
    Keywords:  aging; catalase; interorganelle crosstalk; lipid metabolism; metabolic disorders; neurodegeneration; peroxisomes; pexophagy; reactive oxygen species; therapeutic interventions
    DOI:  https://doi.org/10.3390/cells15030254
  21. Cancer Sci. 2026 Feb 13.
    Mitochondrial Transfer in the Tumor Microenvironment.
    Ryo Omae, Takamasa Ishino, Yosuke Togashi.
      Mitochondria are not merely energy-producing organelles but also regulate metabolism, apoptosis, and inflammation. Recent studies have reported that mitochondria can be transferred between cells, and accumulating evidence suggests that this phenomenon is functionally relevant in the tumor context. Mitochondrial transfer is mediated by multiple routes such as tunneling nanotubes and extracellular vesicles. These pathways are regulated by Miro1/2, connexin 43, ICAM-1, VCAM-1, and intracellular reactive oxygen species. Within the tumor microenvironment, mitochondrial transfer from surrounding cells to tumor cells may serve as a mechanism by which tumor cells adapt to hostile metabolic conditions and evade therapeutic pressure. Furthermore, mitochondrial transfer from tumor cells to T cells in the tumor microenvironment reportedly impairs antitumor immunity. Based on these findings, novel therapeutic strategies targeting mitochondrial transfer are under investigation. Future challenges include the development of specific and safe methods to manipulate mitochondrial transfer in vivo. Understanding mitochondrial transfer and its regulation may offer new avenues to overcome resistance and improve cancer outcomes.
    Keywords:  antitumor immunity; cell‐to‐cell interaction; mitochondria; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.70342
  22. Epigenomics. 2026 Feb 11. 1-8
    Mitochondrial D-loop region methylation differentiates Parkinson's disease from atypical parkinsonism and Parkinson's disease dementia.
    Bilge Karacicek, Bilgesu Ozturk, Ozgur Oztop Cakmak, Fatos Sibel Ertan, Pembe Keskinoglu, Sermin Genc.
       BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. Epigenetic mechanisms, including mitochondrial DNA (mtDNA) methylation, have been implicated in PD pathogenesis. Methylation of the mitochondrial displacement loop (D-loop) region may play a role in neurodegenerative processes.
    RESEARCH DESIGN AND METHODS: This case study assessed D-loop methylation levels in peripheral blood samples from 37 patients with PD, 18 patients with Parkinson's disease dementia (PD-D), 26 patients with atypical parkinsonism (APS), and 26 healthy controls (HC). Associations with clinical parameters, sex, and L-dopa treatment were analyzed.
    RESULTS: D-loop methylation levels were significantly reduced in patients with PD-D and APS compared to PD patients and HC. Methylation levels were not associated with disease duration, clinical variables, sex, or L-dopa treatment.
    CONCLUSIONS: Decreased mitochondrial D-loop methylation in PD-D and APS may reflect disease-specific epigenetic mechanisms rather than clinical characteristics or treatment effects.
    Keywords:  D-loop; Parkinson disease; Parkinson’s disease dementia; atypical parkinsonism; mtDNA methylation
    DOI:  https://doi.org/10.1080/17501911.2026.2627263
  23. Front Endocrinol (Lausanne). 2026 ;17 1694550
    The associations between epilepsy, metabolism, and their clinical implications.
    Juan Li, Yiqing Mao, Haiqing Zhang, Xin Xu.
      Epilepsy can cause metabolic disorders, and metabolic abnormalities can also trigger epilepsy, forming a bidirectional pathological cycle. Over the past century, from the earliest use of ketogenic diets to treat epilepsy, it has been confirmed that metabolic intervention can control seizures. Subsequent studies have gradually revealed that metabolic disorders such as glucose abnormality and vitamin B6 deficiency can directly induce epilepsy, while epileptic seizures themselves can cause lactic acidosis, electrolyte imbalance and other internal environment disorders. With the breakthroughs in metabolomics technology, the research on epilepsy and metabolism has entered a systematic stage, and their relationship has attracted increasing attention. However, current reviews mostly focus on the isolated analysis of a single metabolic element (such as iron, vitamin D), lacking a systematic integration of multiple metabolic elements. This review for the first time integrates the changes of seven major metabolic elements (glucose, lipids, vitamins, minerals, water, adenosine triphosphate, uric acid) in the onset, progression and treatment of epilepsy; summarizes the clinical associations between metabolic diseases (diabetes mellitus, alcoholism, uremia) and epilepsy; reveals the specific metabolic changes in childhood epilepsy; and emphasizes the importance of epilepsy metabolomics data. It provides a reference for basic research and a metabolic monitoring framework for clinicians.
    Keywords:  children; epilepsy; metabolic disease; metabolites; metabolomics
    DOI:  https://doi.org/10.3389/fendo.2026.1694550
  24. Neuromuscul Disord. 2026 Jan 30. pii: S0960-8966(26)00032-5. [Epub ahead of print]60 106364
    MSTO1-related mitochondrial myopathy and ataxia syndrome: Case series and literature review.
    Rishi Sharma, Lisa A Schimmenti, Benn Smith, Filippo Pinto E Vairo, Duygu Selcen, Radhika Dhamija.
      We report clinical and genetic features in four patients from 3 independent families with an ultra-rare autosomal recessive myopathy associated with biallelic pathogenic or likely pathogenic variants in MSTO1. Exome or genome sequencing was used to identify genetic variants in patients with suspected hereditary myopathy who had negative results on targeted genetic panels. Age at diagnosis ranged from 13 to 30 years. All patients exhibited myopathy of variable severity. Two had congenital hypotonia and global developmental delay, while the remaining two developed muscle weakness at ages 2 and 5. Magnetic resonance imaging evidence of cerebellar atrophy was noted in Patient 3. The most common non-neurologic abnormality noted in our cases was skeletal abnormalities. MSTO1-related disease presents primarily as an early-onset myopathy, occasionally accompanied by cerebellar atrophy and skeletal abnormalities. As genome-wide sequencing is increasingly becoming a first line test for unexplained myopathy, further characterization of the phenotypic spectrum is likely.
    Keywords:  Exome sequencing; MSTO1; Mitochondrial myopathy; Myopathy
    DOI:  https://doi.org/10.1016/j.nmd.2026.106364
  25. Front Genet. 2026 ;17 1692489
    Referral route: a determinant of inequity for children with undiagnosed genetic diseases?
    Zeyu Tang, Emily K Mis, Saquib A Lakhani.
      Individuals with rare genetic diseases collectively comprise 3.5%-5.9% of the population, roughly 400 million people worldwide. Undiagnosed rare disease programs have leveraged next-generation sequencing technologies to facilitate genetic diagnoses, thereby shortening the complex diagnostic odysseys that many of these patients and their families endure. However, enrollment data suggest disparities in access to undiagnosed genetic disease programs among racial and ethnic minorities. To better understand this issue, we conducted a retrospective review of our rare undiagnosed disease program to assess whether referral route was a determinant of disparities for minoritized racial and ethnic communities. Participants enrolled in the Yale Pediatric Genomics Discovery Program from 2016 to 2022 were self-categorized into four racial and ethnic groups: Hispanic/Latinx (any race), non-Hispanic White, non-Hispanic Black/African American, non-Hispanic Other. Route of referral was classified as Inpatient, Outpatient, or Outside/Self referrals. Completion rates were the percentage of participants who completed enrollment compared to their respective group. Demographics for program participants were different from Yale-New Haven Children's Hospital demographics, with over-representation of non-Hispanics Whites. Direct inpatient recruitment had a higher yield of Hispanic individuals, which was offset by under-representation of minoritized individuals in the Outside/Self setting. Inpatients had lower referral completion rates compared to Outpatient and Outside/Self referrals. These data suggest that the route of referral may represent different levels of access to care, and inpatient recruitment may be leveraged to promote participation by some minoritized communities. We encourage other programs to examine their cohorts for representation and identify strategies for improving participation.
    Keywords:  disparities; genomics; race and ethnicity; rare disease; undiagnosed
    DOI:  https://doi.org/10.3389/fgene.2026.1692489
  26. Aging Cell. 2026 Feb;25(2): e70402
    p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
    Shan Sun, Jiaqi Xin, Yingping Zhang, Bojun Yang, Dan Su, Rui Ni, Qilian Ma, Ningning Li, Guoqiang Ma, Qiang Peng, Siqian Chen, Jochen H M Prehn, Kin Yip Tam, Hongfeng Wang, Zheng Ying.
      Mitochondrial quality control is tightly associated with aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD-associated protein p62 drives "mitochondrial clustering" (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin-mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form "grape-like" clusters during PINK1/Parkin-mediated mitophagy, which is tightly associated with aging-related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a "brake" to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD-related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the "brake" machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.
    DOI:  https://doi.org/10.1111/acel.70402
  27. BMC Neurol. 2026 Feb 13.
    Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS.
    Xu Liu, Zhe-Sheng Zhang, Qing-Qing Tao.
      
    Keywords:  Cognitive impairment; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; Muscle biopsy; Neurodegenerative disease; Neuronal intranuclear inclusion disease
    DOI:  https://doi.org/10.1186/s12883-026-04705-y
  28. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00036-7. [Epub ahead of print]45(2): 116958
    A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
    Ying Wang, Xinwan Su, Yu Chen, Yijian Chen, Chengyu Shi, Fangzhou Liu, Yuqi Ye, Panyi Sun, Manman Tan, Meng Yu, Ya Wang, Shanshan Xie, Jian Liu, Qingfeng Yan, Qiming Sun, Dante Neculai, Wei Liu, Jianzhong Shao, Yang Liu, Weiqiang Lin, Aifu Lin.
      Mitochondrial genetic diseases arise from mitochondrial DNA (mtDNA) defects, which gene therapy tools may rectify. However, delivering single-guide RNAs (sgRNAs) into mitochondria remains a challenge limiting CRISPR-mediated mtDNA therapy. Here, through network analysis of mitochondrion-localized long noncoding RNAs (lncRNAs) and RNA-binding proteins (RBPs), we found that lncRNA RP11-46H11.3 translocates into mitochondria via binding mitochondria-associated RBPs using its key RNA recognition motifs (RRMs); its derived 30 nt ST2-RNA mitochondrial targeting sequence (RMTS) showed the highest mitochondrial localization efficiency. We engineered the RMTS-CRISPR tool by fusing ST2-RMTS to sgRNA, verifying its ability to target and cleave mtDNA. Strikingly, our results demonstrated that RMTS-CRISPR could achieve heteroplasmic mtDNA shifting efficiencies of up to 26.37% in m.3243A>G mutant cell models and 26.79% in vivo, offering a technological approach for the correction of heterogeneous mtDNA mutations. Taken together, our findings reveal a CRISPR-based mitochondrial gene intervention strategy that may have applications in mitochondrial disorders.
    Keywords:  CP: genomics; CRISPR-Cas system; RNA recognition motif; mitochondrial DNA; mitochondrial disorder; organelle-associated RNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.116958
  29. Biology (Basel). 2026 Jan 26. pii: 228. [Epub ahead of print]15(3):
    New Insights on Mitochondria-Targeted Neurological Drugs.
    Silvia Lores-Arnaiz.
      Aging and neurodegenerative diseases are characterized by common features involving bioenergetics deficiencies, oxidative stress and alterations of calcium buffering. Mechanisms of mitochondrial-targeted drugs include the modulation of electron transport chain and oxidative phosphorylation, the binding to mitochondrial lipids, free-radical scavenging, calcium signaling, and possible effects on mitochondrial biogenesis and dynamics and on the regulation of mitophagic pathways. One of the main sites of action of mitochondria-targeted drugs is the interaction with respiratory chain components. Mitochondrial-targeted compounds such as Mito-Q, and Mito-apocynin have been developed by conjugating triphenylphosphonium (TPP+) lipophilic cation group with natural molecules, therefore obtaining promising drugs for reestablishing the correct functioning of the mitochondrial respiratory chain. Stabilization of cardiolipin at the inner mitochondrial membrane by elamipretide or SkQ1 and mitochondria-targeted ROS scavengers can also offer a therapeutic approach to prevent bioenergetic impairment associated with several diseases. In addition, the modulation of calcium signaling can be achieved using both MCU agonists and antagonists representing another mitochondrial target for drug therapies development. Finally, potential strategies for treating neurodegenerative diseases based on the modulation of mitochondrial biogenesis, dynamics and/or mitophagic pathways are discussed.
    Keywords:  ETC modulation; ROS scavenging; mitochondria-targeted drugs; mitochondrial function
    DOI:  https://doi.org/10.3390/biology15030228
  30. Photobiomodul Photomed Laser Surg. 2026 Feb 09. 25785478251415480
    Transcranial Photobiomodulation in Rett Syndrome: A Mechanistic Review and Therapeutic Hypothesis.
    Fabio Luchese, Carlos Lohmann, Borja Ignacio Ferreras, Paolo Cassano.
       OBJECTIVE: To propose a mechanistic framework for the use of transcranial photobiomodulation (tPBM) as an adjunctive treatment in Rett syndrome (RTT).
    BACKGROUND DATA: RTT is a severe X-linked neurodevelopmental disorder caused mainly by MECP2 variants, with limited disease-modifying therapies. tPBM delivers red-to-near-infrared light to the brain and shows promising effects in several neurocognitive and neuropsychiatric conditions.
    METHODS: We reviewed key cellular mechanisms of RTT, namely mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired synaptic plasticity, and summarized established bioenergetic, redox, anti-inflammatory, and neurotrophic actions of tPBM.
    RESULTS: The convergence between these pathways suggests that tPBM could partially compensate for bioenergetic and signaling abnormalities in RTT, acting as a multi-target, pathophysiology-informed neuromodulation strategy.
    CONCLUSIONS: Although speculative, this mechanistic convergence supports prioritizing preclinical studies in Mecp2-deficient models and early-phase feasibility trials of tPBM in individuals with RTT.
    Keywords:  MECP2; Rett syndrome; mitochondrial dysfunction; neuroinflammation; neuromodulation; transcranial photobiomodulation
    DOI:  https://doi.org/10.1177/25785478251415480
  31. Forensic Sci Int Genet. 2026 Feb 03. pii: S1872-4973(26)00025-6. [Epub ahead of print]83 103444
    Statistical interpretation of mtDNA matches in two uncommon types of forensic cases.
    Gloria Dimick, Mitchell M Holland, Walther Parson, Michael Krawczak.
      Mitochondrial DNA (mtDNA) analysis is a frequently used tool for determining the potential origin of biological traces found at crime scenes. The method typically involves comparing the genetic profile of the trace with that of a suspect. While a mismatch between the two profiles usually leads to the exclusion of the suspect, the evidential value of a match is sometimes difficult to grasp. This is particularly true in cases that are more complex than a simple trace-suspect comparison. We considered two such scenarios and developed means for appropriate statistical interpretation of the respective mtDNA results. One scenario requires the evaluation of a composite hypothesis about trace donorship in multiple cases involving an mtDNA profile match with one and the same suspect. The other scenario calls for the consideration of a second mtDNA profile found at the crime scene that matches a matrilineally unrelated contact person of the suspect. For both scenarios, we propose formally linked mathematical methods for interpreting the mtDNA data which, under certain assumptions, allow valid quantification of the evidential value of the latter for or against the suspect. Furthermore, we illustrate the application of both methods with example calculations under realistic assumptions about the required parameters.
    Keywords:  Evidential value; Likelihood ratio; Match probability; Mitochondrial DNA; Trace donorship
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103444
  32. Sci Data. 2026 Feb 13.
    A full-length mtDNA dataset for studying genetic variations across generations and complex family structures.
    Yanan Liu, Qi Yang, Yujia Xuan, Jinyuan Zhao, Anqi Chen, Suhua Zhang.
      Mitochondrial DNA (mtDNA) mutations are critical to disease research, evolutionary studies, and lineage tracing but are challenging to analyze due to interference from nuclear mitochondrial sequences (NUMTs). Current high-throughput sequencing techniques rely on multiple primers or probes to amplify short mtDNA fragments, followed by alignment to a reference genome. However, this approach fails to mitigate NUMTs interference, leading to ambiguous results. In this study, we presented a nanopore-based third-generation sequencing (TGS) method using a single primer pair to amplify full-length mtDNA, effectively circumventing NUMTs artifacts. Sequencing was carried out on the QITAN TECH QNome-3841hex platform, generating complete mtDNA coverage for 106 samples from eight distinct family pedigrees, including complex familial structures such as half-siblings and multi-generational households. The sequencing achieved 100% genome coverage with an average mapping rate of 99.96%, supporting comprehensive genome characterization. The resulting dataset offers valuable insights into mtDNA mutation detection, mitochondrial genetics, population genetics, ancestry tracing, and forensic identification, and may advance mtDNA sequencing technologies and intergenerational studies.
    DOI:  https://doi.org/10.1038/s41597-026-06824-0
  33. Sovrem Tekhnologii Med. 2025 ;17(6): 56-67
    Gene Therapy Techniques and Delivery Methods (Review).
    E I Shchukina, I O Mazunin, I I Eremin, A A Moskalev.
      Gene therapy has evolved into a sophisticated field encompassing diverse precision editing platforms and advanced delivery systems capable of addressing complex genetic disorders and age-related pathologies. This comprehensive review examines the current landscape of gene therapeutic technologies, including CRISPR-based genome editing, base editing systems, prime editing platforms, and emerging DNA polymerase-based editors alongside their corresponding delivery methodologies. The review encompasses viral vectors, including tissue-specific adeno-associated virus serotypes, non-viral delivery systems such as ionizable lipid nanoparticles and virus-like particles, and innovative platforms, including exosome-based delivery and the SEND system. We examine therapeutic applications spanning nuclear genome editing, mitochondrial genome modification, RNA editing, and epigenetic modulation, demonstrating the expanding scope of gene therapy beyond traditional monogenic disorders. Critical analysis reveals that while fundamental technological capabilities have been established, significant challenges remain in manufacturing scalability, long-term safety assessment, delivery across physiological barriers, and optimization of editing efficiency in post-mitotic tissues. The integration of artificial intelligence approaches for predictive analysis and rational vector design represents a promising avenue for addressing current limitations. This review concludes that successful clinical implementation requires systematic resolution of manufacturing, safety, and delivery challenges alongside the development of standardized protocols for patient stratification and robust regulatory frameworks that accommodate rapid technological innovation while ensuring patient safety.
    Keywords:  CRISPR genome editing; RNA editing; adeno-associated virus vectors; base editing; epigenome editing; gene therapy; lipid nanoparticles; mitochondrial genome editing; prime editing
    DOI:  https://doi.org/10.17691/stm2025.17.6.06
  34. J Infect Dis. 2026 Feb 11. pii: jiag090. [Epub ahead of print]
    Mitochondrial Haplogroups and Left Ventricular Diastolic Dysfunction in People Living with and without HIV.
    Craig Cronin, Jing Sun, Jorge R Kizer, Katherine C Wu, Wendy S Post, David C Samuels, Todd Hulgan, Brad Aouizerat, Frank Palella, Shehnaz Hussain, Jeremy Martinson, Nicole D Armstrong, Claudia Martinez, Caitlin A Moran, Alan Hinderliter, Yasmeen Golzar, Federico M Asch, Jason Lazar, Carlos J Rodríguez, Todd T Brown.
       BACKGROUND: Cardiac dysfunction is more common in people with HIV (PWH) than those without HIV (PWoH), with mitochondrial dysfunction implicated in pathogenesis. We investigated whether variations in mitochondrial DNA (mtDNA) and certain dideoxynucleoside analogues (D-drugs) relate to left ventricular diastolic dysfunction (LVDD) in PWH.
    METHODS: We included individuals with echocardiograms from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. LVDD was defined using Characterizing Heart Function on Antiretroviral Therapy criteria. mtDNA haplogroups were inferred using HaploGrep. Separate exploratory multivariable logistic regressions examined associations between LVDD and African (L0L1, L2, L3 or "other") or European haplogroups (UK, H, JT, or "other"), D-drugs, and their interactions. No adjustments were made for multiple comparisons.
    RESULTS: Among 842 men (455 PWH, 387 PWoH) and 898 women (620 PWH, 278 PWoH), LVDD prevalence was 29% in women and 24% in men. Among non-Hispanic White men with HIV, European haplogroup H was associated with lower odds of LVDD (odds ratio [OR], 0.50; 95% CI, 0.26-0.93), while haplogroup clade JT was associated with increased odds (OR, 2.09; 95% CI, 1.00-4.36). In men with HIV, D-drug exposure was associated with increased odds of LVDD (OR, 1.94; 95% CI, 1.21-3.13). No significant associations were observed between haplogroups and LVDD in women. HIV serostatus modified the association of haplogroup L2 (pinteraction=0.036) and L3 (pinteraction=0.045) with LVDD in women.
    CONCLUSIONS: Mitochondrial genetic variation and D-drug use were associated with altered LVDD risk in men with HIV, highlighting potential biological mechanisms that may be targeted for surveillance or therapeutic strategies.
    Keywords:  HIV; aging; cardiac dysfunction; left ventricular diastolic dysfunction; mitochondrial genetics; mitochondrial-toxic antiretroviral therapy
    DOI:  https://doi.org/10.1093/infdis/jiag090
  35. Neurochem Res. 2026 Feb 11. 51(1): 73
    AQP4-IgG-Induced Astrocyte-Derived Small Extracellular Vesicles Carrying Mitochondrial DNA Regulate the TLR9/MyD88/NF-κB Pathway to Drive Microglial Activation and Neuromyelitis Optica.
    Juan Zhou, Haipeng Li, Ying Wen, Lingli He, Yangli He, Heng Meng.
      Neuromyelitis optica spectrum disorder (NMOSD) is a rare but serious inflammatory demyelinating disease. A key characteristic of NMOSD is the presence of a pathogenic autoantibody in serum called aquaporin-4 immunoglobulin G (AQP4-IgG). This study investigates the mechanism of astrocyte-derived small extracellular vesicles (EVs) carrying mitochondrial DNA (mtDNA) to promote AQP4-IgG-induced microglial activation in neuromyelitis optica (NMO) via the toll-like receptor 9 (TLR9)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway. Serum IgG was isolated from NMOSD patients (AQP4-IgG) and healthy controls (Con-IgG). Astrocytes were treated with AQP4-IgG or Con-IgG. EVs were isolated via ultracentrifugation, characterized, and examined for internalization. Microglia were exposed to EVs, and mtDNA levels were assessed. An NMO mouse model was established, with neurological damage, mouse behaviors, tissue damage, and microglial characterization evaluated using modified neurological severity score, open-field test, rotarod test, luxol fast blue staining, and flow cytometry. Inflammatory cytokines, TLR9, MyD88, p65, IκBα, p-p65, and p-IκBα in BV2 cells and spinal cord tissues were analyzed via ELISA, RT-qPCR, and western blot. AQP4-IgG-induced astrocyte-derived EVs increased Iba1-high-expressing and CD86/tumor necrosis factor-α-high-expressing cells, reduced CD206/transforming growth factor-β-high-expressing cells, and boosted inflammatory responses. AQP4-IgG-induced EVs carried mtDNA to activate microglia via the TLR9/MyD88/NF-κB pathway. TLR9/MyD88/NF-κB pathway inhibition reversed AQP4-IgG-induced EVs' promotion on microglial activation. In vivo, AQP4-IgG-induced EVs-mtDNA exacerbated microglial activation and NMO through the TLR9/MyD88/NF-κB pathway. AQP4-IgG-induced EVs carried mtDNA to upregulate TLR9, further activating the MyD88/NF-κB pathway, thereby promoting microglial activation and transition toward pro-inflammatory gene-high-expressing cells to drive NMO progression.
    Keywords:  Aquaporin-4 immunoglobulin g; Astrocyte-Derived small extracellular vesicles; Microglia; Mitochondrial DNA; Neuroinflammation; Neuromyelitis optica; Toll-like receptor 9/myeloid differentiation primary response 88/Nuclear factor-kappa b
    DOI:  https://doi.org/10.1007/s11064-026-04685-y
  36. J Transl Med. 2026 Feb 07.
    The importance of mitochondria and mitochondrial calcium signaling in health and disease: an updated outlook on inflammation.
    Giampaolo Morciano, Giulia Pellielo, Esther Densu Agyapong, Cristina Pellegrino, Simone Patergnani, Davide Franceschini, Konstantinos Koutsikos, Leonardo Rigon, Paolo Pinton, Alessandro Rimessi.
      
    Keywords:  Aging; Cancer; Cardiovascular diseases; IBD; Inflammation; Mitochondria; Mitochondria targeted-therapy; Neurodegenerative diseases; ROS; Respiratory diseases; mtDNA
    DOI:  https://doi.org/10.1186/s12967-026-07783-1
  37. Neurology. 2026 Mar 10. 106(5): e214687
    A Roadmap to Neurologic Health Equity: An AAN Position Statement.
    Payal B Patel, Roy H Hamilton, Joshua Amit Budhu, Samir R Belagaje, Gregory Eugene Cooper, Franklyn Rocha Cabrero, Anindita Deb, Veronica E Santini, Rashmi Halker, Tiffany L Fisher, Charles C Flippen, Eseosa Ighodaro, Nicole Rosendale, Vijay K Ramanan, Kiran Teresa Thakur, Nimish A Mohile.
      Neurologic disorders affect more than 200 million people in the United States, yet inequities in neurologic health persist particularly among marginalized populations. These disparities are rooted not in biological differences but in inequitable social, economic, and structural conditions and result in disproportionate disease burden, delayed diagnoses, restricted access to specialty care, and subpar brain health outcomes for populations experiencing health disparities (HDPs). Existing national health equity frameworks from the NIH demonstrate that neurologic inequities are shaped by intersecting social determinants of health (SDOH) and structural barriers that limit fair and just opportunities to achieve optimal brain health. In response, the American Academy of Neurology (AAN) proposes a comprehensive Roadmap to Neurologic Health Equity, grounded in the principle that every individual should have the opportunity to attain their highest level of brain health. The AAN roadmap provides a coordinated strategy to address health inequity across 4 domains: (1) Clinical Practice and Quality, (2) Scientific Knowledge and Research, (3) Education and Awareness, and (4) Advocacy. For clinical practice, the roadmap emphasizes integrating SDOH into clinical care delivery, expanding language services and culturally responsive models, and advancing workforce diversity to better reflect and serve diverse communities. Research priorities include strengthening rigor in disparities research, increasing participation of HDPs in clinical studies, and expanding training pathways for investigators committed to health equity. Educational initiatives focus on embedding health equity content throughout neurology curricula, enhancing clinician awareness of health disparities through AAN programming, and strengthening communication skills necessary for effective community engagement. The policy and advocacy framework targets systemic reforms such as expanding insurance coverage, improving reimbursement for complex neurologic care, investing in telehealth infrastructure, and addressing the national neurology workforce shortage through increased Graduate Medical Education funding and secure immigration pathways for international neurologists willing to serve in underserved areas. Together, these strategies provide a unified, actionable approach to advancing brain health equity across the lifespan. The AAN calls upon clinicians, researchers, educators, policymakers, and community advocates to join in implementing this roadmap and ensuring that the pursuit of optimal brain health is attainable and equitable for all.
    DOI:  https://doi.org/10.1212/WNL.0000000000214687
  38. Int J Mol Sci. 2026 Jan 24. pii: 1191. [Epub ahead of print]27(3):
    MitoTex (Mitochondria Texture Analysis User Interface): Open-Source Framework for Textural Characterization and Classification of Mitochondrial Structures.
    Amulya Kaianathbhatta, Malak Al Daraawi, Natasha N Kunchur, Rayhane Mejlaoui, Zoya Versey, Edana Cassol, Leila B Mostaço-Guidolin.
      Mitochondria are essential organelles involved in metabolism, energy production, and cell signaling. Assessing mitochondrial morphology is key to tracking cell metabolic activity and function. Quantifying these structural changes may also provide critical insights into disease pathogenesis and therapeutic responses. This work details the development and validation of a novel, quantitative image analysis pipeline for the characterization and classification of dynamic mitochondrial morphologies. Utilizing high-resolution confocal microscopy, the pipeline integrates first-order statistics (FOS) and a comprehensive suite of gray-level texture analyses, including gray level co-occurrence matrix (GLCM), gray level run length matrix (GLRLM), gray level dependence matrix (GLDM), gray level size zone matrix (GLSZM), and neighboring gray tone difference matrix (NGTDM) with machine learning approaches. The method's efficacy in objectively differentiating key mitochondrial structures-fibers, puncta, and rods-which are critical indicators of cellular metabolic and activation states is demonstrated. Our open-source pipeline provides robust quantitative metrics for characterizing mitochondrial variation.
    Keywords:  machine learning; microscopy; mitochondria; texture analysis
    DOI:  https://doi.org/10.3390/ijms27031191
  39. Int J Mol Sci. 2026 Jan 29. pii: 1345. [Epub ahead of print]27(3):
    Energy Allocation Resilience and Endocrine Integration.
    Corey B Schuler, Allison B Sayre, Lara Zakaria, Shawn Tassone, Alexander Rinehart, Richard Harris.
      Resilience is commonly framed as a psychological trait, yet clinical and experimental evidence demonstrates that resilience failures emerge concurrently across metabolic, endocrine, immune, and cognitive domains. This review examines resilience as a bioenergetic property constrained by how organisms allocate finite metabolic resources under stress. We synthesize evidence from endocrinology, mitochondrial biology, immunometabolism, and stress physiology to propose a parsimonious, hypothesis-driven Energy Allocation System (EAS) in which the hypothalamic-pituitary-adrenal (HPA), thyroid (HPT), and gonadal (HPG) axes are conceptualized as a coordinated energy-governance network. Despite extensive investigation within these individual fields, the literature lacks an integrative physiological framework explaining why multisystem stress responses co-occur in predictable endocrine and metabolic patterns. Within this framework, mitochondrial reserve capacity serves as the limiting substrate through which hormonal signals regulate mobilization, metabolic pacing, immune tolerance, and recovery. The reviewed literature supports predictable patterns of endocrine reorganization during energetic strain, including prioritization of glucocorticoid-mediated mobilization, constrained thyroid hormone activation, suppression of long-term anabolic investment, and impaired recovery following stress. These configurations reflect adaptive energy-conserving strategies rather than isolated organ dysfunction. The novelty of this review lies in organizing established biological mechanisms into a unified, energy-allocation-based framework that generates falsifiable predictions linking endocrine coordination to bioenergetic capacity and recovery dynamics. We further discuss how routinely available biomarkers and validated psychometric measures can be interpreted as functional readouts of energetic allocation rather than static disease markers. Framing resilience through coordinated energy governance offers a unifying mechanistic lens for interpreting multisystem stress responses and generates testable predictions for future experimental and clinical investigation.
    Keywords:  energy allocation; energy governance; hypothalamic-pituitary-adrenal axis; hypothalamic-pituitary-gonadal axis; hypothalamic-pituitary-thyroid axis; immunometabolism; mitochondrial reserve capacity; resilience; stress physiology; thyroid hormone metabolism
    DOI:  https://doi.org/10.3390/ijms27031345
  40. Molecules. 2026 Jan 30. pii: 490. [Epub ahead of print]31(3):
    Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.
    Patrycja Victoria Czaj, Karolina Szewczyk-Golec, Jarosław Nuszkiewicz, Alina Woźniak.
      Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key molecular features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss. Increasing evidence indicates that gut dysbiosis and alterations in microbiota-derived metabolites are involved in these processes through multiple pathways along the gut-brain axis. However, while broad compositional changes are well-documented, a critical knowledge gap remains regarding the specific biochemical signal transduction pathways translating dysbiosis into pathology. This narrative review addresses this gap by synthesizing current human and experimental studies addressing gut microbiota alterations in AD, PD, and ALS, with particular emphasis on the biochemical and molecular mechanisms mediated by gut-derived metabolites. Dysbiosis in neurodegenerative diseases is frequently associated with reduced abundance of short-chain fatty acid (SCFA)-producing bacteria and altered metabolism of SCFAs, bile acids, tryptophan-derived indoles, trimethylamine-N-oxide (TMAO), and lipopolysaccharides (LPS). These microbial metabolites have been shown to modulate intestinal and blood-brain barrier integrity, influence Toll-like receptor- and G protein-coupled receptor-dependent signaling, regulate microglial activation, and affect molecular pathways related to protein aggregation in experimental models. In addition, emerging evidence highlights the involvement of oxidative and nitrosative stress, immune-metabolic crosstalk, and altered xenobiotic metabolism in microbiota-host interactions during neurodegeneration. By integrating microbiological, metabolic, and molecular perspectives, this review underscores the important and emerging role of microbiota-derived molecules in neurodegenerative disorders and outlines key chemical and metabolic pathways that may represent targets for future mechanistic studies and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; gut microbiota; gut–brain axis; microbiota-derived metabolites; neurodegeneration; oxidative stress; short-chain fatty acids
    DOI:  https://doi.org/10.3390/molecules31030490
  41. Neurosci Appl. 2026 ;5 106982
    Old enough to be a model? On the role of maturity in stem cell-based models for neuropsychiatric disorders.
    Bingqing He, Erik Smedler.
      Mental disorders profoundly influence cognition, emotion, and self-perception, and collectively represent a major cause of global disability. Their onset spans distinct developmental periods, from early childhood in neurodevelopmental conditions such as autism spectrum disorder, through adolescence in eating and obsessive-compulsive disorders, to early adulthood in bipolar disorder and schizophrenia. Twin and family studies have established that these disorders are substantially heritable, and large-scale genomic analyses have identified numerous common and rare risk variants. Yet, the biological mechanisms through which genetic and environmental factors converge to shape disease trajectories remain elusive. Patient-derived induced pluripotent stem cells (iPSCs) have emerged as a promising tool for investigating disease-relevant mechanisms in human neurons and neural circuits. However, most iPSC-derived neural cells and organoids resemble embryonic/fetal-stage brain tissue in both molecular and functional characteristics, raising questions about their relevance for disorders that manifest later in life. In this narrative review, we discuss how developmental timing, both in disease onset and in cellular models, shapes the interpretation of iPSC-based findings. We outline how differences in neuronal maturity may constrain or enable mechanistic insight, summarize emerging methods for accelerating or extending neuronal aging in vitro, and consider how leveraging developmental immaturity might illuminate early pathogenic processes underlying mental disorders.
    DOI:  https://doi.org/10.1016/j.nsa.2026.106982
  42. Biol Reprod. 2026 Feb 09. pii: ioag035. [Epub ahead of print]
    DRP1 in Reproduction and Reproductive Aging.
    Cheng-Rung Huang, Yin-Hua Cheng, Yung-Chiao Chang, Pei-Ling Weng, Kuo-Chung Lan.
      Dynamin-related protein 1 (DRP1) is a central regulator of mitochondrial fission and plays a critical role in maintaining mitochondrial function, distribution, and turnover in reproductive cells. Mitochondrial integrity is essential for oocyte quality, folliculogenesis, fertilization, embryonic development, and ultimately, female reproductive longevity. In this review, we synthesize evidence from mammalian and invertebrate models to illustrate the essential roles of DRP1 in reproductive physiology and aging. Genetic deletion or pharmacologic inhibition of DRP1 results in mitochondrial clustering, energy failure, increased reactive oxygen species (ROS) production, meiotic arrest, and embryo fragmentation. Furthermore, DRP1 dysfunction has been increasingly implicated in age-associated reproductive decline due to impaired mitophagy and defective organelle crosstalk. Model systems such as mice, pigs, and C. elegans have demonstrated that DRP1 activity is modulated by metabolic and epigenetic pathways, including NAD+/sirtuin signaling and GTP metabolism. Therapeutic interventions aimed at restoring DRP1 function-including nicotinamide mononucleotide (NMN), coenzyme Q10 (CoQ10), and dietary modulation-have shown promising effects in delaying reproductive aging and improving oocyte or embryo competence in animal models. Despite the current absence of human interventional efficacy data, DRP1 is a plausible and testable target in reproductive biology, with preclinical findings indicating potential relevance to infertility treatment and reproductive aging. This review highlights DRP1 as a key target in reproductive biology, emphasizing its translational potential for treating infertility and mitigating age-related oocyte deterioration.
    Keywords:  Aging; DRP1; Fertility; Mitochondria; Oocyte; Reproduction
    DOI:  https://doi.org/10.1093/biolre/ioag035
  43. Cells. 2026 Jan 27. pii: 248. [Epub ahead of print]15(3):
    Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System.
    Feliciano Protasi, Matteo Serano, Alice Brasile, Laura Pietrangelo.
      In skeletal muscles fibers, cellular respiration, excitation-contraction (EC) coupling (the mechanism that translates action potentials in Ca2+ release), and store-operated Ca2+ entry (SOCE, a mechanism that allows recovery of external Ca2+ during fatigue) take place in organelles specifically dedicated to each function: (a) aerobic ATP production in mitochondria; (b) EC coupling in intracellular junctions formed by association between transverse tubules (TTs) and sarcoplasmic reticulum (SR) named triads; (c) SOCE in Ca2+entry units (CEUs), SR-TT junctions that are in continuity with membranes of triads, but that contain a different molecular machinery (see Graphical Abstract). In the past 20 years, we have studied skeletal muscle fibers by collecting biopsies from humans and isolating muscles from animal models (mouse, rat, rabbit) under different conditions of muscle inactivity (sedentary aging, denervation, immobilization by casting) and after exercise, either after voluntary training in humans (running, biking, etc.) or in mice kept in wheel cages or after running protocols on a treadmill. In all these studies, we have assessed the ultrastructure of the mitochondrial network and of the sarcotubular system (i.e., SR plus TTs) by electron microscopy (EM) and then collected functional data correlating (i) the changes occurring with aging and inactivity with a loss-of-function, and (ii) the structural improvement/rescue after exercise with a gain-of-function. The picture that emerged from this long journey points to the importance of the internal architecture of muscle fibers for their capability to function properly. Indeed, we discovered how the intracellular organization of the mitochondrial network and of the membrane systems involved in controlling intracellular calcium concentration (i[Ca2+]) is finely controlled and remodeled by inactivity and exercise. In this manuscript, we give an integrated picture of changes caused by inactivity and exercise and how they may affect muscle function.
    Keywords:  Ca2+ release unit (CRU); excitation-contraction (EC) coupling; mitochondria; sarcoplasmic-reticulum (SR); store-operated Ca2+ entry (SOCE); transverse tubule (TT); triad
    DOI:  https://doi.org/10.3390/cells15030248
  44. bioRxiv. 2026 Feb 02. pii: 2026.01.30.702567. [Epub ahead of print]
    "Tumor-to-endothelium mitochondrial transfer licenses endothelial cells for CD8 + T cell recognition via mitochondrial neoantigen presentation".
    Francesca Costabile, Pierini Stefano, Renzo Perales-Linares, Nektaria Leli, Adham Bear, Cameron J Koch, Beatriz M Carreno, Michael Lotze, Lerry Singh, Marny Falck, Andrea Facciabene.
      Renal cell carcinoma (RCC) frequently exhibits resistance to immune checkpoint blockade, highlighting the need for strategies that enhance tumor-specific T cell priming and improve immune access to the tumor microenvironment. Here we show that vaccination targeting tumor-associated mitochondrial antigens (TAMAs), derived from tumor-specific mitochondrial DNA (mtDNA) missense mutations, synergizes with PD-1/PD-L1 blockade to overcome checkpoint refractoriness in the RENCA RCC model. TAMAs vaccination elicits antigen-specific T cell responses, increases intratumoral CD8 + T cell infiltration, and reduces immunosuppressive myeloid populations, resulting in delayed tumor progression and improved survival when combined with checkpoint inhibition. In parallel, TAMAs + checkpoint blockade induces vascular remodeling characterized by increased pericyte coverage, reduced vascular leakage, improved perfusion and reduced hypoxia. Mechanistically, vascular remodeling is driven by CD8 + T cell-dependent, IFN γ -associated immune activity and is associated with endothelial apoptosis and diminished intratumoral CD31 signal. We further identify tumor-to-endothelium mitochondrial transfer as a mechanism linking mitochondrial neoantigens to the tumor vascular compartment: tumor-derived mitochondria enter human and mouse endothelial cells in vitro and in vivo , and tumor-associated mtDNA mutations are detectable in endothelial fractions from murine tumors and human RCC specimens. Human endothelial cells can present mitochondrial neoantigens via MHC class I and become targets of TAMAs-specific CD8 + T cell cytotoxicity, including following mitochondrial acquisition from tumor cells. Together, these findings establish mitochondrial neoantigen immunity as a tractable approach to enhance checkpoint responses and reveal mitochondrial transfer as an antigenic bridge that expands immune targeting to the tumor vasculature.
    DOI:  https://doi.org/10.64898/2026.01.30.702567
  45. Sleep Breath. 2026 Feb 13. 30(1): 45
    Sleep in MELAS syndrome.
    Alejandro Herrero San Martin, Eva María Arias, Cristina Dominguez Gonzalez, Montserrat Morales Conejo, Trinidad Diaz Cambriles.
      
    Keywords:  MELAS syndrome; Mitochondrial diseases; REM sleep behavior; Sleep; Sleep apnea
    DOI:  https://doi.org/10.1007/s11325-026-03611-4
  46. Mol Biol Rep. 2026 Feb 13. 53(1): 385
    Assay for numerical and graphical detection of Native American mitochondrial haplogroup B with real-time PCR.
    Richell Maribet Ramírez-Molina, Humberto García-Ortiz, Angélica González-Oliver.
      
    Keywords:  Melting curve; Melting temperature; Mitochondrial DNA; Mitochondrial haplogroup B ; Real-time PCR
    DOI:  https://doi.org/10.1007/s11033-026-11544-0
  47. Med. 2026 Feb 10. pii: S2666-6340(25)00420-9. [Epub ahead of print] 100993
    Analysis of biomarkers in the Human Phenotype Project using disease models from UK Biobank.
    David Pellow, Gil A Geva, Anastasia Godneva, Yotam Reisner, Yeela Talmor-Barkan, Eran Segal.
       BACKGROUND: We integrate longitudinal health outcomes from the UK Biobank (UKBB) with our own Human Phenotype Project (HPP) cohort. The HPP contains a range of data per participant that are not found in the UKBB, including microbiome, liver ultrasound, continuous glucose monitoring, and more. Conversely, the UKBB includes a much larger cohort and longer follow-up durations with large numbers of disease outcomes already tracked.
    METHODS: To leverage the scale and extended follow-up of the UKBB in our study, we model disease outcomes in the UKBB to predict pseudo-outcomes in the HPP. Correlating these predicted pseudo-outcomes with unique measurements in the HPP study, we identify individual biomarkers for those conditions, including those from gut microbiome, liver ultrasound, and other modalities. Multivariate analysis identifies the contribution of each modality in predicting each pseudo-outcome.
    FINDINGS: Our method enabled us to recapitulate known biomarkers across the spectrum of diseases studied as well as to reveal less-attested biomarkers in a range of different modalities. We further identify systemic biomarkers correlated with many diseases and sex-specific biomarkers with higher correlation to a pseudo-outcome for one sex as compared to the other.
    CONCLUSIONS: Our method enables analysis of biomarkers leveraging both the scale and follow-up of the UKBB and the unique measurements of the HPP. This analysis provides a broad perspective across the landscape of many diseases through the lens of many modalities, providing a framework for transferring knowledge from large longitudinal cohorts to smaller, more deeply phenotyped cohorts, advancing discovery across modalities.
    FUNDING: E.S. is supported by the European Research Council and the Israel Science Foundation.
    Keywords:  biobanks; disease biomarkers; disease outcome prediction; human phenotype project; survival models; translation to population health
    DOI:  https://doi.org/10.1016/j.medj.2025.100993
  48. Chin Med J (Engl). 2026 Feb 13.
    Regulation of mitochondrial biogenesis and energy metabolism in the heart.
    Peilu She, Fei Mo, Ping Zhu, Tao P Zhong.
       ABSTRACT: Mitochondrial homeostasis is regulated by processes such as biogenesis, dynamics, and mitophagy, and is essential for maintaining cardiac function while preserving structural integrity, energy supply, and redox balance. Given their high reliance on mitochondrial adenosine triphosphate generation, cardiomyocytes are particularly vulnerable to mitochondrial dysfunction. In the cardiovascular system, mitochondria respond to various pathophysiological conditions, such as ischemia-reperfusion injury, hypertension, diabetic cardiomyopathy, and heart failure. Mitochondrial impairment drives cardiovascular disease progression through deficient energy production, elevated oxidative stress, activation of inflammatory responses, and programmed cell death. Growing evidence highlights the critical roles of epigenetic and transcriptional networks in the coordinated regulation of mitochondrial biogenesis and metabolism. Targeting these processes is a promising therapeutic strategy to improve mitochondrial health in cardiovascular diseases. This review systematically summarizes recent advances, outlines the key regulatory mechanisms of mitochondrial biogenesis and metabolism, and explores their pathophysiological roles and therapeutic potential.
    Keywords:  Epigenetics; Heart; Homeostasis; Mitochondria; Transcription
    DOI:  https://doi.org/10.1097/CM9.0000000000004011
  49. Cell Tissue Res. 2026 Feb 13. 403(2): 20
    Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.
    Rizwan Qaisar.
      Extracellular vesicles (EVs) have emerged as pivotal modulators of neuromuscular junction (NMJ) biology, reshaping our understanding of synaptic communication, maintenance, and degeneration. This review consolidates current insights into the roles of EVs derived from motor neurons, muscle fibers, and Schwann cells in regulating NMJ integrity. In healthy states, EVs deliver trophic factors, structural proteins, and regulatory RNAs that promote the clustering of acetylcholine receptors, presynaptic stability, and axonal growth. Motor neuron EVs carry Wnt7a, synaptophysin, and PGC-1α, while muscle-derived EVs deliver miR-206, agrin, and caveolin-3. Schwann cell EVs contribute neurotrophic support via NRG1 and GDNF. In contrast, diseased or aged NMJs exhibit EV cargo dysregulation, marked by the presence of misfolded proteins (e.g., SOD1, TDP-43), pro-inflammatory cytokines, and reduced regenerative miRNAs. These changes contribute to synaptic dismantling, neuroinflammation, and impaired repair in conditions such as ALS, SMA, MG, and sarcopenia. The review highlights the bidirectional nature of EV signalling and its dynamic regulation by neuronal activity and stress. Emerging therapeutic strategies include engineering EVs to deliver protective cargo, targeting them to NMJ components, and designing biomaterial-based depots for sustained release. Furthermore, EV signatures in blood and muscle hold promise as non-invasive biomarkers for early detection of NMJ decline in ALS, SMA, MG, and sarcopenia. Despite promising preclinical data, challenges remain in EV characterization, targeting specificity, and clinical translation. This review underscores a paradigm shift: EVs are not passive byproducts but active messengers of neuromuscular health and disease, with realistic applications in diagnostics, regenerative therapy, and personalized medicine.
    Keywords:  EV-based therapeutics; Extracellular vesicles; Motor neuron disease; Neuromuscular junction; Sarcopenia
    DOI:  https://doi.org/10.1007/s00441-026-04050-z
  50. Neurology. 2026 Mar 24. 106(6): e214645
    Diagnostic Yield of Comprehensive Reanalysis After Nondiagnostic Short-Read Genome Sequencing in Infants With Unexplained Epilepsy.
    Gene-STEPS Study Group, IPCHiP Executive Committee,
       BACKGROUND AND OBJECTIVES: The highest incidence of epilepsy in childhood occurs in the first year of life. Infantile epilepsies are associated with substantial morbidity and mortality. Although most are presumed to have genetic etiologies, many infants with nonacquired epilepsy remain genetically unsolved after clinical genome sequencing. The yield of reanalysis after nondiagnostic genome sequencing in this population is unknown. We aimed to determine the diagnostic yield of comprehensive reanalysis after nondiagnostic genome sequencing in infants with unexplained epilepsy.
    METHODS: This cohort study included infants with unexplained epilepsy or complex febrile seizures who were recruited from 4 pediatric referral centers from September 2021 to March 2024 and had nondiagnostic clinical rapid genome sequencing. We performed comprehensive reanalysis of genome sequencing data from infants and available biological parents using multiple bioinformatics pipelines through July 2025 and clinically confirmed reanalysis findings. The primary outcome was diagnostic yield of genome sequencing reanalysis, defined as the percentage of infants who received genetic diagnoses from reanalysis. The secondary outcome was clinical utility of reanalysis findings.
    RESULTS: From an initial cohort of 312 infants with unexplained epilepsy who underwent clinical rapid genome sequencing, we performed comprehensive genome reanalysis in 176 infants with initially nondiagnostic results at a median age of 642 days, including 63 female patients (36%) and 30 (17%) with neonatal-onset seizures. The diagnostic yield of reanalysis was 5.1% (9/176, 95% CI 2.4%-9.5%), increasing the overall yield from 43.6% (136/312, 95% CI 38.0%-49.3%) to 46.5% (145/312, 95% CI 40.8%-52.2%). Of the new diagnoses, 6 involved variants not reported by clinical laboratories (2 single nucleotide variants, 2 structural variants, 1 tandem repeat expansion, 1 mosaic variant) and 3 involved previously reported variants of uncertain significance with new evidence. All diagnoses had clinical utility.
    DISCUSSION: Comprehensive reanalysis after nondiagnostic rapid genome sequencing has utility for infants with unexplained epilepsy. Our findings support implementation of reanalysis within 1-2 years after nondiagnostic genomic sequencing into routine clinical care of children with unexplained epilepsy and the expansion of clinically accredited genomic sequencing to include complex and noncoding variant detection.
    DOI:  https://doi.org/10.1212/WNL.0000000000214645
  51. Phytomedicine. 2026 Feb 05. pii: S0944-7113(26)00162-5. [Epub ahead of print]153 157923
    Ginsenoside Rg5 targets the KAT8-CISD2 axis to maintain mitochondrial homeostasis and antagonize senescence.
    Jinmeng Chu, Qingzhi Zhao, Yizhen Wang, Chengyu Cai, Xueli Cui, Na Zhang, Tiantian Xu, Haoqing Dou, Fei Wang, Feiran Yu, Yong Cai, Jingji Jin.
       BACKGROUND: Mitochondria are central regulators of cellular energy metabolism and its dysfunction drives cellular senescence. CISD2, a mitochondrial outer membrane protein and longevity gene, declines with age, highlighting its role in cellular senescence; however, how its post-translational modifications (PTMs) regulate cellular senescence remains poorly understood.
    PURPOSE: This study aimed to elucidate the molecular mechanisms by which ginsenoside Rg5, as a regulator of histone acetyltransferase KAT8 activity, modulates CISD2 PTMs and thereby exerts anti-aging effects.
    METHODS: Using SILAC-based acetyl-proteomics, CISD2 was identified as a substrate of the KAT8/MSL acetyltransferase complex. The interaction between KAT8 and CISD2 was examined by Co-immunoprecipitation, GST pull-down, cycloheximide chase, and protein stability assays. KAT8-mediated acetylation of CISD2 was evaluated using in vitro lysine acetyltransferase assays, modification-specific antibodies, and site-directed mutagenesis. The functional impact of CISD2 acetylation on mitochondrial homeostasis was assessed by comparing CISD2 wild-type and K74 mutant cell lines using a series of assays, including ROS production, JC-1 staining, ATP measurement, SA-β-Gal staining, and analyses of mitochondrial morphology. The interaction between Rg5 and KAT8 was investigated using cellular thermal shift assays (CETSA), Rg5-PEGA pull-down, competitive binding assays, and UV-absorption spectroscopy. Evolutionary conservation was evaluated in C. elegans through genetic depletion of mys-2 (the KAT8 homolog) and cisd-1 (the CISD2 homolog). Mitochondrial function (JC-1, DCFH-DA, mtDNA content, and ATP levels) and cellular senescence (SA-β-Gal staining, EdU incorporation, and CCK-8 assays) were assessed in senescent cells and in C. elegans following CISD-1 and/or MYS-2 RNAi.
    RESULTS: We demonstrate for the first time that the KAT8/MSL complex acetylates CISD2 at K74, thereby preventing STUB1-mediated ubiquitination and degradation at K105. Importantly, acetylation of CISD2 at K74 preserves mitochondrial homeostasis and enhances cellular resistance to oxidative stress and aging. In C. elegans, simultaneous knockdown of MYS-2 and CISD-1 exacerbates mitochondrial dysfunction and shortens lifespan. Moreover, ginsenoside Rg5 directly binds to KAT8, promotes CISD2 acetylation at the K74 site, maintaining mitochondrial homeostasis, and alleviates aging-associated phenotypes in both cells and nematodes.
    CONCLUSION: This study reveals that KAT8-mediated acetylation of CISD2 at K74 preserves mitochondrial homeostasis by inhibiting ubiquitin-mediated degradation, representing a critical mechanism for counteracting cellular senescence. Ginsenoside Rg5 acts as a KAT8 agonist to target and activate this pathway, thereby providing a novel strategy for anti-aging intervention.
    Keywords:  Acetylation; CISD2; Cellular senescence; Ginsenoside Rg5; KAT8; Mitochondria
    DOI:  https://doi.org/10.1016/j.phymed.2026.157923
  52. ArXiv. 2026 Feb 03. pii: arXiv:2602.04058v1. [Epub ahead of print]
    RareCollab -- An Agentic System Diagnosing Mendelian Disorders with Integrated Phenotypic and Molecular Evidence.
    Guantong Qi, Jiasheng Wang, Mei Ling Chong, Zahid Shaik, Shenglan Li, Shinya Yamamoto, Undiagnosed Diseases Network, Pengfei Liu, Hu Chen, Zhandong Liu.
      Millions of children worldwide are affected by severe rare Mendelian disorders, yet exome and genome sequencing still fail to provide a definitive molecular diagnosis for a large fraction of patients, prolonging the diagnostic odyssey. Bridging this gap increasingly requires transitioning from DNA-only interpretation to multi-modal diagnostic reasoning that combines genomic data, transcriptomic sequencing (RNA-seq), and phenotype information; however, computational frameworks that coherently integrate these signals remain limited. Here we present RareCollab, an agentic diagnostic framework that pairs a stable quantitative Diagnostic Engine with Large Language Model (LLM)-based specialist modules that produce high-resolution, interpretable assessments from transcriptomic signals, phenotypes, variant databases, and the literature to prioritize potential diagnostic variants. In a rigorously curated benchmark of Undiagnosed Diseases Network (UDN) patients with paired genomic and transcriptomic data, RareCollab achieved 77% top-5 diagnostic accuracy and improved top-1 to top-5 accuracy by ~20% over widely used variant-prioritization approaches. RareCollab illustrates how modular artificial intelligence (AI) can operationalize multi-modal evidence for accurate, scalable rare disease diagnosis, offering a promising path toward reducing the diagnostic odyssey for affected families.
  53. Front Neurol. 2025 ;16 1737468
    CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.
    Raya Kh Yashooa, Ari Q Nabi, Shukur Wasman Smail, Sarkar Sardar Azeez, Wissam Albeer Nooh, Suhad A Mustafa, Abd Al-Bar Al-Farha, Nazzareno Capitanio, Mudhir Sabir Shekha.
      CRISPR-Cas genome-editing technologies have emerged as powerful tools for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review critically evaluates current CRISPR/Cas applications in neurodegeneration, with emphasis on mechanistic insights, therapeutic outcomes, and translational feasibility. Preclinical and early translational studies demonstrate that CRISPR-Cas platforms can correct pathogenic mutations, suppress toxic gene expression, and restore neuronal function. Advanced modalities, including base and prime editing, CRISPRi/a, and RNA-targeting Cas systems, improve precision and reduce genomic damage, which is particularly advantageous in post-mitotic neurons. Emerging CRISPR-based diagnostics (e.g., SHERLOCK and DETECTR), AI-assisted sgRNA design, and machine-learning approaches for predicting off-target effects further enhance the safety, stratification, and monitoring of CRISPR therapeutics. In parallel, patient-derived brain organoids and assembloids provide scalable human-relevant platforms for mechanistic studies and preclinical validation. Despite this progress, major challenges remain, including efficient delivery across the blood-brain barrier, immune responses, long-term safety, and ethical and regulatory considerations. Overall, CRISPR-Cas technologies hold strong potential as disease-modifying interventions for neurodegenerative disorders, provided that advances in delivery systems, artificial intelligence integration, and regulatory oversight continue to evolve toward clinical translation.
    Keywords:  CRISPR–Cas; applications; challenges; neurodegenerative disorders; therapeutic strategies
    DOI:  https://doi.org/10.3389/fneur.2025.1737468
  54. Orphanet J Rare Dis. 2026 Feb 12.
    Myopathy and ataxia related to impaired mitochondrial function in mevalonate kinase deficiency.
    Alessia Pugliese, Christina von Landenberg, Romina Gallizzi, Alba Migliorato, Sabata Pierno, Carmelo Rodolico, Cornelia Kornblum, Ignazio Giuseppe Arena, Wolfram S Kunz, Jens Reimann, Antonio Toscano, Olimpia Musumeci.
      
    Keywords:  Ataxia; Coenzyme Q10; Metabolic myopathy; Mevalonate kinase deficiency; Mevalonic aciduria; Mitochondrial dysfunction; hyperCKemia
    DOI:  https://doi.org/10.1186/s13023-026-04248-y
  55. Kidney Med. 2026 Mar;8(3): 101233
    Mitochondrial DNA Analysis Should Be Considered in the Genetic Assessment of Focal Segmental Glomerulosclerosis or Unexplained Chronic Kidney Disease: A Case Report.
    Chloe Borden, Iman Chaudhry, Rhyan Maditz, Sarah Mazzola, Ronit Salomon Kent, Kristen Tomaszewski, Xiangling Wang.
      Genetic testing is increasingly used to assist the precise diagnosis and clinical management of suspected genetic kidney diseases; however, mitochondrial DNA (mtDNA) analysis remains underutilized. Here we report a 61-year-old man who presented with chronic kidney disease (CKD), microscopic hematuria since childhood, bilateral sensorineural hearing loss (SNHL), and peripheral polyneuropathy. Laboratory reports showed serum creatinine 1.5 mg/dL with an estimated glomerular filtration rate of 55 mL/min/1.73m2, no proteinuria, and a negative serological workup. Kidney biopsy demonstrated focal segmental glomerulosclerosis (FSGS) with segmental thinning of glomerular basement membrane and dysmorphic mitochondria. A 401 renal disease gene panel was negative, including type IV collagen genes. mtDNA analysis identified a pathogenic variant in the MT-TV gene (m.1642 G>A; NC_012920.1) with 2% heteroplasmy in leukocyte-derived DNA, confirmed in urine-derived DNA at 5% heteroplasmy. Genetic counseling was offered along with systemic evaluation revealing left ventricular hypertrophy on echocardiogram. The patient was started on levocarnitine and coenzyme Q10 with multidisciplinary care. This is the first reported case of FSGS with dysmorphic mitochondria and a pathogenic MT-TV variant confirmed via both leukocyte-derived and urine-derived DNA. It supports the role of mitochondrial dysfunction in CKD and highlights the importance of mtDNA analysis in the evaluation of FSGS and unexplained CKD.
    Keywords:  Mitochondrial disorders; case report; chronic kidney disease (CKD); focal segmental glomerulosclerosis (FSGS); genetic testing
    DOI:  https://doi.org/10.1016/j.xkme.2025.101233
  56. Biomed Pharmacother. 2026 Feb 06. pii: S0753-3322(26)00136-8. [Epub ahead of print]196 119104
    Telomerase and chronic inflammation as central molecular links in aging.
    Temesgen Baylie, Endalkachew Gugsa, Mohammed Jemal, Gelagay Baye, Mamaru Getinet, Gashaw Azanaw Amare, Adane Adugna, Desalegn Abebaw, Zigale Hibstu, Bantayehu Addis Tegegne, Tadegew Adane, Baye Ashenef, Deresse Sinamaw.
      Unraveling complex mechanisms of telomere biology is central to understanding the close link between aging and inflammation. Telomeres are repetitive heterochromatin DNA structures at the ends of eukaryotic chromosomes, and their length is universally accepted as a marker of biological aging. Telomeres progressively shorten with every cell division until they ultimately trigger cellular senescence and apoptosis. Telomere shortening is also promoted by chronic inflammation and oxidative stress. Chronic inflammation and oxidative stress have been shown to be key drivers of age-related diseases, including neurodegeneration, cardiovascular disease, and cancer. Telomerase is central regulator at the intersection of genomic stability, mitochondrial function, epigenetic integrity, and proteostasis. Through its direct and indirect actions, telomerase modulates inflammatory pathways that drive aging and age-related diseases, highlighting its potential as a therapeutic target to mitigate inflammaging and extend healthspan.
    Keywords:  Aging; Cellularsenescence; Inflammation; Telomeres
    DOI:  https://doi.org/10.1016/j.biopha.2026.119104
  57. Annu Rev Biophys. 2026 Feb 10.
    Systems Biology of Aging, Metabolism, and Mitochondria.
    Miguel Antonio Aon, Sonia Cortassa.
      Since the beginning of this century, the emergence of systems biology, driven by technological, informatic, and theoretical advances, has led to an unprecedented generation of data and information about biological systems at multiple levels of organization. We now have access not only to components of living systems but also to some of the underlying principles governing their organization within networks. This review focuses on the systems biology of aging, metabolism, and mitochondria, along with the integration of experimental and computational systems biology approaches as applied to multilayered biological networks, spanning from the molecular-subcellular to the whole organism. Sections 2 and 3 provide an overview of the insights gained from systems biology and multi-omics approaches as applied to aging and metabolism. Using the spatiotemporal dynamics of biological networks as a unifying thread, Sections 4 and 5 explore how systems biology and current methods can leverage the understanding of complex biological phenomena through integrated experimental-computational strategies, utilizing iterative, verification-validation loops between experiments and models. Section 6 concludes by highlighting the autonomously dynamic, self-organizing, and self-regulating integrative nature of living systems and the need to address these properties at the emerging convergence of biology, medicine, physics, and powerful computational technologies that include artificial intelligence.
    DOI:  https://doi.org/10.1146/annurev-biophys-021424-011852
  58. Front Neurosci. 2026 ;20 1742318
    Case Report: Progressive myoclonus epilepsy as an early manifestation of neuronopathic Gaucher disease.
    Zhou Fang, Xixi Sun, Ying Hu, Chengjuan Xie, Xingui Chen, Yubao Jiang.
      Gaucher disease (GD) is a lysosomal storage disorder caused by biallelic GBA1 variants. Epilepsy is uncommon in GD and rarely manifests as progressive myoclonus epilepsy (PME), making early recognition difficult. We describe a 20-year-old man with childhood-onset myoclonus that progressed to drug-resistant generalized seizures and cognitive decline. Video-electroencephalography (VEEG) showed generalized polyspike-wave discharges associated with myoclonic jerks, whereas brain magnetic resonance imaging was initially normal. Cerebrospinal fluid studies, metabolic screening, and autoimmune encephalitis antibody panels were unremarkable. Glucocerebrosidase activity was markedly reduced, and a targeted myoclonic-epilepsy gene panel identified two GBA1 variants: c.907C > A (p. Leu303Ile) and c.1505G > A (p. Arg502His), indicating a presumed compound-heterozygous state consistent with neuronopathic GD type 3. No hepatosplenomegaly or skeletal abnormalities were detected. Seizure control remained poor despite multiple antiseizure medications and vagus nerve stimulation (VNS). To contextualize this case, we systematically reviewed 22 publications encompassing 71 GD3-PME patients. Most cases presented in childhood, frequently showed typical electrophysiological patterns of generalized or multifocal polyspike-wave discharges, and had early normal MRI followed by later cerebellar or brainstem atrophy. Recurrent compound-heterozygous GBA1 variants, markedly reduced enzyme activity, and poor therapeutic response were common findings. The accompanying systematic review highlights the heterogeneity and therapeutic limitations of GD3-associated PME and underscores the importance of incorporating metabolic and genetic testing into the evaluation of unexplained PME for timely diagnosis and tailored management.
    Keywords:  GBA1 variant; case report; drug-resistant epilepsy; neuronopathic Gaucher disease; progressive myoclonus epilepsy
    DOI:  https://doi.org/10.3389/fnins.2026.1742318
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