bims-polgdi Biomed News
on POLG disease
Issue of 2026–04–12
forty papers selected by
Luca Bolliger, lxBio
  1. Ophthalmic manifestations of mitochondrial disorders.
  2. A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
  3. Mitochondrial Transfer: From Bench to Bedside.
  4. Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
  5. Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
  6. Reframing AI for Rare Disease Recognition.
  7. Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
  8. Rethinking Mitochondria: The Extracellular Dimension.
  9. Mitochondria transfer in tissue homeostasis and diseases.
  10. Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
  11. Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.
  12. Silver nanoparticles induce binding of mitochondrial DNA polymerase gamma subunit Polg2 and mitochondrial dysfunction in HeLa cells.
  13. Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
  14. Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
  15. Intercellular Mitochondrial Transfer: Implications in Cardiovascular Health.
  16. The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
  17. Beyond Hemoglobin polymerization: Mitochondrial Pathobiology and Therapeutic Frontiers in Sickle Cell Disease.
  18. The role of real-world data and real-world evidence in advancing regulatory science and targeted therapeutics: a narrative review from the United States perspective.
  19. Metabolomics across scales: from single cells to population studies.
  20. Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.
  21. Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
  22. Public support for mitochondrial donation: an Australian knowledge and attitudes study.
  23. Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
  24. Mitochondrial Quality Control as a Central Pharmacological Target in Aging.
  25. MitoEdit: A pipeline for optimizing mtDNA base editing and predicting bystander effects.
  26. Bringing the rare into sight: applications of haploidentical stem cell transplantation in the treatment of rare diseases.
  27. mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.
  28. The Role of Digital Tools and Their Implementation Within Patient Care Pathways for Rare Brain Disorders: The Case of Phenylketonuria.
  29. Deep learning-based stratification of Schizophrenia Spectrum Disorder from real-world data reveals distinct profiles of common and rare variant genetic signal.
  30. Experiences from inborn errors of immunity registry of India: A preliminary report.
  31. Delivering Health Education to Children With Chronic Conditions: A Scoping Review and Evidence and Gap Map.
  32. Beyond disease treatment and prevention: From geroscience and molecular hallmarks to gerotherapeutics and precision geromedicine.
  33. IL-13 promotes accumulation of esophageal epithelial mitochondria with translational implications for eosinophilic esophagitis.
  34. CRISPR-Cas Systems in Human Disease Therapy: Advances, Clinical Applications, Limitations, and Future Directions.
  35. High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.
  36. Temporal AI model predicts drivers of cell state trajectories across human aging.
  37. Recalibrating cell fate: targeting the mitochondrial signaling hub with natural active compounds to inhibit regulated cell death in diabetic kidney disease.
  38. Dual role of MIF in aging and cellular senescence.
  39. Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
  40. Mitochondrial dysfunction in Alzheimer's disease and related sex differences.
  1. Prog Retin Eye Res. 2026 Apr 03. pii: S1350-9462(26)00032-7. [Epub ahead of print] 101466
    Ophthalmic manifestations of mitochondrial disorders.
    Megan F Baxter, Grace A Borchert, Emma L Blakely, Claire W Ruan, Robert E MacLaren, Robert McFarland, Robert W Taylor.
      Mitochondrial diseases are the most common group of inherited neurometabolic disorders and frequently involve multiple organ systems with high energy demands. Ophthalmic manifestations are a common occurrence in affected individuals and may be the earliest or predominant clinical feature. However, the marked clinical heterogeneity of mitochondrial eye disease often delays recognition and therefore diagnosis. Mitochondria play a central role in cellular metabolism through the process of oxidative phosphorylation. Genetic mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can impair this key metabolic process leading to clinical disease. Diagnosing such mitochondrial diseases is however often complicated - the same genetic change can result in different symptoms (variable expressivity); different genes can cause similar conditions (allelic and locus heterogeneity); a single genetic change may affect multiple body systems (pleiotropy); and the proportion of affected mitochondrial DNA molecules can vary between tissues (mtDNA heteroplasmy). While the diagnostic process will certainly be influenced by the initial clinical presentation, perhaps more important is clinician awareness and early consideration of an underlying mitochondrial disorder. Early and accurate molecular genetic diagnosis is both available and essential, not only for prognostication and management, but also for reproductive counselling, access to appropriate clinical trials, cascade testing of relevant family members and consideration of emerging mitochondrial therapeutics(1,2). In this review, we summarise the biochemical and genetic foundations of mitochondrial eye disease, describe the spectrum of clinical phenotypes, outline diagnostic approaches and considerations, and highlight the importance of precise early diagnosis in guiding management and reproductive decision-making.
    Keywords:  mitochondria; mitochondrial counselling; ophthalmology
    DOI:  https://doi.org/10.1016/j.preteyeres.2026.101466
  2. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123
    A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
    Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.
      Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.
    Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis
    DOI:  https://doi.org/10.1073/pnas.2535453123
  3. Circ Res. 2026 Apr 10. 138(8): e326984
    Mitochondrial Transfer: From Bench to Bedside.
    Gentaro Ikeda, Jiwen Li, Alyssa Wang, Amogha Medha Paleru, Phillip C Yang.
      Intercellular mitochondrial transfer has emerged as a fundamental mechanism of tissue adaptation and repair in the cardiovascular system, with major implications for cardiovascular, neurological, metabolic, and inflammatory diseases. Once thought to be static, mitochondria are now recognized as mobile organelles that move between cells via tunneling nanotubes, extracellular vesicles, and free mitochondria. These pathways support 2 complementary axes of mitochondrial communication: Rescue by Replenish, in which healthy mitochondria or mitochondrial components restore bioenergetics and stress resistance in recipient cells, and Relief by Release, in which damaged mitochondria are exported for degradation to preserve homeostasis and limit inflammation. We summarize the molecular machinery governing tunneling nanotube formation, mitochondria-derived vesicle biogenesis, extracellular vesicle sorting, and free mitochondrial release and uptake, and discuss how these processes shape organ function. Building on these mechanistic insights, we outline 4 translational strategies: (1) cell-based therapies that donate healthy mitochondria or scavenge damaged ones; cell-free approaches using (2) mitochondria-containing extracellular vesicles or (3) purified mitochondria; (4) pharmacological, nutritional, and lifestyle interventions that augment endogenous mitochondrial turnover and intercellular exchange. Finally, we discuss key barriers to clinical translation, including inflammatory and oncogenic risks, mitonuclear incompatibility, incomplete understanding of the fate and durability of transferred mitochondria, and the lack of standardized manufacturing, potency assays, and long-term storage methods. Continued integration of mechanistic biology with bioengineering and regulatory science will be essential to safely move mitochondrial transfer-based therapies from bench to bedside in cardiovascular medicine.
    Keywords:  cell communication; energy metabolism; extracellular vesicles; homeostasis; inflammation; mitochondria; nanotubes
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326984
  4. Circ Res. 2026 Apr 10. 138(8): e326987
    Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
    Florian Tupin, Jorge A Gonzalez-Chapa, Jay H Chung, Christian Lood, Eric Boilard.
      Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions after platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of antimitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context.
    Keywords:  DNA, mitochondrial; autoantibodies; immunity, adaptive; immunity, innate; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326987
  5. Circ Res. 2026 Apr 10. 138(8): e326982
    Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
    Gwang-Bum Im, Juan M Melero-Martin.
      Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.
    Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
  6. Res Sq. 2026 Apr 02. pii: rs.3.rs-9036259. [Epub ahead of print]
    Reframing AI for Rare Disease Recognition.
    Wei-Qi Wei, Chao Yan, Wu-Chen Su, Yi Xin, Monika Grabowska, Vern Kerchberger, Victor Borza, Jinlian Wang, Liwei Wang, Rui Li, Jacob Lynn, Alyson Dickson, Cathy Shyr, QiPing Feng, C Stein, Kai Wang, Peter Embí, Bradley Malin, Hongfang Liu.
      Rare diseases affect over 300 million people worldwide, yet patients often endure years-long diagnostic delays that limit timely intervention and trial opportunities. Computational rare disease recognition (RDR) remains constrained by knowledge resources that are often incomplete, heterogeneous, and dependent on extensive multi-disciplinary expert curation that cannot scale. Large language models (LLMs) applied directly for end-to-end diagnosis or disease discrimination face similar knowledge bottlenecks while also raising concerns around cost, reproducibility, and data governance. Here, we introduce GEN-KnowRD, a knowledge-layer-first framework that leverages LLMs to generate schema-guided rare disease profiles, systematically assesses their quality, and constructs a computable knowledge base (PheMAP-RD) for local deployment. GEN-KnowRD integrates this knowledge into lightweight inference pipelines for both general-purpose disease screening and specialized early discrimination from longitudinal electronic health records. In tests using six public benchmarks for general-purpose screening (9,290 patients spanning 798 rare diseases), GEN-KnowRD substantially improved disease ranking versus 1) a state-of-the-art, HPO-centered diagnostic framework (up to 345.8% improvement in top-1 success), 2) advanced end-to-end LLM reasoning (up to 129.1% improvement), and 3) a variant of GEN-KnowRD instantiated with expert-curated knowledge rather than LLM-generated profiles. In two real-world cohorts for early diagnosis of idiopathic pulmonary fibrosis (511 patients) as a use case, GEN-KnowRD also demonstrated robust discrimination performance gains, supporting effective RDR during the pre-diagnostic window. These findings demonstrate that repositioning LLMs from diagnostic reasoning to the knowledge layer-decoupling knowledge construction from patient-level inference-yields stronger RDR, while providing scalable, continuously updatable, and reusable infrastructure for diagnosis, screening, and clinical research across the rare disease landscape.
    DOI:  https://doi.org/10.21203/rs.3.rs-9036259/v1
  7. Circ Res. 2026 Apr 10. 138(8): e326985
    Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
    Xi Fang, Åsa B Gustafsson.
      Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.
    Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
  8. Circ Res. 2026 Apr 10. 138(8): e326988
    Rethinking Mitochondria: The Extracellular Dimension.
    Laura Pena-Couso, Magdalena Makuch, Jose Angel Nicolas-Avila.
      Mitochondria are essential organelles that transform the energy contained in metabolic substrates into ATP while supporting numerous cellular processes. Traditionally regarded as strictly intracellular, growing evidence now demonstrates that mitochondria and mitochondria-derived components can also be released into the extracellular space, giving rise to extracellular mitochondria. extracellular mitochondria display remarkable heterogeneity, ranging from intact organelles to individual molecular components, free to vesicle-encapsulated structures, and with functional states spanning from severely damaged to metabolically active. Their release is mediated by tightly regulated mechanisms in both living and dying cells, and is influenced by cellular stress, activation state, and pathways that control mitochondrial selection, compartmentalization, trafficking, and extrusion. Extracellular release fulfills multiple functions across the organism, including quality control, modulation of cellular identity, inflammatory signaling, and functional support of recipient cells. In the cardiovascular system, extracellular mitochondria contribute to both homeostasis and disease progression. This review summarizes current knowledge of extracellular mitochondria forms, mechanisms of release, and pathophysiological relevance, and highlights their emerging potential as therapeutic targets in cardiovascular pathophysiology and beyond.
    Keywords:  cardiovascular system; extracellular space; homeostasis; mitochondria; organelles
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326988
  9. Int J Biol Sci. 2026 ;22(6): 3144-3173
    Mitochondria transfer in tissue homeostasis and diseases.
    Lei Qin, Donghao Gan, Zecai Chen, Zhen Xu, Mingyue Wu, Bimin Gao, Yufeng Long, Xihong Mou, Wenqing Li, Weihong Yi, Guozhi Xiao.
      Mitochondria serve as the essential powerhouse for virtually all eukaryotic cells and have been implicated in other crucial functions in both physiological and disease contexts. As cytoplasmic organelles, mitochondria are segregated and transported from parent to daughter cells during division or differentiation, a process known as vertical mitochondria transfer (VMT). A growing body of literature indicates that various cell types can export mitochondria for delivery to developmentally unrelated cell types without division, a process termed horizontal mitochondria transfer (HMT). In this review, we summarize current understanding of the modes of mitochondria transfer and illustrate the phenomenon of HMT across different tissue backgrounds, including the immune, cardiovascular, respiratory, hepatic, renal, musculoskeletal, adipose, and reproductive systems. Moreover, updated applications and functions of mitochondria transfer are discussed. Additionally, we also highlight the therapeutic potential of mitochondria transfer in current preclinical and clinical trials for inherited mitochondrial diseases, cancer, wound healing, and injuries of the respiratory and central nervous systems.
    Keywords:  extracellular vesicles (EVs); gap junctions (GJs); horizontal mitochondria transfer; intercellular mitochondria transfer; tunneling nanotubes (TNT); vertical mitochondria transfer
    DOI:  https://doi.org/10.7150/ijbs.129709
  10. Front Bioeng Biotechnol. 2026 ;14 1765995
    Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
    Evgeniy V Lapshin, Alexander D Egorov, Alexander S Malogolovkin, Nizami B Gasanov, Svetlana A Smirnikhina, Vyacheslav Yu Tabakov, Alexander V Karabelsky.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by central vision loss, primarily resulting from mutations disrupting the electron transport chain. The most prevalent LHON-causing mutation is mt.11778G>A in the mitochondrial MT-ND4 gene, which encodes a critical subunit of complex I. Allotopic expression, a promising gene therapy strategy, aims to deliver a functional nuclear version of ND4 into the cell nucleus and target the resulting protein to the mitochondria. The efficiency of this approach critically depends on the mitochondrial targeting signal used. In this study, we screened five different MTS sequences to optimize the allotopic expression of ND4 in a HEK-293 cellular model of LHON harboring the mt.11778G>A mutation. We identified MTS-cox8k as the most effective signal for restoring mitochondrial function. Treatment with this construct significantly mitigated key pathological hallmarks: reactive oxygen species decreased by 72%, mitochondrial calcium levels dropped by 47%, and mitochondrial membrane potential (ΔΨm) increased by 38%. These results underscore the therapeutic potential of allotopic ND4 expression and highlight the critical importance of MTS optimization for developing effective treatments for mitochondrial diseases like LHON.
    Keywords:  Leber’s neuropathy; gene therapy; mitochondrial function test; mitochondrial localization; mitochondrial transport
    DOI:  https://doi.org/10.3389/fbioe.2026.1765995
  11. Free Radic Biol Med. 2026 Apr 06. pii: S0891-5849(26)00266-2. [Epub ahead of print]
    Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.
    Ajay Ashok, Kin-Sang Cho, Wai Lydia Tai, Lu Huang, Hio Tong Kam, Suman Chaudhary, Karen Chang, Sarita Pooranawattanakul, Julie Chen, Anton Lennikov, Dong Feng Chen.
      Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochondrial pool through exogenous mitochondrial transplantation ("mitotherapy") in adult mice not only preserves neuronal survival but also promotes regenerative competence in the central nervous system (CNS). In aging or injured RGCs, we identified profound deficits in mitochondrial biogenesis, fission-fusion balance, and mitophagy. Transplantation of functional mitochondria in in vitro models of trophic deprivation and glutamate excitotoxicity restored mitochondrial homeostasis, improved energy production, reduced reactive oxygen species, enhanced RGC survival, and drove robust neurite outgrowth, with transplanted mitochondria actively trafficking to growth cones. This effect was dampened following inhibition of mitochondrial fusion indicating a pivotal role of fusion-dependent functional integration of exogenous mitochondria. Strikingly, intravitreal delivery of mitochondria in an optic nerve crush model of adult mice enabled their integration into RGCs, improved survival and electrophysiological responses, and supported axonal regeneration across the lesion site. These findings indicate that mitochondrial transplantation strategy rescues bioenergetic failure and supports a pro-regenerative activity of neurons, highlighting the potential of mitotherapy as a transformative approach for neurodegenerative eye diseases and CNS injuries.
    Keywords:  Mitochondrial transplantation; PC12 cells; SH-SY5Y cells; nerve regeneration; neuroprotection; optic nerve crush; retinal ganglion cells
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.069
  12. Ecotoxicology. 2026 Apr 07. pii: 95. [Epub ahead of print]35(5):
    Silver nanoparticles induce binding of mitochondrial DNA polymerase gamma subunit Polg2 and mitochondrial dysfunction in HeLa cells.
    Xueling Peng, Qingdai Liu.
      
    Keywords:  AgNPs; Manomaterials; Mitochondria; Polg2
    DOI:  https://doi.org/10.1007/s10646-026-03081-0
  13. Cell Commun Signal. 2026 Apr 06.
    Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
    Eve Harding, Veronica Bazzani, Carlo Vascotto.
      
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial-derived Peptides; Mitochondrial-derived non-coding RNAs; Retrograde signalling
    DOI:  https://doi.org/10.1186/s12964-026-02858-4
  14. J Neurol. 2026 Apr 10. pii: 263. [Epub ahead of print]273(5):
    Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
    Ignazio Giuseppe Arena, Shamini Saravanabavan, Rita Horvath, Jelle van den Ameele.
      Primary mitochondrial diseases (PMDs) represent a clinically and genetically heterogeneous group of disorders characterized by impaired oxidative phosphorylation and multisystem involvement, commonly affecting the nervous system. As therapeutic development accelerates, there is a growing need for robust biomarkers capable of supporting diagnosis, stratifying patient subgroups, monitoring disease progression, and providing sensitive pharmacodynamic readouts for clinical trials. This review summarizes recent advances in three major non-invasive biomarker domains relevant to PMDs: circulating serum and molecular biomarkers, functional and digital endpoints, and neuroimaging modalities. Circulating markers, such as FGF21, GDF15, NfL, and NAD⁺-related signatures, have each been proposed for diagnosis and to follow disease progression, while multi-omics approaches are paving the way toward integrated molecular phenotyping. Digital health technologies, including accelerometry and gait analytics, enable objective quantification of real-world functional impairment, although disease-specific validation remains an unmet need. Neuroimaging offers mechanistic insights through metabolic (MRS, CEST), perfusion (ASL), and molecular modalities (mitochondrial PET tracers). Cutting-edge tools, such as Multi-Spectral Optoacoustic Tomography (MSOT), Raman spectroscopy, and Near-Infrared Spectroscopy (NIRS), promise real-time or spatially resolved assessment of mitochondrial function. Together, these developments outline multidimensional biomarker approaches for PMDs, with the potential to directly measure target engagement and clinically meaningful phenotypes in future therapeutic trials. Future progress will depend on longitudinal validation, harmonized acquisition protocols, and the integration of multimodal platforms to support upcoming therapeutic trials and precision medicine strategies.
    Keywords:  Biomarkers; Clinical trials; Digital health technologies; Functional endpoints; Magnetic resonance imaging; Mitochondrial disease; Neuroimaging; Phenotyping; Positron emission tomography; Precision medicine; Wearable devices
    DOI:  https://doi.org/10.1007/s00415-026-13794-1
  15. Circ Res. 2026 Apr 10. 138(8): e326986
    Intercellular Mitochondrial Transfer: Implications in Cardiovascular Health.
    Yajun Wang, Rong Tian.
      Mitochondria are important organelles for metabolic homeostasis, cell fate, and survival. Emerging evidence suggests that mitochondria are not confined to the cells. Intercellular mitochondrial transfer (IMT) is increasingly recognized between a variety of cells, including major cell types in the cardiovascular system. Observations made by coculture systems, genetic lineage-tracing approaches, and animal models indicate that mitochondria can be transferred between cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, cardiac macrophages, and mesenchymal stromal cells. IMT has also been reported between a remote organ, for example, adipose tissue, and the heart, suggesting that mitochondrial trafficking can mediate communications not only between individual cells but also across organs. Two principal modes of IMT are reported. One involves directed, contact-dependent trafficking of mitochondria through membranous contacts or nanotubes. The other relies on the release of mitochondria, either packaged in membrane-bound vesicles or as free mitochondria, into the extracellular space followed by import into the acceptor cells. Consequences of IMT can be beneficial or detrimental depending on the cell type and the conditions under which the IMT occurs. Mechanisms underlying the transfer or its consequences are not fully understood, however. The role of IMT in cardiovascular health is, therefore, interpreted with certain assumptions. In this review, we first summarize the evidence of IMT in the cardiovascular system and the observed functional outcome. We then aim to identify the knowledge gaps and critical questions to be addressed, followed by a discussion of challenges and opportunities to advance the field.
    Keywords:  cardiovascular system; cell communication; extracellular vesicles; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326986
  16. Nat Commun. 2026 Apr 09.
    The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-71630-6
  17. Int J Biochem Cell Biol. 2026 Apr 07. pii: S1357-2725(26)00047-6. [Epub ahead of print] 106943
    Beyond Hemoglobin polymerization: Mitochondrial Pathobiology and Therapeutic Frontiers in Sickle Cell Disease.
    Rikesh K Dubey, Apoorva Narain.
      Sickle cell disease (SCD) is a global health issue that affects millions of individuals and is caused by a mutation in the β-globin gene (HBB), leading to the formation of sickle-shaped erythrocytes. Traditionally, the primary focus in SCD has been vaso-occlusion, hemoglobin polymerization, and hemolysis; however, recent studies have started to unravel the role of mitochondrial dysfunction in SCD pathophysiology. The current review aims to present the role of mitochondrial dysfunction in SCD-related clinical features and associated outcomes. It uniquely integrates mitochondrial dynamics, inter-organelle communication, and immune activation. The review highlights the multifaceted role of mitochondria as a central molecular regulator, ranging from inflammation control, disease progression, and immune responses in SCD to their effect on erythropoiesis, endothelial dysfunction, organ damage, and vaso-occlusion. In addition, this review also addresses the potential of targeting mitochondrial pathways to improve therapeutic outcomes in SCD. Unveiling mitochondrial dynamics not only provides new insights into disease pathology but also opens avenues for targeted therapeutic interventions. Dissecting these mitochondrial mechanisms provides novel therapeutic insight and highlights the potential of targeting mitochondrial pathways for the management of SCD. Overall, this review highlights the importance of mitochondrial research in the current landscape of SCD and identifies it as a promising therapeutic target that may open new dimensions in disease management.
    Keywords:  HbS; Mitochondria; erythrocytes; mitochondrial DNA; sickle cell disease
    DOI:  https://doi.org/10.1016/j.biocel.2026.106943
  18. Per Med. 2026 Apr 04. 1-8
    The role of real-world data and real-world evidence in advancing regulatory science and targeted therapeutics: a narrative review from the United States perspective.
    Emily Nagel, Youssef M Roman.
      Randomized controlled trials (RCTs) encounter feasibility gaps when addressing rare genetic disorders and molecularly defined patient subgroups. The U.S. Food and Drug Administration has increasingly integrated real-world evidence (RWE) into the regulatory lifecycle. The objective of this article is to analyze the regulatory evolution following the 21st Century Cures Act and evaluate landmark drug approvals and expansions where real-world data (RWD) provided the primary or supplementary evidentiary foundation. A structured search of electronic databases, including PubMed, Embase, and Web of Science, was performed to identify relevant peer-reviewed articles. The tumor-agnostic approval of pembrolizumab demonstrated how RWE can establish clinical utility across multiple cancer types sharing specific biomarkers. For rare diseases like N-acetylglutamate synthase deficiency (carglumic acid), RWE provided essential external comparators where RCTs were impossible. In cystic fibrosis (ivacaftor), the U.S. Cystic Fibrosis Foundation Patient Registry facilitated indication expansions to ultra-rare genetic variants through longitudinal real-world outcomes. RWE proved vital for post-market surveillance in populations typically excluded from trials. While technical challenges in data interoperability and ethical concerns regarding genomic privacy remain, RWE offers a dynamic model that accelerates access to targeted therapies. The integration of high-fidelity RWD ensures that the safety and efficacy of precision medicines are validated within the complex global clinical practice.
    Keywords:  Real-world evidence; U.S. food and drug administration; data governance; drug development; pharmacovigilance; precision medicine; real-world data; regulatory affairs
    DOI:  https://doi.org/10.1080/17410541.2026.2655298
  19. Nature. 2026 04;652(8109): 313-320
    Metabolomics across scales: from single cells to population studies.
    Theodore Alexandrov, Nicola Zamboni.
      Metabolomics has matured into a powerful approach for probing metabolism, offering readouts that closely reflect cellular and organismal function in health and disease. Here we highlight two rapidly advancing frontiers: single-cell metabolomics and population-scale metabolomics. Single-cell metabolomics resolves the metabolic states of individual cells, uncovering cell-to-cell heterogeneity and spatial organization within tissues. Population-scale profiling profiles metabolites across large cohorts, enabling the discovery of markers of disease, environmental exposures and genetic variation. Although these approaches operate at different scales, they face shared challenges-including metabolite identification, quantification and multimodal data integration-and offer common advantages, such as the ability to capture non-genetic influences on phenotype and to scale to high throughput. We propose that continued advances in scalability will bring these domains together, enabling the construction of comprehensive metabolic atlases that chart cellular and interindividual variation and provide training data for foundation models of metabolism. By integrating cellular and population-level insights, single-cell and population-scale metabolomics promise to advance our understanding of metabolism across biology, medicine and pharmacology.
    DOI:  https://doi.org/10.1038/s41586-026-10277-1
  20. Redox Biol. 2025 Dec 20. pii: S2213-2317(25)00489-6. [Epub ahead of print]93 103976
    Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.
    Kai-Yang Chen, Hoi-Chun Chan, Wan-Wan Lin, Chi-Ming Chan.
      Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly and has a multifactorial etiology involving advanced age, genetic susceptibility, and environmental risk factors. Accumulating evidence suggests that mitochondrial dysfunction is a central pathogenic mechanism in AMD, particularly in the retinal pigment epithelium (RPE). The RPE is critical for retinal homeostasis, and its high metabolic activity renders it vulnerable to age-related mitochondrial dysfunction. In AMD, the core processes of mitochondrial dynamics-fission, fusion, biogenesis, and mitophagy-are profoundly dysregulated, leading to a fragmented and dysfunctional mitochondrial network. This failure of quality control results in bioenergetic deficits, excessive oxidative stress, and the release of damage-associated molecular patterns that fuel chronic inflammation and complement-mediated damage. Experimental models and human tissue studies have strengthened the link between mitochondrial dysfunction and AMD pathology, revealing structural abnormalities, mitochondrial DNA (mtDNA) damage, and altered metabolic signatures. Therapeutic strategies targeting mitochondrial pathways, including mitochondria-targeted antioxidants, dynamic modulators, and enhancers of biogenesis and mitophagy, such as agents that restore defective mitophagosome formation, represent promising avenues for intervention. As the field advances, the integration of biomarker development and personalized approaches holds the potential to transform the clinical landscape of AMD by addressing the root causes of cellular dysfunction.
    Keywords:  Age-related macular degeneration; Biogenesis; Fission; Fusion; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.redox.2025.103976
  21. Ageing Res Rev. 2026 Apr 07. pii: S1568-1637(26)00123-6. [Epub ahead of print] 103131
    Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
    Linbo Peng, Kexin Wang, Limin Wu, Lei Yao, Bin Shen, Jian Li.
      Degenerative musculoskeletal diseases (DMDs), including osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration, are highly prevalent age-related conditions characterized by progressive tissue dysfunction and loss of musculoskeletal integrity. Aging is accompanied by profound alterations in organelle homeostasis, metabolic signaling, and stress adaptation, among which mitochondria-endoplasmic reticulum communication has emerged as a critical regulatory axis. Mitochondria-associated membranes (MAMs) are specialized contact sites that spatially and functionally couple the endoplasmic reticulum and mitochondria, thereby coordinating calcium signaling, redox balance, lipid metabolism, and cell fate decisions. Accumulating evidence indicates that aging-related disruption of MAMs integrity and signaling contributes to mitochondrial dysfunction, oxidative stress, aberrant stress responses, and inflammatory activation across multiple musculoskeletal tissues. In this review, we synthesize current evidence linking MAMs-associated signaling pathways-including calcium flux, reactive oxygen species regulation, unfolded protein response signaling, autophagy, inflammasome activation, and regulated cell death-to the pathogenesis of major degenerative musculoskeletal diseases. We further highlight shared and tissue-specific mechanisms through which age-dependent MAMs dysregulation drives musculoskeletal degeneration. By framing MAMs as aging-sensitive signaling hubs, this review provides an integrated perspective on how organelle crosstalk contributes to degenerative musculoskeletal diseases and identifies conceptual frameworks for understanding disease convergence during musculoskeletal aging.
    Keywords:  Calcium homeostasis; Degenerative musculoskeletal diseases; ER–mitochondria crosstalk; Mitochondria-associated ER membranes; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.arr.2026.103131
  22. Reprod Biomed Online. 2026 Jan 12. pii: S1472-6483(26)00005-2. [Epub ahead of print]52(6): 105464
    Public support for mitochondrial donation: an Australian knowledge and attitudes study.
    Ezra Kneebone, Zachary Russell, Ainsley J Newson, Chris Degeling, Karinne Ludlow, Narelle Warren, Catherine Mills.
       RESEARCH QUESTION: What does the Australian public know about mitochondrial donation and think about its potential clinical implementation?
    DESIGN: 1042 people aged ≥18 years living in Australia completed an online anonymous survey between October and December 2022. Participants were recruited through a market research company. The survey included multiple choice and Likert-scale questions gauging respondents' knowledge and attitudes. Bivariate analysis investigated differences in support for mitochondrial donation based on different sociodemographic groups.
    RESULTS: Just 19% of respondents had ever heard of mitochondrial donation prior to participation (n = 202). The average level of agreement with the statement 'If the clinical trial proves mitochondrial donation is safe, I support it becoming available in Australia' was 3.36 out of a possible 4, indicating agreement. Significant differences in the average agreement level were reported across the different 'prior use of assisted reproductive technology', 'sexual orientation', 'genetic condition' and 'mitochondrial disease' groups; however, the average level of agreement in each group was consistently >3.
    CONCLUSIONS: The findings indicate broad public support for the clinical implementation of mitochondrial donation in Australia, provided that clinical trials demonstrate its safety. Although these results may not extrapolate directly to other contexts, they may guide other jurisdictions in considering their position towards mitochondrial donation.
    Keywords:  Assisted reproductive technology; Mitochondrial diseases; Mitochondrial replacement techniques; Public opinion
    DOI:  https://doi.org/10.1016/j.rbmo.2026.105464
  23. Orphanet J Rare Dis. 2026 Apr 09. pii: 143. [Epub ahead of print]21(1):
    Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
    Annamaria Sapuppo, Grete Francesca Privitera, Vincenzo Sortino, Piero Pavone, Agata Polizzi, Martino Ruggieri, Raffaele Falsaperla.
      
    Keywords:  Blueprint genetics; Buccal swab; Clinical phenotype; Diagnostic sensitivity; Early onset; Mitochondrial diseases; Next-generation sequencing; Pediatric neurology
    DOI:  https://doi.org/10.1186/s13023-026-04213-9
  24. Pharmacol Res. 2026 Apr 07. pii: S1043-6618(26)00103-9. [Epub ahead of print] 108188
    Mitochondrial Quality Control as a Central Pharmacological Target in Aging.
    Kuan-Hao Tsui, Shih-Hsuan Cheng, Boyang Wang, Pei-Hsuan Lin, Emmanuel Naveen Raj, Li-Te Lin, Renin Chang, Zhi-Hong Wen, Andy P Tsai, Chia-Jung Li.
      Mitochondrial dysfunction is a convergent hallmark of biological aging and a mechanistically attractive target for gerotherapeutic development. Yet translation of mitochondria-focused interventions has been limited by pathway complexity, tissue heterogeneity, and insufficiently harmonized endpoints. This review synthesizes recent original evidence through a unifying mitochondrial quality control (MQC) framework comprising four interdependent modules: removal (mitophagy and mitochondrial-derived vesicles), repair (mitochondrial proteostasis and UPRmt/ISR signaling), remodeling (fission-fusion control and cristae architecture), and renewal (biogenesis coupled to turnover). We map druggable nodes across these modules and organize therapeutic efforts into five pharmacological classes: autophagy/mitophagy enhancers (including pathway-brake inhibitors and emerging mitophagy-targeting chimeras), NAD+/sirtuin-AMPK-mTOR axis modulators, mitochondria-targeted redox modulators, cristae/mPTP/cardiolipin-directed stabilizers, and mitochondria-targeted delivery platforms. Drawing on recent human studies and late-stage mitochondrial therapeutic programs, we highlight practical lessons on dosing schedules, baseline vulnerability, and the importance of pairing molecular engagement with performance endpoints. We then outline a translational strategy that prioritizes flux-aware readouts and triangulates mechanism with function using in vivo bioenergetics (31P-MRS), blood-based cellular respiration (PBMC/platelet assays and composite indices), and circulating stress/damage signals (cell-free mtDNA species and mitokines). Finally, we discuss key bottlenecks including tissue selective exposure, long term safety for maintenance therapies, and inconsistency in clinical endpoints, and we propose actionable directions such as biomarker guided precision geroscience, intermittent or sequential combination strategies that balance clearance with renewal, and next generation chemical biology approaches to improve target specificity. Collectively, this framework seeks to accelerate the development of pharmacotherapies targeting mitochondrial quality control with clinically interpretable endpoints in aging.
    Keywords:  Aging; Metabolism; Mitochondrial quality control; Mitophagy; Translational biomarkers
    DOI:  https://doi.org/10.1016/j.phrs.2026.108188
  25. Comput Struct Biotechnol J. 2025 ;27 1673-1676
    MitoEdit: A pipeline for optimizing mtDNA base editing and predicting bystander effects.
    Devansh Shah, Kelly McCastlain, Ti-Cheng Chang, Xun Zhu, Gang Wu, Mondira Kundu.
      Human mitochondrial DNA (mtDNA) mutations are causally implicated in maternally inherited mitochondrial respiratory disorders; however, the role of somatic mtDNA mutations in both late-onset chronic diseases and cancer remains less clear. Recent advances in mtDNA base editing technologies offer exciting opportunities to model and study these mutations. However, current approaches are hindered by the challenge of unintended bystander edits, which are often identified only through labor-intensive empirical testing, leading to inefficiencies in construct development. To address this limitation, we developed MitoEdit, an innovative computational tool designed to optimize mtDNA base editing by leveraging empirical base editor patterns. MitoEdit enables users to input DNA sequences in a simple text-based format, specify the target base position and define the desired modification. The tool outputs a list of candidate target windows, predicts the number and functional impact of bystander edits and provides flanking nucleotide sequences tailored for TALE (transcription activator-like effectors) array protein binding. In silico evaluations demonstrate that MitoEdit accurately predicts the majority of bystander edits, reducing the number of constructs that need to be tested empirically. By streamlining the design process, MitoEdit accelerates the development of mitochondrial base editing constructs, thereby facilitating functional studies and enabling faster discovery. Ultimately, MitoEdit has the potential to advance disease modeling and support the development of therapeutic strategies for mitochondrial-related disorders.
    Keywords:  Base editing; Genome engineering; Mitochondria; mtDNA
    DOI:  https://doi.org/10.1016/j.csbj.2025.04.027
  26. Bone Marrow Transplant. 2026 Apr 10.
    Bringing the rare into sight: applications of haploidentical stem cell transplantation in the treatment of rare diseases.
    Xiao-Di Ma, Zheng-Li Xu, Xiao-Jun Huang.
      Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) has transformed the management of haematological diseases by enabling the use of partially matched family donors, thereby markedly expanding donor availability. Advances in transplant platforms, including ex vivo TCRαβ+/CD19+ depletion and unmanipulated approaches such as the G-CSF/ anti-thymocyte globulin (ATG)-based Beijing protocol and post-transplant cyclophosphamide (PTCy)-based Baltimore protocol, have led to survival outcomes comparable to those of matched sibling donor transplantation. These strategies provide complementary advantages in graft-versus-host disease prevention, immune reconstitution, and logistical feasibility. Initially developed for common haematological malignancies, haplo-HSCT is increasingly applied to rare haematological, metabolic, and immunological disorders, for which suitable donors are often lacking and delayed treatment is associated with poor prognosis. Although individually uncommon, rare diseases collectively affect millions worldwide and are frequently genetic, progressive, and life-threatening, with limited curative options. While gene therapy represents a promising alternative, its widespread use is constrained by cost, accessibility, and long-term safety concerns. This review summarises current evidence supporting haplo-HSCT in rare diseases, compares outcomes across transplant platforms, and discusses disease-specific protocol adaptations, while highlighting future directions to improve safety and expand clinical applicability.
    DOI:  https://doi.org/10.1038/s41409-026-02839-8
  27. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2526136123
    mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.
    Rupa Banerjee, Vanessa Trauschke, Nils Bertram, Ina Aretz, Christof Osman, Don C Lamb, Dejana Mokranjac.
      Heat shock proteins 70 (Hsp70) represent a ubiquitous and conserved family of molecular chaperones involved in a variety of cellular processes. The conformational cycles of several Hsp70 chaperones, driven by ATP binding and hydrolysis, and regulated by cochaperones and substrate proteins, were analyzed in vitro in great detail. In contrast, little is known about the conformation Hsp70s adopt in their natural environments. In mitochondria, mtHsp70 is distributed between the TIM23 complex at the inner membrane, where it is involved in import of proteins from the cytosol, and a matrix-pool that is primarily involved in folding of proteins and prevention of their aggregation. Here, we used fluorescence microscopy to analyze the conformation of mtHsp70 at the single molecule level within physiologically active mitochondria. Our results revealed that the majority of mtHsp70 molecules are present in a substrate-bound state, suggesting that the mtHsp70 network functions at the limits of its capacity. To understand the biological significance of this finding, we modulated the levels of unfolded proteins in the matrix. Unfolded proteins reduced the association of mtHsp70 with the TIM23 complex and specifically impaired mtHsp70-dependent import of proteins. Our data show that unfolded proteins lead to a redistribution of mtHsp70 within mitochondria revealing how mitochondrial proteostasis stress is signaled to the cell-unfolded proteins remove mtHsp70 from the import sites, reducing the efficiency of protein import and initiating cellular programs to rescue or remove dysfunctional mitochondria. Thus, mtHsp70 acts as a mitochondrial quality control sensor that converts proteostasis stress into impaired protein import.
    Keywords:  Hsp70 chaperones; mitochondria; protein homeostasis; protein import; single molecule FRET
    DOI:  https://doi.org/10.1073/pnas.2526136123
  28. Eur J Neurol. 2026 Apr;33(4): e70575
    The Role of Digital Tools and Their Implementation Within Patient Care Pathways for Rare Brain Disorders: The Case of Phenylketonuria.
    Sara Cannizzo, Vinciane Quoidbach, Bernadette Sheehan-Gilroy, Tobias Hagedorn, Agata Bak, Suzanne L Dickson, Eileen P Treacy, Alvaro Hermida, Anita MacDonald, Eva Venegas, James O'Byrne, Maurizio Scarpa, Francjan Van Spronsen, Eric Lange, Tim Buckinx, Ahmad Monavari, Stephan Vom Dahl, Leopoldo Trieste, Giuseppe Turchetti.
       INTRODUCTION: The COVID-19 pandemic accelerated the adoption of digital health solutions in healthcare. Phenylketonuria (PKU) is a rare condition requiring chronic management and frequent assessments, making it a useful model for examining how digital health tools support patient and caregiver education, communication with healthcare professionals and facilities, and patient care pathways.
    METHODS: Patient representatives and expert clinicians developed qualitative, co-designed ad hoc surveys during virtual workshops. From October 2023 to March 2024, the surveys were available online through EUSurvey English, Spanish, and German, and distributed to PKU patients in Spain, Germany, and Ireland by national PKU patient associations.
    RESULTS: The survey co-design process identified crucial topics significant to key stakeholders in rare disease management. Diverse perspectives emerged on the roles and utility of digital tools: (1) rare disease patients may prefer hybrid care models combining face-to-face and digital interactions; (2) digital tools were perceived as particularly useful for supporting information exchange, education, preparation for clinical visits, and patient engagement.
    CONCLUSIONS: This paper examines unmet needs in digital care pathways for PKU from the perspectives of patients, caregivers, and clinicians. Findings provide important insights into the needs of patients with rare diseases and the most effective channels for engaging and communicating with them. Although clinical and cost-effectiveness were not evaluated, these findings could guide future research and policy discussions on incorporating digital solutions into rare diseases patient care pathways.
    Keywords:  European Reference Networks for rare diseases; digital patient care pathways; healthcare professionals' expert opinion; patients' perspectives; phenylketonuria
    DOI:  https://doi.org/10.1111/ene.70575
  29. medRxiv. 2026 Apr 04. pii: 2026.03.30.26349393. [Epub ahead of print]
    Deep learning-based stratification of Schizophrenia Spectrum Disorder from real-world data reveals distinct profiles of common and rare variant genetic signal.
    iPSYCH Study Consortium
      Schizophrenia spectrum disorder (SSD) is a clinically and genetically heterogeneous condition, yet few studies have integrated real-world clinical data with both common and rare genetic variation to explore this complexity. In this study, we analyzed real-world data from 22,092 individuals in the Danish iPSYCH cohort (11,046 SSD cases and 11,046 matched population controls) leveraging nationwide registry data on diagnoses, hospitalizations, and parental history. Using a variational autoencoder (VAE), we compressed these features into a latent space and identified ten clinically distinct SSD subgroups that varied in comorbidity, parental diagnoses, hospital burden, and early-life adversity. Polygenic scores (PGSs) for five psychiatric disorders showed subgroup-specific enrichment, highlighting potential links between complex clinical profiles and common variant liability. In a subset with exome data (N=5,969), we assessed rare deleterious variant burden across SCZ-informed gene sets and Protein-Protein Interaction (PPI) networks, observing suggestive network-specific trends. This framework for integrating real world-based stratification with genetic evidence is scalable and transferable across cohorts, offering a path toward biologically informed patient classification.
    DOI:  https://doi.org/10.64898/2026.03.30.26349393
  30. Indian J Med Res. 2026 Feb;pii: 10.25259/IJMR_1850_2025. [Epub ahead of print]163(2): 207-214
    Experiences from inborn errors of immunity registry of India: A preliminary report.
    NRROID Registry PID Contributors group
      Background and objectives Global estimates identify about 7,000 rare diseases affecting 6-8% of the population, with 80% being genetic. India lacks comprehensive data on their prevalence, distribution, and natural history. Inborn errors of immunity (IEI) registry was developed by Indian Council of Medical Research (ICMR) as part of a comprehensive multi-centric 'National Registry for Rare and Other Inherited Disorders', from centres which expressed interest in contributing to this national database in 2019. This study aims to establish an Indian rare-disease registry to assess disease burden, collect clinical and demographic data, understand natural history, support research on underlying mechanisms, create cohorts for evaluating therapies and orphan products, and strengthen connections among patients, families, and clinicians to improve comprehensive care across the country effectively. Methods After ethics approval from the participating centres, data were collected in a structured format developed jointly by ICMR- National Institute of Immunohaematology, Mumbai and Postgraduate Institute of Medical Education and Research, Chandigarh, identified as nodal centres for inborn errors of immunity (IEI) by ICMR. Cases with molecular confirmation of diagnosis or those satisfying the European Society for Immunodeficiencies (ESID) registry working definition in absence of molecular confirmation were included. The Data were compiled in excel format and analysed using Epi Info v7.2.5.0. Results Data for 676 patients enrolled between January 2019- October 2024 from six participating centres including ICMR-NIIH Mumbai, PGI Chandigarh, Apollo Chennai, JIPMER Pondicherry, Nizams Institute Hyderabad, and Sir Gangaram Hospital Delhi was analysed. Immunodeficiencies affecting cellular and humoral immunity (CID) and CID with associated or syndromic features (n=187,27.6%), predominantly antibody deficiency (n=146,21.6%), congenital defects of phagocyte number or function (n=117,17.3%) were the most frequent IEIs. The median age of presentation was 16 (IQR 4,63) months and diagnostic delay of 16 (IQR 3,55) months. The presenting clinical manifestations comprised of recurrent infections (n=459,67.9%), autoimmunity or auto-inflammation (n=292,43.2%), adverse effect following immunisation (n=38,5.6%), and malignancy (n=5,0.73%). 103/146 (70%) patients with antibody deficiency received IVIG and 90 (13.3%) IEI patients underwent hematopoietic stem cell transplant. On follow up, 118 (17.4%) patients died due to infections by 2024. Interpretation and conclusions The IEI registry developed by ICMR as an attempt to maintain a patient database gives us insights on the demographic, clinical presentation, diagnostic-delay and treatment outcomes of these disorders.
    Keywords:  Genetics; Inborn errors of immunity; Infections; Primary immunodeficiency; Registry
    DOI:  https://doi.org/10.25259/IJMR_1850_2025
  31. Child Care Health Dev. 2026 May;52(3): e70271
    Delivering Health Education to Children With Chronic Conditions: A Scoping Review and Evidence and Gap Map.
    Meredith Smith, Nicole Pope, Nadine Smith, Georgina Henry, Ingrid Honan, Kiara Corso, Grace Evans, Caitlin Doyle, Adrienne Harvey.
       INTRODUCTION: Developmentally appropriate health education is essential for children with chronic conditions and their families to support self-management and improve quality of life. Although a range of educational approaches have been reported, no comprehensive review has examined how these interventions are developed, which approaches are most used, or their outcomes. Accessibility is also critical given diverse cognitive, communication and motor abilities within paediatric populations. This review aimed to map and synthesise evidence on health education interventions for children (5-12 years) with chronic conditions.
    METHODS: Studies reporting health education interventions for children (5-12 years) with chronic conditions were identified from MEDLINE, CINAHL, PsycINFO, ERIC, Scopus and Cochrane Library. Data were extracted using predefined categories, including delivery approaches aligned with Saxby's (2020) framework for paediatric supported self-management. Participant (knowledge, behaviour change or health/symptom) and implementation outcomes were extracted. Findings were synthesised using an Evidence and Gap Map to identify strengths and gaps in delivery and implementation.
    RESULTS: A total of 118 studies were included. Most interventions targeted endocrine/metabolic conditions and were delivered in hospital outpatient settings. Health professionals primarily facilitated education, though self-directed and digital facilitators are emerging. Delivery was mainly face-to-face, with increasing use of remote approaches. Over half of studies incorporated multiple recommended approaches: peer/cooperative learning (50%), story/play-based strategies (35%), caregiver involvement (27%), pictorial representation (25%) and active/experiential learning (14%). Most studies reported at least one participant outcome (86%) and nearly three-quarters reported an implementation outcome (73%). Only 14% of studies addressed accessibility considerations, predominantly for children with diverse cognitive abilities.
    CONCLUSIONS: This review highlights a growing emphasis on active learning strategies to support health education for chronic conditions, moving beyond passive learning. To improve inclusivity and accessibility, interventions should prioritise individualised content, multimodal delivery and flexible approaches with meaningful involvement of children and families in intervention design and development.
    Keywords:  accessibility; children; chronic conditions; health education
    DOI:  https://doi.org/10.1111/cch.70271
  32. J Chin Med Assoc. 2026 Apr 10.
    Beyond disease treatment and prevention: From geroscience and molecular hallmarks to gerotherapeutics and precision geromedicine.
    Li-Ning Peng, Fei-Yuan Hsiao, Liang-Kung Chen.
      Geroscience - the interdisciplinary field investigating the causal relationship between the biology of aging and age-related chronic disease - has undergone a remarkable evolution since its formalization within the United States National Institutes of Health in the early 2010s. Grounded in the recognition that aging is the paramount modifiable risk factor for most noncommunicable diseases, geroscience has produced a coherent molecular taxonomy of aging processes (twelve hallmarks), delineated pro-aging and anti-aging molecular pathways (gerogenes, gerosuppressors, and gerozymes), and catalyzed a new clinical vocabulary - geroprotection, gerodiagnostics, and gerotherapeutics. Two institutional milestones anchor the field's translational ambitions: the WHO's codification of Ageing-Associated Decline in Intrinsic Capacity as ICD-11 code MG2A; and the FDA's acceptance of the Targeting Aging with Metformin (TAME) trial - the first prospective clinical trial designed to delay aging as a composite multi-disease outcome, currently underway. The biomarker science of aging has advanced in parallel, from first-generation DNA methylation clocks to organ-specific plasma proteomic signatures capable of predicting various age-related diseases with clinical-grade precision. The gerotherapeutic landscape has expanded substantially. Metformin, which engages more aging hallmarks than any other candidate gerotherapeutic, provided the regulatory impetus for TAME; in a rigorous 40-month multi-omics study in cynomolgus monkeys, it decelerated plasma proteomic biological age by 6.41 years - the strongest pharmacological evidence to date for systemic biological age modification in a primate model. Senolytics and senomorphics target senescent cell burden; SGLT-2 inhibitors represent the first approved class with direct senotherapeutic properties; GLP-1 receptor agonists attenuate inflammaging; NAD⁺ precursors restore mitochondrial and sirtuin function; and the gerozyme (15-PGDH) inhibitor offers a mechanistically distinct pro-regenerative approach with emerging relevance as an adjunct to GLP-1 receptor agonist therapy. Multidomain lifestyle programs address multiple aging hallmarks simultaneously and have demonstrated measurable intrinsic capacity improvement in randomized trials. Building on these foundations, this review proposes the Geroscience-Responsive Aging Care Ecosystem (GRACE) - a three-element service model operationalizing geroscience and gerotherapeutic evidence within the WHO Integrated Care for Older People (ICOPE) framework.
    Keywords:  Biological age; Geroscience; Gerotherapeutics; Intrinsic capacity; Precision geromedicine
    DOI:  https://doi.org/10.1097/JCMA.0000000000001374
  33. Cell Mol Gastroenterol Hepatol. 2026 Apr 07. pii: S2352-345X(26)00060-3. [Epub ahead of print] 101782
    IL-13 promotes accumulation of esophageal epithelial mitochondria with translational implications for eosinophilic esophagitis.
    Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Courtney Worrell, Jasmine Cruz, No'ad Shanas, Alena Klochkova, Travis H Bordner, John M Crespo, Annie D Fuller, B S William-Nazario-Lugo, Grace Davis, Hailey Golden, Andres J Klein-Szanto, Tatiana A Karakasheva, Adam Karami, John W Elrod, Gary W Falk, Zachary Wilmer Reichenbach, Melanie Ruffner, Amanda B Muir, Kelly A Whelan.
       BACKGROUND & AIMS: Metabolic and mitochondrial dysfunction have recently been implicated in eosinophilic esophagitis (EoE) pathogenesis. However, there is a need to define the influence of EoE-associated inflammatory cues upon mitochondrial biology, mechanisms mediating these effects, and the clinical significance of mitochondrial alterations in EoE.
    METHODS: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes stimulated with EoE-relevant cytokines. Mitochondrial mediators were assessed via qRT-PCR and western blotting. Metabolism, mitochondrial membrane potential, and apoptosis were measured. Mitochondrial DNA (mtDNA)-encoded genes, ND1 and ND6 were assessed by qPCR in DNA from culture media and circulating nucleic acids from human serum samples. Effects of JAK inhibitor ruxolitinib or genetic inhibition of STAT3 or STAT6 on mitochondria were assessed in vitro.
    RESULTS: We identified evidence of increased mitochondria in esophageal mucosa of EoE patients and mice with EoE-like inflammation. IL-13 consistently induced mitochondrial accumulation in esophageal keratinocytes in vitro and this response was associated with increased expression of mediators of mitochondrial biogenesis, fusion, and mitophagy. IL-13 suppressed mitochondrial respiration and ATP production, without impacting membrane polarization or apoptosis. Active EoE patients exhibited elevated serum mtDNA levels and upregulation of mediators of mtDNA-associated inflammatory signaling. Increased mitochondrial mass and accumulation of extracellular mtDNA in IL-13-treated esophageal keratinocytes were dependent on JAK/STAT signaling.
    CONCLUSIONS: We identify IL-13 as a mediator of increased mitochondrial mass in EoE through JAK/STAT signaling. We further demonstrate that IL-13 promotes accumulation of extracellular mtDNA and that circulating mtDNA is elevated in EoE patients.
    Keywords:  Eosinophilic esophagitis; Interleukin-13; JAK/STAT pathway; mitochondria
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101782
  34. J Gene Med. 2026 04;28(4): e70091
    CRISPR-Cas Systems in Human Disease Therapy: Advances, Clinical Applications, Limitations, and Future Directions.
    Gedion Mengistu.
      CRISPR-Cas systems have emerged as versatile platforms for targeted genome and transcriptome engineering, enabling precise manipulation of disease-associated genetic pathways. Continued advances in CRISPR technologies including base editing, prime editing, and epigenome modulation have expanded therapeutic possibilities beyond nuclease-mediated DNA cleavage, allowing programmable gene correction and regulation. Early clinical studies demonstrate sustained therapeutic benefit in selected monogenic disorders and highlight the feasibility of both ex vivo and in vivo editing strategies. However, clinical translation remains constrained by challenges such as off-target activity, delivery inefficiency, immune responses to Cas proteins, editing heterogeneity, and uncertainties regarding long-term safety. This review critically synthesizes recent advances in CRISPR-Cas systems for human disease therapy, integrating molecular innovations, delivery strategies, clinical progress, and ethical considerations. By evaluating both technological achievements and unresolved limitations, this article outlines key priorities for advancing CRISPR-based therapeutics toward safe, effective, and equitable precision medicine.
    Keywords:  CRISPR–Cas systems; base editing; cancer immunotherapy; delivery systems; gene therapy; genome editing; infectious diseases; monogenic disorders; off‐target effects; prime editing
    DOI:  https://doi.org/10.1002/jgm.70091
  35. Cell Biochem Funct. 2026 Apr;44(4): e70211
    High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.
    Liying Tang, Xiuting Huang, Pei Li.
      Chronic hyperglycemia accelerates immune aging and contributes to diabetic complications, yet the mitochondrial mechanisms responsible for macrophage senescence remain unclear. In this study, both cultured and primary macrophages were treated with high glucose to model hyperglycemic conditions. High glucose significantly increased markers of macrophage senescence, including SA-β-Gal staining, expression of p16 and p21, and secretion of pro-inflammatory cytokines. Mitochondrial dysfunction was evident, as shown by loss of mitochondrial membrane potential (ΔΨm) and elevated mitochondrial reactive oxygen species (mtROS). In addition, mitophagy was impaired, with PINK1 accumulation and reduced Parkin recruitment. Rescue experiments demonstrated that treatment with the mitochondria-targeted antioxidant MitoTempo, the general antioxidant N-acetylcysteine, or the anti-diabetic drug metformin effectively restored mitochondrial function and alleviated senescence. These findings indicate that mitochondrial dysfunction and impaired mitophagy are central to high glucose-induced macrophage senescence, and that targeting mitochondrial oxidative stress with antioxidants or metformin may offer a promising strategy to mitigate immune aging and inflammation associated with metabolic disorders.
    Keywords:  high glucose; inflammation; macrophage; mitophagy; senescence
    DOI:  https://doi.org/10.1002/cbf.70211
  36. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715396. [Epub ahead of print]
    Temporal AI model predicts drivers of cell state trajectories across human aging.
    Javier Gόmez Ortega, Rangarajan D Nadadur, Akira Kunitomi, Steven Kothen-Hill, Julian U G Wagner, Sarp D Kurtoglu, Bumjoon Kim, Madigan M Reid, Thomas Lu, Kaho Washizu, Lukas Zanders, Han Chen, Yujie Zhang, Sarah Ancheta, Sara Lichtarge, William A Johnson, Chris Thompson, Dereck M Phan, Alexis J Combes, Andrew C Yang, Neha Tadimeti, Stefanie Dimmeler, Shinya Yamanaka, Michael Alexanian, Christina V Theodoris.
      Foundational AI models have recently shown promise for predicting the impact of perturbations on cell states. However, current models typically consider only one cell state at a time, limiting their ability to learn how cellular responses unfold over time, particularly across long trajectories such as diseases of aging. Here, we develop a temporal AI model, MaxToki, trained on nearly 1 trillion gene tokens including cell state trajectories across the human lifespan to generate cell states across long timelapses of human aging. MaxToki generalized to unseen trajectories through in-context learning and predicted novel age-modulating targets that were experimentally verified to influence age-related gene programs and functional decline in vivo. MaxToki represents a promising strategy for temporal modeling to accelerate the discovery of interventions for programming therapeutic cellular trajectories.
    DOI:  https://doi.org/10.64898/2026.03.30.715396
  37. Front Physiol. 2026 ;17 1774714
    Recalibrating cell fate: targeting the mitochondrial signaling hub with natural active compounds to inhibit regulated cell death in diabetic kidney disease.
    Yinzhong Dai, Chenguang Wu, Jiaying Zheng, Keqin Zhao, Shimei Hua, Jianing Sun, Han Zhu, Jun Luo, Junwei Shi, Lu Han, Lifan Wang, Peng Liu.
      Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. The progression of DKD is closely related to various cell death (RCD) pathways such as apoptosis, pyroptosis and ferroptosis. Although historically viewed as distinct events, we propose that mitochondria function as the central hub integrating hyperglycemic, lipotoxic, and pro-inflammatory insults. We delineate how initial hyperglycemic and hemodynamic insults compromise mitochondrial quality control, triggering a vicious cycle: dysfunctional mitochondria release ROS and damage-associated molecular patterns to initiate regulated cell death and inflammation, which in turn further impairs mitochondrial bioenergetics, thereby amplifying diabetic kidney injury. Mechanistically, mitochondrial outer membrane permeabilization triggers intrinsic apoptosis, while the cytosolic leakage of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) primes the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to drive pyroptosis. In parallel, organelle-level metabolic and redox instabilities fuel the lipid peroxidation characteristic of ferroptosis. We highlight the sophisticated crosstalk within this network, such as the Caspase-3/Gasdermin E switch, arguing that these pathways function as a network of molecular crosstalk and functional interdependence with distinct spatiotemporal dynamics, rather than a singular execution program. Regarding therapeutic interventions, we summarize preclinical evidence for natural active compounds like berberine and quercetin. These phytochemicals act as network-level modulators of mitochondrial targets to restore cellular homeostasis. Finally, we critically address the "translational gap" posed by poor oral bioavailability and lack of human target validation. We also explore emerging biophysical concepts, such as liquid-liquid phase separation, as a speculative yet novel frontier for organizing pathological metabolic signals. Therefore, disrupting this mitochondrial feedback loop, when coupled with advanced delivery strategies, represents a strategic therapeutic avenue to arrest DKD progression.
    Keywords:  apoptosis; diabetic kidney disease; ferroptosis; mitochondria; phytochemicals; pyroptosis; regulated cell death
    DOI:  https://doi.org/10.3389/fphys.2026.1774714
  38. Cytokine Growth Factor Rev. 2026 Apr 01. pii: S1359-6101(26)00028-6. [Epub ahead of print]89 5-14
    Dual role of MIF in aging and cellular senescence.
    Abdullah Altulea, Jamil Nehme, Marco Demaria.
      Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that bridges innate immunity, cellular senescence and age‑related pathology. In this review, we describe the unique secretion mechanisms, compartment‑specific signaling, and redox‑dependent conformational states that MIF has in different contexts. We detail how extracellular MIF amplifies chronic inflammation through CD74, CXCR2/4 and NF‑κB, while intracellular MIF sustains proliferation, DNA repair, and autophagy by antagonizing p53. We also highlight oxidized MIF as an emerging marker with unique relevance in age-related diseases. Through systematic comparison of evidence from cardiovascular, neurodegenerative, musculoskeletal and pulmonary disease studies, this review reveals context‑dependent protective versus deleterious outcomes of MIF signaling. The nature of MIF and its involvement in age-related diseases makes it a challenging yet intriguing therapeutic target.
    Keywords:  Aging; Inflammation; MIF; Senescence
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.03.001
  39. J Transl Med. 2026 Apr 10.
    Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
    Chengqian Teng, Jianjie Wei, Yixiao Zhu, Andi Chen, Xiaohui Chen.
       BACKGROUND: Neonatal brain injury, including hypoxic-ischemic encephalopathy, preterm brain injury, and neonatal infectious brain injury, remains a major cause of death and long-term neurodevelopmental disability worldwide. The immature brain is highly dependent on oxidative metabolism yet particularly vulnerable to energy failure and oxidative stress, placing mitochondria at the core of injury cascades. By integrating disturbances in energy production, redox balance, calcium homeostasis, and cell death signaling, mitochondrial dysfunction is increasingly recognized as a unifying driver of diverse neonatal brain injury phenotypes.
    MAIN BODY: This narrative review synthesizes current knowledge on the main clinical forms of neonatal brain injury and their developmental context, alongside an overview of mitochondrial physiology in neural cells, including the regulation of bioenergetics, reactive oxygen species, calcium signaling, mitochondrial dynamics, and inter‑organelle communication. It critically examines how mitochondrial dysfunction contributes to injury across hypoxic-ischemic, preterm, and infectious or inflammatory insults, emphasizing links between impaired oxidative phosphorylation, excessive oxidative and nitrosative stress, calcium overload with pathological opening of the mitochondrial permeability transition pore, activation of apoptosis and regulated necrosis, disrupted mitochondrial fusion-fission balance and biogenesis, and defective mitophagy and mitochondrial quality control. These mitochondrial disturbances precipitate acute neuronal and oligodendroglial injury and hinder the long-term maturation and connectivity of neural circuits. Finally, we review emerging mitochondria‑targeted neuroprotective strategies, focusing on approaches that enhance mitochondrial biogenesis, reduce mitochondrial oxidative stress, and target mitochondrial dynamics to restore mitochondrial homeostasis and improve cellular resilience in the immature brain.
    CONCLUSION: By linking specific patterns of mitochondrial dysfunction to distinct forms and stages of neonatal brain injury, this review provides a mechanistic framework for identifying high‑risk infants, refining pathophysiological understanding, and guiding the rational development of mitochondria‑targeted interventions aimed at improving neurological outcomes in vulnerable newborns.
    Keywords:  Energy metabolism; Hypoxic–ischemic encephalopathy; Mitochondrial dynamics and mitophagy; Mitochondrial dysfunction; Mitochondria‑targeted therapy; Neonatal brain injury; Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1186/s12967-026-08104-2
  40. Front Aging Neurosci. 2026 ;18 1761702
    Mitochondrial dysfunction in Alzheimer's disease and related sex differences.
    Afzal Misrani, Conelius Ngwa, Fudong Liu.
      Alzheimer's disease (AD), the most common form of dementia, accounts for 70% of cases and remains a major healthcare challenge due to its rising prevalence and lack of disease-modifying treatments. Clinically, AD is a sexually dimorphic disease. Women exhibit more rapid cognitive decline and accelerated brain atrophy during mild cognitive impairment and early dementia, whereas men more frequently present cardiovascular comorbidities, earlier mitochondrial dysfunction, and greater neuropsychiatric symptoms. AD is marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss, with mitochondrial dysfunction emerging as a key early contributor that exhibits sex specific phenotypes. Mitochondria are vital for neuronal function by generating ATP, maintaining calcium homeostasis, and regulating oxidative stress. However, mitochondria in AD exhibit impaired ATP synthesis, excessive reactive oxygen species (ROS) production, calcium dysregulation, and disrupted fission-fusion dynamics. AD mitochondrial dysfunction can be measured by molecular markers, such as increased expression of fission-related protein Drp1, decreased biogenesis regulator PGC-1α, and elevated oxidative stress markers like malonaldehyde, nitotyrosine and protein carbonyls. Accumulating data suggest that sex differences in mitochondrial dysfunction are attributed to either sex hormonal or sex chromosomal effects, which eventually contribute to sex dichotomic phenotypes of AD. This review collected data regarding mitochondrial dysfunction in AD, with an emphasis on sex differences in oxidative stress, energy metabolism, and regulatory pathways.
    Keywords:  Alzheimer's disease; dementia; mitochondria; oxidative stress; sex differences
    DOI:  https://doi.org/10.3389/fnagi.2026.1761702
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