bims-polgdi Biomed News
on POLG disease
Issue of 2026–07–19
forty-five papers selected by
Luca Bolliger, lxBio
  1. AI Models Could Improve Diagnosis and Care for Rare Diseases.
  2. Headache in mitochondrial diseases: From migraine to stroke-like episodes.
  3. Mitochondrial transfer and mesenchymal stem cells in ophthalmology: current evidence and therapeutic implications.
  4. Karnofsky performance scale and modified Rankin scale as indicators of functional capacity in patients with mitochondrial disease.
  5. MHRA's radical rare disease proposal.
  6. The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.
  7. The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
  8. Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
  9. Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.
  10. Mitochondrial morphology and mtDNA content in fibroblasts from patients with different types of mucopolysaccharidosis.
  11. Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers.
  12. Mitochondrial transplantation and neuromuscular recovery after skeletal muscle injury.
  13. Dopaminergic neurons preferentially accumulate mtDNA rearrangements.
  14. Beyond innovation: why rare disease gene therapy needs a reset.
  15. "It didn't feel like anything unusual because we had already been through so much": Disability-Related Research Experiences of Families with Children Enrolled in the Undiagnosed Diseases Network.
  16. Stress Induced Mitochondrial Hyperfusion (SIMH): A Concise Review on SIMH in Neurodegenerative Disorders and Other Diseases.
  17. Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.
  18. Advancements in the study of gut microbiome in disease diagnosis.
  19. A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases.
  20. Advancing the diagnosis of rare neuromuscular and neurological diseases through the collaborative Solve-RD research framework.
  21. Repercussions of Diagnostic Delay in Rare Diseases.
  22. Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.
  23. Why do astronauts' bodies waste away? Space-station study points to mitochondria.
  24. LKB1/ AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene.
  25. Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.
  26. Mitochondrial Dysfunction in Ulcerative Colitis: Pathogenic Mechanisms and Novel Therapeutics.
  27. Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.
  28. Mitochondrial Immunometabolism in Sepsis: From Oxidative Stress and mtDAMP Signaling to Biomarker-Guided Therapy.
  29. A Compendium of Circulating Biomarkers of Senescence in Humans: Insights on Mechanistic Impact Across Health Domains and Modulation by Therapeutic Interventions.
  30. Individual and joint association of maternal and cord blood mitochondrial DNA heteroplasmy and copy number with preterm birth.
  31. ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
  32. Perspectives on genomic newborn screening studies: design, implementation, and outcomes.
  33. Construction and Applications of Knowledge Graphs in Ophthalmology.
  34. Modification and aminoacylation of human mitochondrial tRNAs.
  35. Letter to editor: Mitochondrial DNA release contributes to neuropathic pain via a cGAS-STING-IRF3 CMPK2-associated immunometabolic feedback mechanism.
  36. Cellular Senescence and Aging: Mechanisms, Disease Convergence, and Therapeutic Frontiers.
  37. The EV-mitochondrial outsourcing network as a therapeutic target for age-related testosterone deficiency: from network collapse to clinical intervention.
  38. Astrocytes in Parkinson's Disease: From Guardians to Accomplices.
  39. Intranasal dopamine: Anatomical pathways, biological mechanisms and neuromodulatory potential.
  40. Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.
  41. Mitochondrial-Epigenetic Crosstalk in Autism Spectrum Disorder: Linking Cellular Stress to Synaptic Dysfunction and Treatment Resistance.
  42. CAPNS1 restoration partially alleviates mitochondrial dysfunction and synaptic deficits in Alzheimer's disease through the Ca2+-CaMKIIβ-MAPK-PGC-1α axis.
  43. Trends in the Engineering of Adeno-Associated Virus (AAV) for Precision Gene Delivery to the Central Nervous System (CNS).
  44. Thermodynamic Frontiers in Hemoglobin-Inspired Polymer Science for Diagnosis and Modulation of Neurodegenerative Diseases.
  45. Karyopherin Dysfunction Is a Key Driver of Aging.
  1. J Med Internet Res. 2026 Jul 16. 28 e106582
    AI Models Could Improve Diagnosis and Care for Rare Diseases.
    Simon Spichak.
       Unlabelled: Rare diseases are often critically underfunded, leaving many patients without timely diagnosis and treatment. In this News and Perspectives article, JMIR Correspondent Simon Spichak, who was a 2025 recipient of the National Press Foundation Rare Disease Reporting Fellowship, reports on advances in AI modeling that may offer new promise for rare disease detection and care.
    Keywords:  artificial intelligence; diagnosis, computer-assisted; foundation models; frontier models; genetic variation; machine learning; rare diseases
    DOI:  https://doi.org/10.2196/106582
  2. Headache. 2026 Jul 14.
    Headache in mitochondrial diseases: From migraine to stroke-like episodes.
    Matteo Azzimonti, Samuel Padelli, Dario Ronchi, Simona Sacco, Giacomo Pietro Comi, Stefania Corti.
       OBJECTIVE: Headaches in primary mitochondrial diseases (PMDs) present distinctive features that warrant differentiation from primary headache disorders. Current knowledge on clinical manifestations, pathophysiology, diagnosis, and treatment is here reviewed.
    BACKGROUND: Among the most frequent and disabling symptoms affecting patients with PMDs, headache occurs in approximately 55-71% of individuals. Those with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and related phenotypes are particularly affected. Compared to the general population, migraine prevalence in patients with PMD is up to three- to four-fold higher.
    METHODS: To examine headache across the full spectrum of PMDs, a narrative literature review was conducted. PubMed, Scopus, and Web of Science databases were searched using the terms "mitochondrial disease," "migraine," "headache," "MELAS," and "stroke-like episodes," with no date restrictions. Relevant references from identified articles were also reviewed.
    RESULTS: In PMDs, migraine with or without aura is the most common type of headache disorder, especially among carriers of the m.3243A>G mutation, the most prevalent pathogenic variant found in MELAS syndrome. Recent data from Mendelian randomization studies have suggested a potential causal link between low mitochondrial DNA copy number and migraine without aura. The clinical characteristics that help differentiate headache in PMDs include protracted or atypical aura, co-occurring neurological and systemic manifestations, temporal relationship with stroke-like episodes, and variable response to conventional therapy. The use of mitochondrial cofactors such as riboflavin, coenzyme Q10, and L-arginine as adjuncts to standard preventive strategies has been supported by only limited evidence.
    CONCLUSIONS: Specialized diagnostic and therapeutic approaches are required for headache management in PMDs, combining mitochondrial-targeted interventions with evidence-based headache treatments. When atypical migraine features are present, particularly prolonged aura or aura occurring with epileptic seizures or encephalopathy, evaluation for underlying mitochondrial disease should be considered.
    Keywords:  MELAS; headache; migraine; primary mitochondrial disorder; stroke‐like episodes
    DOI:  https://doi.org/10.1111/head.70180
  3. Exp Biol Med (Maywood). 2026 ;251 11128
    Mitochondrial transfer and mesenchymal stem cells in ophthalmology: current evidence and therapeutic implications.
    Xiaoli Liu, Mingqi Zhang, Zhuoshi Wang.
      Mitochondrial dysfunction, driven by genetic mutations or oxidative stress, is a central contributor to the onset and progression of ophthalmic diseases. In recent years, intercellular mitochondrial transfer (MT) has emerged as a novel mechanism of cellular communication and repair in ocular tissues. MT occurs through tunneling nanotubes, extracellular vesicles (EVs), cell fusion, or transmitophagy, and has been shown to support photoreceptor survival, maintain retinal homeostasis, and protect against oxidative injury. Mesenchymal stem cells (MSCs), owing to their remarkable reparative and immunomodulatory properties, have attracted particular attention as efficient mitochondrial donors. Evidence from experimental models demonstrates that MSC-mediated MT can restore bioenergetics, mitigate oxidative stress, and rescue cellular function in inherited optic neuropathies, corneal injuries, retinal degenerative diseases, and ischemic retinopathies. This review summarizes current evidence of MT in ophthalmology, highlights the therapeutic contributions of MSCs, discusses the molecular and microenvironmental factors regulating MT efficiency, and outlines unresolved challenges. We further provide perspectives on how mitochondrial transfer may be translated into innovative therapies for ocular disorders.
    Keywords:  clinical translation; mesenchymal stem cells; mitochondrial transfer; ophthalmic diseases; retinal degeneration
    DOI:  https://doi.org/10.3389/ebm.2026.11128
  4. Neurol Sci. 2026 Jul 15. pii: 629. [Epub ahead of print]47(8):
    Karnofsky performance scale and modified Rankin scale as indicators of functional capacity in patients with mitochondrial disease.
    Jasmin A Koskiniatis, Mika H Martikainen.
       BACKGROUND: Mitochondrial diseases are genetic multisystem disorders. Only symptomatic treatment is available, and clinical progression is common. We investigated whether two commonly used quantitative measures of functional capacity, modified Rankin scale (mRS) and Karnofsky Performance scale (KPS) scores, could be determined retrospectively based on electronic patient records (EPRs) and whether they provided insights into disability and disease progression.
    METHODS: Previously identified 52 patients (28 women) with clinically and genetically confirmed mitochondrial disease at Turku University Hospital (TUH, Turku, Finland) were investigated. Genetic diagnoses were the m.3243 A > G mitochondrial DNA (mtDNA) variant (N = 21), other pathogenic mtDNA variants (N = 22), and nuclear gene variants causing mitochondrial disease (N = 9). Mean age was 50 years (range 10-85 years); average follow-up was nine years. Available neurology and emergency medicine EPRs were reviewed, and mRS and KPS scores determined.
    RESULTS: Patients harbouring the m.3243 A > G, other mtDNA variants, or nuclear gene variants were compared. In all groups, functional capacity declined over time. Those with m.3243 A > G had lower first and latest KPS and mRS values than those with nuclear gene variants (p < 0.004 for all). Differences between the m.3243 A > G and other pathogenic mtDNA variants were not significant.
    CONCLUSION: Functional decline seems a common feature in mitochondrial disease. The KPS and mRS scales may offer a simple tool for long-term evaluation of the functional capacity of patients with mitochondrial disease, especially in non-specialist and primary healthcare. Further studies are needed to confirm whether patients with nuclear gene defects are at particular risk of progression.
    Keywords:  Functional capacity; Genetics; Mitochondrial disease; Performance scales
    DOI:  https://doi.org/10.1007/s10072-026-09212-z
  5. Nat Biotechnol. 2026 Jul;44(7): 1070
    MHRA's radical rare disease proposal.
      
    DOI:  https://doi.org/10.1038/s41587-026-03244-8
  6. Front Immunol. 2026 ;17 1881243
    The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.
    Yu Huan, Qiqi Wang, Rongkaixuan Fang, Yue Sun, Meiya Suo, Chenghong Cao, Shuya Zhang, Lan A, Wenzhou Xu.
      The conversion of metabolic disequilibrium into chronic inflammatory signaling represents a central and actively investigated question in ageing biology. Among stromal cells, fibroblasts are key effectors of tissue remodeling and inflammation, acquiring a senescence-associated secretory phenotype (SASP) that sustains age-related pathology. Here, we delineate a mechanistic framework in which disruption of energy homeostasis drives mitochondrial dysfunction, innate immune activation, and SASP secretion. Mitochondria act as metabolic sentinels that sense energetic stress through altered AMP/ATP and NAD+/NADH ratios, leading to the generation of mitochondrial danger signals-reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). These signals converge on canonical immune pathways, including the cGAS-STING axis, NLRP3 inflammasome, and NF-κB signaling, thereby converting metabolic distress into persistent pro-inflammatory output. Using periodontal ligament fibroblasts as a disease-relevant model, we highlight how microbial biofilm exposure induces mitochondrial metabolic reprogramming that amplifies fibroblast SASP, promotes osteoclastogenesis, extracellular-matrix degradation, and alveolar bone resorption. At the transcriptional level, regulatory networks involving NF-κB, C/EBPβ, STATs, and the mTOR-AMPK hub integrate mitochondrial signals to sustain inflammatory senescence. We propose that restoring mitochondrial metabolic homeostasis serves as a highly promising strategy to break the self-perpetuating cycle in which energy imbalance triggers SASP activation, which in turn contributes to chronic inflammation. Researchers must first characterize the tissue-specific mitochondrial signatures of SASP. Subsequently, developing precise, lesion-targeted metabolic interventions will open new avenues for mitigating inflammaging and rejuvenating stromal function across ageing tissues.
    Keywords:  cellular senescence; fibroblasts; inflammaging; innate immune signaling; metabolic reprogramming; mitochondrial dysfunction; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3389/fimmu.2026.1881243
  7. Int J Mol Sci. 2026 Jul 01. pii: 5931. [Epub ahead of print]27(13):
    The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
    Anastasia Kolotova, Alexandr Shestopalov, Sergey Kutsev.
      Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.
    Keywords:  apoptosis; ferroptosis; iron metabolism; lipid peroxidation; mitochondria; mitochondrial diseases; molecular crosstalk; oxidative stress; regulated cell death; tissue specificity
    DOI:  https://doi.org/10.3390/ijms27135931
  8. Int J Mol Sci. 2026 Jul 07. pii: 6073. [Epub ahead of print]27(13):
    Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
    Ana Beatriz Ramos, Vanessa Alexandra Morais.
      Increasing evidence highlights a tight interplay between lipid metabolism and mitochondrial homeostasis in neurons, with disruptions in either pathway amplifying cellular vulnerability. PTEN-induced kinase 1 (PINK1), a familial Parkinson's disease (PD)-related gene and a key regulator of mitochondrial quality control and homeostasis, emerges at the intersections of lipid metabolic pathways, influencing membrane composition, fatty acid utilization, and neuronal energy balance. Within this review, we discuss the role of mitochondria as hubs for lipid metabolism, the mechanisms and functional consequences of neuronal lipid handling, and the complex bidirectional relationship between lipid dysregulation and PD pathology. Special focus is given to lipid-mitochondria crosstalk and how PINK1 orchestrates this interface to maintain neuronal homeostasis. Finally, we consider therapeutic perspectives that target lipid and mitochondrial pathways, highlighting strategies to restore cellular function and PD pathology.
    Keywords:  PINK1; Parkinson’s disease; lipids; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms27136073
  9. Res Sq. 2026 Jul 06. pii: rs.3.rs-10105855. [Epub ahead of print]
    Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.
    Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.
      Mitochondria are dynamic organelles essential for neuronal survival and synaptic function, and their dysfunction is a key consequence of excitotoxicity following traumatic brain injury (TBI). While intercellular mitochondrial transfer and exogenous mitochondrial transplantation have emerged as mechanisms to restore cellular bioenergetics, its in vivo relevance in the central nervous system remains incompletely understood. Here, we used astrocyte and neuron-specific mitochondrial reporters (GFP or Dendra2) in mice to assess cell-type-specific mitochondrial morphology, bioenergetics, and transfer 24hrs after TBI. Neurons exhibited marked mitochondrial dysfunction, including altered morphology and reduced bioenergetic capacity across somatic, synaptic, and non-neuronal fractions. In contrast, astrocytic mitochondria showed morphological changes but preserved bioenergetic function. Concomitantly, astrocyte-to-neuron mitochondrial transfer was significantly increased following injury, although transfer to synapses remained limited. Single-cell RNA sequencing of astrocytes revealed upregulation of genes involved in extracellular vesicle (EV) biogenesis and mitochondrial translation following injury compared to controls. In vitro co-culture studies confirmed that astrocytes transfer mitochondria to neurons via EVs containing mitochondria (EV-mito). Isolated EV-mito from astrocyte-conditioned media improves neuronal mitochondrial function under NMDA (N-methyl-D-aspartate) induced excitotoxic conditions. Together, these findings demonstrate that neuronal mitochondrial dysfunction drives astrocyte-mediated mitochondrial transfer as an adaptive neuroprotective response after TBI. This process preserves neuronal bioenergetics in the soma and neurites but not at synapses, highlighting both its therapeutic potential and spatial limitations.
    DOI:  https://doi.org/10.21203/rs.3.rs-10105855/v1
  10. Acta Biochim Pol. 2026 ;73 16345
    Mitochondrial morphology and mtDNA content in fibroblasts from patients with different types of mucopolysaccharidosis.
    Klaudia Walczak, Lidia Gaffke, Karolina Pierzynowska, Natalia Sowa-Rogozińska, Ewa Piotrowska.
      Mucopolysaccharidosis (MPS) is a group of inherited metabolic diseases, characterized by defects in the degradation of glycosaminoglycans and their accumulation in lysosomes. However, various secondary cellular changes also contribute to the pathomechanism of MPS. Previous studies have reached contradictory conclusions about the changes in mitochondria in MPS, from increased numbers of mitochondria to impaired activities of some mitochondrial respiratory chain enzymes to no changes in mitochondrial respiration. In this preliminary, hypothesis-generating study, mitochondrial network morphology and mitochondrial DNA (mtDNA) abundance were investigated in fibroblasts derived from patients suffering from diverse MPS types. Fluorescence microscopy and real-time PCR were used to estimate these parameters, respectively. No significant changes in the mitochondrial network morphology were detected in MPS fibroblasts relative to control cells. Decreased levels of mtDNA relative to nuclear DNA levels were evident in some (I, II, IIIA, IIID, and VI) but not all MPS types compared to control fibroblasts. The results of this study suggest that there are some, although perhaps not dramatic, impairments of mitochondrial functions in some MPS types; however, they do not provide direct evidence of mitochondrial dysfunction. Therefore, these findings should be interpreted as descriptive and exploratory, highlighting the need for further functional and mechanistic studies.
    Keywords:  MPS; fluorescence microscopy; mitochondria; mitochondrial DNA; mucopolysaccharidosis
    DOI:  https://doi.org/10.3389/abp.2026.16345
  11. Molecules. 2026 Jul 01. pii: 2317. [Epub ahead of print]31(13):
    Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers.
    Wojciech Rzeski.
      Aging is the dominant risk factor for most chronic diseases, yet the mechanisms driving this relationship remain poorly integrated across biological scales. Existing frameworks have catalogued key hallmarks of aging but do not explain how these processes converge to produce organism-level decline and multimorbidity. A systems-level framework is introduced in which aging is conceptualized as progressive destabilization of interacting regulatory networks. Mitochondrial quality control, nutrient-sensing pathways, and chronic inflammatory signaling form a putative high-centrality network core: mitochondria coordinate redox balance, bioenergetics, and transcriptional adaptation, while NAD+-dependent signaling and NLRP3 inflammasome activation propagate perturbations across regulatory layers. This architecture provides a mechanistic basis for the convergence of neurodegenerative, cardiovascular, metabolic, and oncological phenotypes as emergent consequences of shared network instability. Reframing the hallmarks as coupled network nodes shifts the explanatory focus from isolated mechanisms to system-level resilience and non-linear dynamics. This narrative and conceptual review integrates evidence across mitochondrial biology, metabolic signaling, and inflammatory pathways to develop these arguments, with explicit acknowledgment that the proposed framework is hypothesis-generating rather than formally validated. Interventions targeting high-centrality nodes, including mTOR modulation, NAD+ restoration, mitophagy activation, and anti-inflammatory strategies, may exert system-wide effects by reconfiguring network dynamics rather than correcting individual pathways. This perspective suggests that biomarker-stratified, network-calibrated interventions may offer a broader systems-level therapeutic rationale than single-pathway approaches.
    Keywords:  NAD+ metabolism; aging; chronic inflammation; integrative biology; mitochondria; mitophagy; multimorbidity; network medicine
    DOI:  https://doi.org/10.3390/molecules31132317
  12. J Physiol. 2026 Jul 15.
    Mitochondrial transplantation and neuromuscular recovery after skeletal muscle injury.
    Sina Hadipour-Lakmehsari, Sara Al Mouaswas.
      
    Keywords:  injury; mitochondria; mitochondrial transplantation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP291869
  13. Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2601897123
    Dopaminergic neurons preferentially accumulate mtDNA rearrangements.
    Tania Arguello, Christian D Alcalde Pretel, Nadee Nissanka, Derek Van Booven, Milena Pinto, Monica Rodriguez-Silva, Lise-Michelle Theard, Anthony J Griswold, Carlos T Moraes.
      High levels of mitochondrial DNA (mtDNA) deletions have been described in the substantia nigra. However, the mechanisms involved are poorly understood. We found that transient expression of a mitochondrial targeted restriction endonuclease (mitoPstI) in mice leads to an accumulation of mtDNA rearrangements that involve both the PstI cleavage sites and unrelated specific regions of the mtDNA, including the MTERF1 binding site and the edge of the D-loop. This pattern of rearrangements after double-strand breaks supports the presence of recombination hotspots in the mtDNA. Transient expression of mitoPstI in dopaminergic neurons led to further accumulation of mtDNA rearrangements in dopaminergic neurons after expression was suppressed, a pattern that was not observed in glutamatergic neurons. This accumulation was also blunted when a mtDNA replisome factor was absent, suggesting that robust mtDNA replication is required for the accumulation of preexisting mtDNA rearrangements in dopaminergic neurons over time.
    Keywords:  Parkinson’s disease; deletions; dopaminergic; double strand break; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2601897123
  14. Expert Opin Biol Ther. 2026 Jul 16.
    Beyond innovation: why rare disease gene therapy needs a reset.
    Maram E Abdalla Elsayed, Robert E MacLaren.
      
    Keywords:  Adeno-associated virus; European Medicines Agency; Food and Drug Administration; cell therapy; clinical trials; gene therapy; natural history; rare disease; translation; translational development
    DOI:  https://doi.org/10.1080/14712598.2026.2706035
  15. Genet Med. 2026 Jul 13. pii: S1098-3600(26)00981-0. [Epub ahead of print] 102663
    "It didn't feel like anything unusual because we had already been through so much": Disability-Related Research Experiences of Families with Children Enrolled in the Undiagnosed Diseases Network.
    Undiagnosed Diseases Network
       PURPOSE: In recent years, researchers have brought attention to the underrepresentation of people with disabilities in biomedical research, including genomics research. However, little is known about how disability-related experiences influence participation in rare disease research. This omission is striking, because rare diseases are associated with disabling phenotypes that affect multiple body systems. As part of a study interrogating the relationship between rare disease status and disability identity, we conducted mixed-methods research to address this knowledge gap.
    METHODS: Parents of children enrolled in the UDN (n=25) completed semi-structured interviews to assess disability-related experiences in research participation. Directed content analysis was used to identify common themes.
    RESULTS: Participants' disability-related research experiences were characterized by: 1) disability-related facilitators to research participation, including benefits of research participation and disability-conscious approaches; 2) disability-related logistical barriers to research participation; and 3) research procedures, and the perception of research as minimally burdensome relative to clinical encounters.
    CONCLUSION: Parents of children in the UDN make considerable investments of time and resources to accommodate their children's disabilities to facilitate their participation. Future research should explore these issues in other genomic research studies and practical approaches to mitigating barriers and employing facilitators to disability-related research participation.
    Keywords:  List of Keywords: disability inclusion in genomics research; UDN; and social implications of genetics and genomics; ethical; legal; qualitative research; rare/undiagnosed diseases
    DOI:  https://doi.org/10.1016/j.gim.2026.102663
  16. Organelle. 2025 ;3
    Stress Induced Mitochondrial Hyperfusion (SIMH): A Concise Review on SIMH in Neurodegenerative Disorders and Other Diseases.
    Jeffrey D Brown, Mei-Zhen Cui, Xuemin Xu.
      Mitochondria are critical for cell health, and damaged or dysfunctional mitochondria have been strongly linked to various human diseases, particularly neurodegenerative disorders. Mitochondrial function is regulated by several mechanisms, including the regulation of mitochondrial shape, size, number, and morphology. Mitochondria constantly fuse together and separate; this fusion and fission process is known as mitochondrial dynamics. These mitochondrial dynamics are modulated in response to various stimuli, and recent reports have demonstrated that mitochondria undergo hyperfusion under mild to moderate stress conditions, resulting in the formation of elongated filaments. This phenomenon is referred to as stress induced mitochondrial hyperfusion (SIMH). SIMH is associated with enhanced protection of mitochondria and improved cell viability under stress conditions. The induction of hyperfusion can be triggered by diverse stressors, each with distinct and unique mechanisms. This mini review will focus on these stressors and their corresponding mechanisms, as well as the subsequent effects on mitochondrial and cell health. Additionally, disease models which demonstrate a correlation between specific disease-related stress conditions and mitochondrial hyperfusion are discussed.
    Keywords:  Drp1; ER Stress; MAM; Mfn; Mitochondrial dynamics; Neurodegenerative disorders; OPA1; SIMH; UPR
    DOI:  https://doi.org/10.61747/0ifp.202503002
  17. Drug Discov Today. 2026 Jul 17. pii: S1359-6446(26)00147-9. [Epub ahead of print] 104742
    Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.
    Alise Zagare, Javier Jarazo, Jens Schwamborn.
      Parkinson's disease (PD) poses a major unmet therapeutic challenge, with most drug candidates failing in clinical translation despite promising animal model data. Human induced pluripotent stem cell-derived midbrain organoids recapitulate key PD pathological hallmarks - including dopaminergic neuron loss, α-synuclein aggregation, and neuroinflammation - in a genetically defined, human-specific context. This review summarizes drug screening studies in midbrain organoids across genetic, toxin-based, and α-synuclein preformed fibril models. We highlight therapeutic interventions that rescue PD phenotypes, compare organoid and animal model systems, and discuss the personalized medicine potential of patient-derived organoids. We also critically assess current limitations and outline how artificial intelligence integration and assembloid platforms are advancing organoid-based drug discovery towards regulatory acceptance.
    Keywords:  Parkinson’s disease; drug development; organoids; translational models
    DOI:  https://doi.org/10.1016/j.drudis.2026.104742
  18. Antonie Van Leeuwenhoek. 2026 Jul 17. pii: 168. [Epub ahead of print]119(8):
    Advancements in the study of gut microbiome in disease diagnosis.
    Kun Liu, Zhiqiang Huang, Qing Liu.
      This review summarizes disease-associated changes in gut microbial composition and evaluates the diagnostic performance of models constructed with different machine-learning algorithms. The review seeks to answer questions related to the relationship between the human gut microbiome and disease progression, how different machine learning algorithms affect disease diagnosis using gut microbiome data, and how disease-specific microbial communities impact diagnostic models. Multiple studies report that gut microbiome dysbiosis is commonly observed in many diseases, though patterns vary between conditions and cohorts. Large-scale computational analyses are increasingly applied to identify microbial signatures and to build diagnostic models; however, model performance often depends on data source, preprocessing and choice of algorithm. Overall, evidence indicates disease-associated shifts in gut microbial composition, and that diagnostic model accuracy is sensitive to cohort, sequencing and modeling choices. While certain taxa recur across studies for some diseases, heterogeneity between cohorts limits immediate clinical translation; thus, harmonized study designs and external validation are required. Future work should prioritize reproducible multi-cohort analyses, transparent reporting (e.g., PRISMA for reviews) and prospective validation before clinical deployment.
    Keywords:  Clinical diagnosis; Diseases; Machine learning; Microbiome
    DOI:  https://doi.org/10.1007/s10482-026-02369-9
  19. Syst Rev. 2026 Jul 16.
    A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases.
    Iméze J Hieltjes, Mirthe J Klein Haneveld, Ingeborg Van Dusseldorp, Charlotte M W Gaasterland, Johanna H van der Lee.
       BACKGROUND: Rare diseases impose substantial challenges on affected individuals and healthcare systems. While clinical practice guidelines (CPGs) are crucial for standardizing care, tools to assess their trustworthiness are limited, particularly for rare diseases. There is a need for minimum quality criteria to ensure CPG reliability and utility.
    OBJECTIVE: This systematic scoping review aims to identify a set of criteria that can be used for evaluating and endorsing CPGs for rare diseases.
    METHODS: A systematic scoping review was conducted using four databases (Ovid/Medline, Embase.com, Scopus, and Google Scholar) from inception to April 9, 2024. The search was developed by a medical information specialist. Titles and abstracts were independently screened by two reviewers, with disagreements resolved through discussion or a third reviewer. Articles were included if they addressed quality criteria for guidelines on rare diseases in general, excluding disease-specific guidelines.
    RESULTS: From 9587 unique titles, only one study met the inclusion criteria. The included study, published by Hilton-Boon et al. (2015), summarized an international workshop on the applicability of AGREE II criteria for rare disease guidelines.
    CONCLUSION: Our systematic review identified a single report detailing an international workshop that evaluated the utility of the AGREE II instrument for assessing two guidelines focused on rare diseases. This limited finding highlights a significant gap in methodologies tailored to the specific complexities of rare disease guidelines. The findings underscore the need for a tailored, streamlined set of criteria to address the unique challenges of rare disease guidelines, supporting their development, evaluation, and endorsement in clinical practice.
    DOI:  https://doi.org/10.1186/s13643-026-03247-1
  20. J Neuromuscul Dis. 2026 Jul 15. 22143602261460689
    Advancing the diagnosis of rare neuromuscular and neurological diseases through the collaborative Solve-RD research framework.
    Solve-RD DITF-RND
      Rare neuromuscular and neurological diseases (NMDs and RNDs) present diagnostic challenges due to their clinical heterogeneity and genetic complexity. Despite the advancements in next-generation sequencing (NGS) and other high-throughput genomic technologies, a significant proportion of patients with NMDs and RNDs remain undiagnosed. This is primarily due to genetic heterogeneity, the presence of novel or private variants, and incomplete variant detection by short-read sequencing platforms. The Solve-RD project, a pan-European initiative funded by the Horizon 2020 programme, established a robust interdisciplinary framework integrating expert clinical and bioinformatics teams through Data Interpretation Task Forces (DITFs) and Data Analysis Task Force (DATF). Focusing on previously undiagnosed NMD and RND patients, Solve-RD implemented a systematic reanalysis of exome/genome data. For specific cohorts, various omics approaches were added, including long-read genome sequencing, RNA sequencing, and optical genome mapping. This collaborative framework significantly improved diagnostic yield in RND and NMD cohorts and led to the identification of novel pathogenic variants and mechanisms. The Solve-RD model exemplifies how structured expert collaboration, data sharing and harmonisation, and cutting-edge multi-omics technologies can overcome current diagnostic limitations in rare disease research.
    Keywords:  RNAseq; Solve-RD; diagnostic reanalysis; long-read sequencing; multi-omics; optical genome mapping; rare neurological diseases; rare neuromuscular diseases
    DOI:  https://doi.org/10.1177/22143602261460689
  21. J Genet Couns. 2026 Aug;35(4): e70258
    Repercussions of Diagnostic Delay in Rare Diseases.
    Luisa Rezende Batista, Luiza Fernandes Valente, Fernando Spina, Davi Said Gonçalves Celso, Israel Gomy, Christiane Mariotini-Moura.
      Rare diseases (RDs) are often subject to diagnostic delays due to their low prevalence, clinical variability, and limited professional awareness. This scoping review aimed to map the literature on these delays, examining their clinical, emotional, and socioeconomic consequences. Conducted in accordance with the PRISMA-ScR guidelines, the review identified 23 studies published between 2010 and 2025. The included studies spanned 13 countries, with a notable concentration in Europe and increasing publication trends in recent years, reflecting growing international recognition of the challenges associated with delayed diagnosis. Across diverse study designs and disease contexts, commonly reported consequences included misdiagnosis and inappropriate treatment, psychological distress such as anxiety and frustration, disease progression, increased healthcare utilization, social isolation, reduced quality of life, and financial burden. These findings underscore the broad clinical and psychosocial impact experienced by patients during delayed diagnostic processes. Reducing diagnostic delay in RDs requires coordinated public health efforts, improved diagnostic infrastructure, and greater investment in professional training. Such efforts are essential to ensure earlier diagnosis, improve health outcomes and quality of life, as well as to enable timely access to genetic counseling to better support patients and families.
    Keywords:  delayed diagnosis; neglected diseases; rare diseases
    DOI:  https://doi.org/10.1002/jgc4.70258
  22. Int J Mol Sci. 2026 Jul 06. pii: 6066. [Epub ahead of print]27(13):
    Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.
    Hirotaka Tao, Koichi Fujisawa.
      Mitochondrial dysfunction and impairment of high-energy phosphate transfer are increasingly recognised as shared pathogenic features across neurological disorders. Because neurons require large amounts of ATP to sustain synaptic transmission, ion gradients, axonal transport, and intracellular signalling, they are especially vulnerable to disturbances in energy metabolism. Neurological dysfunction, therefore, cannot be explained solely by reduced mitochondrial ATP production. It also involves failure of the creatine kinase/phosphocreatine (CK/PCr) and adenylate kinase/AMP-activated protein kinase (AK-AMPK) systems, which normally support local ATP buffering, high-energy phosphate transfer, and intracellular energy homeostasis. In parallel, extracellular ATP-dependent purinergic dysregulation contributes to glia-mediated inflammation, synaptic dysfunction, and cell death, linking intracellular energy failure to abnormal intercellular signalling. In this review, we integrate these mechanisms into a shared pathological continuum of disrupted energy homeostasis. We then compare Alzheimer's disease, Parkinson's disease, and epilepsy as representative disorders with shared and disease-specific manifestations of this continuum, characterised respectively by chronic cerebral energy crisis, selective metabolic fragility, and acute energy overload with purinergic dysregulation. Finally, we discuss how this comparative perspective may help identify shared therapeutic opportunities while preserving disorder-specific interpretation.
    Keywords:  energy homeostasis; extracellular ATP-dependent purinergic dysregulation; glia-dependent inflammation; high-energy phosphate transfer; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms27136066
  23. Nature. 2026 Jul 16.
    Why do astronauts' bodies waste away? Space-station study points to mitochondria.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-02089-0
  24. Chem Biol Interact. 2026 Jul 16. pii: S0009-2797(26)00369-8. [Epub ahead of print] 112261
    LKB1/ AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene.
    Lifu Zhu, Chenghuan Wan, Zijun Li, Xuan Fan, Dongsheng Liu, Xueqian Jia, Hui Li, Jiaxiang Zhang.
      Occupational medication-like dermatitis induced by trichloroethylene (OMDT) is a severe systemic allergic disease, often accompanied by acute liver injury. However, the underlying mechanisms linking metabolic disorders and immune damage remain unclear. In a TCE-sensitized mouse model, we demonstrated that TCE sensitization inhibited LKB1/AMPK/mTOR signaling pathway (LKB1 overexpression, AICAR, rapamycin) or autophagy (3-MA) in hepatocytes, resulting in defective mitophagy. This mitochondrial dysfunction leads to leakage of mitochondrial DNA (mtDNA) into the cytoplasm, where mtDNA acts as a damage-associated molecular pattern (DAMP) to activate the cGAS-STING pathway, driving the production of proinflammatory cytokines (IL-1β, IL-6, TNF-α), and exacerbating liver inflammation. Restoration of LKB1/AMPK signaling or inhibition of mTOR rescued mitophagi, reduced mitochondrial DNA leakage, inhibited cGAS-STING activation, and alleviated liver pathology, while inhibition of autophagy alone recapitulated the TCE-induced phenotype. Taken together, our findings demonstrate that failure of TCE via LKB1/AMPK/mTOR mediated mitophagy destroys hepatocyte homeostasis, leading to mtDNA-driven cGAS-STING activation and immune-mediated liver injury in the pathogenesis of OMDT, thus providing a potential therapeutic target for OMDT-related liver injury.
    Keywords:  LKB1/AMPK/mTOR; Mitophagy; OMDT; TCE; mtDNA
    DOI:  https://doi.org/10.1016/j.cbi.2026.112261
  25. Pharmacol Ther. 2026 Jul 16. pii: S0163-7258(26)00113-0. [Epub ahead of print] 109086
    Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.
    Woo Hyun Park.
      Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.
    Keywords:  Drp1; Intercellular mitochondrial transfer; Macrophage polarization; Mitochondrial dynamics; Mitoimmunity; NLRP3 inflammasome; Pharmacological intervention; cGAS-STING
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109086
  26. J Biochem Mol Toxicol. 2026 Jul;40(7): e71021
    Mitochondrial Dysfunction in Ulcerative Colitis: Pathogenic Mechanisms and Novel Therapeutics.
    Hongyan Ran, Siyuan Zhou, Hui Zou, Juan Deng, Fei Yin.
      Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by a complex interplay of mitochondrial dysfunction. These defects impair energy production, increases oxidative stress, and disrupts immune balance. Here we review three therapeutic classes that target mitochondrial pathways: antioxidants, metabolic modulators, and microbiota-directed strategies. In UC, mitochondrial dysfunction creates a self-perpetuating cycle through metabolic-immune crosstalk, the leakage of mitochondrial DNA, and the redistribution of cardiolipin. Moreover, the gut microbiota and mitochondria engage in bidirectional crosstalk that amplifies intestinal inflammation. Encouragingly, agents that restore mitochondrial function have shown therapeutic benefit in preclinical and early clinical studies. Notable examples include the mitochondria-targeted antioxidant MitoQ (currently in a Phase 2b trial for UC), ClpP (caseinolytic protease P) activators that reprogram T-cell metabolism, and engineered probiotics that deplete pro-inflammatory succinate. This review synthesizes current evidence on mitochondrial dysfunction in UC, bridging molecular mechanisms, immune-metabolic interactions, and emerging therapeutics to propose a new treatment paradigm centered on mitochondrial restoration.
    Keywords:  inflammation; metabolic reprogramming; mitochondrial dysfunction; oxidative stress; ulcerative colitis (UC)
    DOI:  https://doi.org/10.1002/jbt.71021
  27. Mol Neurobiol. 2026 Jul 17. pii: 775. [Epub ahead of print]63(1):
    Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.
    Shobha Kumari, Hemraj Singh, Shravani Vaidya, Rajeev Taliyan.
      Neurodegenerative diseases are characterized by progressive neuronal loss driven by protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Among these, Parkinson's disease (PD) is a prevalent disorder marked by degeneration of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates. Emerging evidence indicates that mitochondrial dysfunction and metabolic dysregulation are central contributors to PD pathogenesis. Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, have emerged as key regulators of neuronal survival and metabolic homeostasis. Mechanistically, SIRT1 regulates α-synuclein aggregation, autophagy, and neuroinflammatory signaling, while SIRT3 preserves mitochondrial integrity and reduces oxidative stress. In contrast, SIRT2 has been implicated in microtubule destabilization and neurotoxicity, and its inhibition has demonstrated neuroprotective effects in experimental models. This review provides a comprehensive, up-to-date synthesis of the molecular mechanisms underlying sirtuin-mediated neuroprotection in PD and related neurodegenerative disorders. We further discuss the translational potential of targeting sirtuin pathways, including pharmacological modulators and NAD+-boosting strategies, while addressing current limitations and future directions for clinical translation.
    Keywords:  Epigenetic regulation; Mitochondrial dysfunction; NAD+ metabolism; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Sirtuins
    DOI:  https://doi.org/10.1007/s12035-026-06062-w
  28. Int J Mol Sci. 2026 Jun 30. pii: 5918. [Epub ahead of print]27(13):
    Mitochondrial Immunometabolism in Sepsis: From Oxidative Stress and mtDAMP Signaling to Biomarker-Guided Therapy.
    Minsoo Kim, Phyu Phyu Khin, Hyeran Jung, Chang Woo Chae, Byeong Hwa Jeon, Cuk-Seong Kim.
      Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine.
    Keywords:  biomarkers; immunometabolism; mitochondria; mitochondria-targeted therapy; mitochondrial DNA; mitophagy; organ dysfunction; oxidative stress; sepsis
    DOI:  https://doi.org/10.3390/ijms27135918
  29. Ageing Res Rev. 2026 Jul 14. pii: S1568-1637(26)00246-1. [Epub ahead of print] 103254
    A Compendium of Circulating Biomarkers of Senescence in Humans: Insights on Mechanistic Impact Across Health Domains and Modulation by Therapeutic Interventions.
    Bradley Olinger, Nathan Basisty.
      Cellular senescence is a hallmark of aging and a contributing factor to many age-related morbidity and decline. A key characteristic of senescent cells is a pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP). When tracked in circulation, SASP factors associate with age-related clinical traits and diseases, raising the captivating possibility that the senescence burden, and concomitant susceptibility to age-related morbidity, can be noninvasively assessed in clinical settings. This review consolidates human-focused evidence identifying these biomarkers of senescence in circulation, and emerging drug and lifestyle-based senotherapeutic interventions that modulate senescence burden and associated clinical parameters. Clinical parameters associated with the circulating senescence burden generally fall into four interrelated health domains: neurodegeneration, pulmonary disease, cardiometabolic disease, and musculoskeletal disorders. For each domain, the biological basis for the negative impact of senescence is explored in clinical and preclinical models, revealing that the accumulation of senescence often suppresses stemness throughout the body, suggesting that senescence plays a causal role in age-related decline and highlighting potential novel therapeutic avenues. Importantly, some circulating biomarkers of senescence, such as GDF15 and Activin A, demonstrate cross-study clinical relevance and are implicated in morbidities across multiple health domains. Collectively, these insights provide a framework for understanding the role that senescence plays in aging and the development of diagnostic biomarker panels that could better inform future clinical care.
    Keywords:  SASP; clinical; plasma; proteomics; senolytics; senotherapeutics
    DOI:  https://doi.org/10.1016/j.arr.2026.103254
  30. Pediatr Res. 2026 Jul 16.
    Individual and joint association of maternal and cord blood mitochondrial DNA heteroplasmy and copy number with preterm birth.
    Xueqi Qu, Xiumei Hong, Guoying Wang, Jessica An, Jing Sun, Ashley Song, Hilary J Vernon, Xiaobin Wang.
       BACKGROUND: The biological mechanisms underlying preterm birth (PTB) are not fully understood. This study examined the individual and joint associations of mitochondrial DNA (mtDNA) heteroplasmy and copy number (mtDNA-CN) in maternal and cord blood with PTB.
    METHODS: This study analyzed 998 mother-infant dyads (18% PTB). MtDNA heteroplasmy and mtDNA-CN were measured by a targeted DNA sequencing approach using umbilical cord blood collected at birth and maternal blood collected 24-72 hours postpartum. Multivariable logistic regressions were used to evaluate the associations with PTB.
    RESULTS: Maternal predicted pathogenic heteroplasmy was associated with a twofold increased risk of PTB (adjusted OR (95% CI) = 2.08 (1.07, 4.05)), whereas no significant associations were observed for maternal overall or functional heteroplasmy. No significant associations were observed for cord blood heteroplasmy measures. A U-shaped association between maternal mtDNA-CN and PTB was observed. Higher cord mtDNA-CN were associated with increased PTB odds (1.36 (1.14, 1.62)). Notably, a significant interaction between maternal and cord mtDNA-CN was found for PTB risk.
    CONCLUSION: Maternal, but not fetal, mtDNA heteroplasmy was associated with increased PTB risk. Both maternal and cord blood mtDNA-CN demonstrated individual and interactive associations with PTB, suggesting that maternal and fetal mitochondrial genomic variations may jointly influence PTB risk.
    IMPACT: We found that maternal predicted pathogenic mtDNA heteroplasmy was associated with increased PTB risk; maternal mtDNA-CN showed a U-shaped association with PTB; and higher cord blood mtDNA-CN was positively associated with PTB. This study provides the first evidence from a large birth cohort simultaneously assessing maternal and fetal mtDNA heteroplasmy and mtDNA-CN in relation to PTB, adding a mitochondrial genetics perspective to PTB research. This study highlights mitochondrial genomic variation as a novel pathway in PTB pathogenesis and suggests the potential utility of mtDNA measures as biomarkers for early risk assessment and as a basis for future mitochondria-targeted interventions.
    DOI:  https://doi.org/10.1038/s41390-026-05307-7
  31. J Mol Endocrinol. 2026 Jul 15. pii: JME-25-0203. [Epub ahead of print]
    ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
    Dandan Chen, Yuxin Jia, Xiaohong Duan, Jianhua Huang, Xiaohong Deng.
      Mitochondrial dysfunction driven by chronic hyperglycemia is a hallmark of diabetes, yet how this metabolic stress communicates pathological signals beyond individual cells remains poorly understood. In this study, we identified a novel mechanism linking chronic hyperglycemia to systemic metabolic impairment through ROS-mediated extracellular release of structurally intact mitochondria and mitochondrial DNA (mtDNA). In HepG2 cells exposed to high glucose (HG), extracellular release of structurally intact mitochondria was visualized by co-staining of mitochondria and the plasma membrane, together with electron microscopy. Mitochondria-enriched fractions isolated from culture supernatants were further quantified using flow cytometry and qPCR. Cell-free mtDNA (cf-mtDNA) was visualized with co-staining of mitochondria and double- stranded DNA, isolated through differential centrifugation and ultrafiltration, and quantified by qPCR. We demonstrate that HG stimulates the release of exosome-enclosed mtDNA as well as fragmented cf-mtDNA. Concurrently, HG induces mitochondrial dysfunction and markedly increases mitochondrial ROS (mtROS). Treatment with MitoTEMPO, a mitochondria-targeted ROS scavenger, significantly reduced HG-induced extracellular release of mitochondria and mtDNA, supporting the ROS dependence of this process. In diabetic mice, we detected elevated circulating mtDNA copy number and pronounced mitochondrial dysfunction in liver and muscle, including reduced ATP production, mitochondrial swelling, cristae disruption, and elevated MDA levels. Resting metabolic rate was markedly decreased, indicating impaired systemic respiratory metabolism. Serum analyses revealed increased 8-OHdG, pyruvic acid, GDF-15, and FGF-21, along with reduced FT3, reflecting severe oxidative stress and mtDNA damage. These findings uncover a novel mechanism in which hyperglycemia-induced ROS drive mitochondrial extrusion, potentially linking metabolic stress to systemic metabolic deterioration.
    Keywords:  Diabetes mellitus; ROS; mitochondrial release; resting metabolic rate
    DOI:  https://doi.org/10.1530/JME-25-0203
  32. Pediatr Res. 2026 Jul 13.
    Perspectives on genomic newborn screening studies: design, implementation, and outcomes.
    Mehmet Bugrahan Duz, Wendy K Chung.
       BACKGROUND: With decreasing sequencing costs and increasingly accurate and scalable methods to interpret genetic variation, genomic newborn screening (gNBS) is being assessed for feasibility, acceptability, and impact worldwide. The field is evolving to determine the genes and variants to report, how to communicate with parents and pediatricians, and confirm results, and how to medically manage children with confirmed diagnoses.
    CONTENT: This review summarizes global gNBS studies, including recruitment methods, consent models, sample types, participant characteristics, sequencing methods, gene selection criteria, test performance, variant interpretation, automated reporting, turnaround time, methods to return results, confirmatory diagnostic testing, and comparisons with standard NBS (stdNBS) results. Early experience supports the feasibility and positive clinical impact of gNBS. Variability in study design, gene selection, and reporting limits direct comparability across studies but increasing and diverse experience will optimize parameters prior to broad implementation.
    IMPACT: Genomic newborn screening is feasible and expands the screening of treatable genetic conditions beyond standard newborn screening, and improves the diagnostic accuracy of standard newborn screening. Comparison of genomic newborn screening studies around the world, highlighting key differences in study design, technical approaches, clinical implementation, and current challenges. Key evidence supporting the implementation of genomic newborn screening is summarized to guide future policy and clinical practice.
    DOI:  https://doi.org/10.1038/s41390-026-05283-y
  33. Ophthalmic Res. 2026 Jul 16. 1-22
    Construction and Applications of Knowledge Graphs in Ophthalmology.
    Siyani Chen, Haoyu Chen.
      Knowledge Graph (KG) is an artificial intelligence technique that provides a structured representation of medical entities and their relationships, thereby facilitating integration of heterogeneous information, knowledge discovery, and intelligent reasoning. The process of KG construction includes knowledge acquisition, knowledge extraction, knowledge fusion, knowledge inference, knowledge graph visualization and knowledge graph evaluation. In ophthalmology, KGs have demonstrated significant potential in advancing disease understanding, supporting clinical decision-making, assisting in ophthalmic image analysis, and facilitating clinical intelligent question answering. This paper reviews the methodologies for constructing medical KGs and highlights their applications in ophthalmology, with particular emphasis on the integration of ophthalmic KGs with medical imaging and large language models (LLMs). Furthermore, it discusses existing challenges-ranging from privacy and regulatory constraints to high construction and maintenance costs, limited fusion of imaging and multimodal data, insufficient coverage of rare eye diseases and insufficient application in education and basic research-aiming to provide insights that promote deeper research and clinical translation of ophthalmology KGs.
    DOI:  https://doi.org/10.1159/000553612
  34. Trends Biochem Sci. 2026 Jul 15. pii: S0968-0004(26)00204-5. [Epub ahead of print]
    Modification and aminoacylation of human mitochondrial tRNAs.
    Shi-Ying Yao, Meng Wang, Fan-Yan Wei, Xiao-Long Zhou.
      Mitochondrial tRNAs (mt-tRNAs) are central to energy production by translating essential oxidative phosphorylation subunits. Following transcription, mt-tRNAs undergo diverse processing steps, post-transcriptional modifications, and aminoacylation, which are critical for their functions. In this article, we review how human mt-tRNA-modifying enzymes deposit various post-transcriptional modifications onto mt-tRNAs, encompassing both well-characterized and less-understood marks. We also summarize the principles, peculiarities, and critical roles of mt-tRNA charging and proofreading, and highlight recently uncovered noncanonical functions of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Collectively, these recent findings demonstrate the dynamic regulatory mechanisms of mt-tRNA modification and aminoacylation, the extensive involvement of mt-aaRSs in cellular metabolic pathways, and the promising potential of targeting these enzymes in therapeutics.
    Keywords:  editing; mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs); mitochondrial diseases; mitochondrial translation; noncanonical functions; post-transcriptional modification
    DOI:  https://doi.org/10.1016/j.tibs.2026.06.009
  35. J Transl Med. 2026 Jul 15. pii: 915. [Epub ahead of print]24(1):
    Letter to editor: Mitochondrial DNA release contributes to neuropathic pain via a cGAS-STING-IRF3 CMPK2-associated immunometabolic feedback mechanism.
    Renyuan Tian, Shengwei He, Bo Yuan.
      
    DOI:  https://doi.org/10.1186/s12967-026-08600-5
  36. MedComm (2020). 2026 Jul;7(7): e70827
    Cellular Senescence and Aging: Mechanisms, Disease Convergence, and Therapeutic Frontiers.
    Guowei Cai, Jia Ren, Li Wang, Yingying Wu, Huirui Wang, Xiaomeng Cao, Hao Shang, Xuben Hou, Yujiu Wang, Haibo Xue, Ting Dong.
      Cellular senescence, a stress-induced, irreversible cell cycle arrest coupled with a proinflammatory secretory phenotype, has emerged as both a central driver of aging and a tractable therapeutic target. Although acute senescence contributes beneficially to tumor suppression and wound healing, chronic accumulation of senescent cells sustains systemic inflammaging and accelerates organ dysfunction. This review synthesizes current progress in aging biology into a unified mechanistic and translational framework. We first examine how primary aging hallmarks, such as genomic instability and epigenetic dysregulation, interact to trigger cellular senescence, then explore how these converging molecular processes give rise to distinct age-related pathologies across reproductive, pulmonary, hepatic, neurological, skeletal, and metabolic systems. We further evaluate emerging interventional strategies, from senolytics and senomorphics to rejuvenation approaches, while addressing key translational barriers including targeting specificity, senescence heterogeneity, and equitable access. By uniting mechanistic insight with disease-oriented and therapeutic perspectives, this review charts a strategic roadmap for deploying senescence-targeting therapies to extend human healthspan.
    Keywords:  age‐associated diseases; aging hallmarks; aging mechanisms; antiaging strategies; cellular senescence
    DOI:  https://doi.org/10.1002/mco2.70827
  37. Front Endocrinol (Lausanne). 2026 ;17 1866059
    The EV-mitochondrial outsourcing network as a therapeutic target for age-related testosterone deficiency: from network collapse to clinical intervention.
    Lu Zhou, Xingzhao Tian, Xiteng Wang, Xiucheng Lan, Meijing Wang, Junjun Li, Liang Dong, Xujun Yu, Fang Yang.
      The longevity and functional maintenance of Leydig cells (LCs) depend on an extracellular vesicle (EV)-mediated mitochondrial outsourcing system. In contrast to the conventional focus on intracellular quality control, LCs orchestrate a bidirectional EV transfer network with testicular macrophages: they export EVs containing defective mitochondria to CD206+ macrophages for clearance (the scavenger pathway), while importing EVs with healthy mitochondria from MHCII+ macrophages (the donor pathway). During aging, this network undergoes three-dimensional disruption-donor-side collapse characterized by diminished PGC-1α, a shift toward Drp1 predominance over Mfn2, and NAD+ depletion; scavenger-side obstruction reflected in reduced TREM2 and impaired phagosome-lysosome fusion; and communication uncoupling driven by decay of the VCAM1/ITGβ1 axis. These coordinated failures precipitate a mitochondrial quality crisis, steroidogenic enzyme dysfunction, and progressive loss of LCs, thereby initiating and driving late-onset hypogonadism (LOH). Individual variability in EV network efficiency dictates LOH susceptibility, and the point of network decompensation marks the transition from a compensated state to clinical disease. In-depth dissection of this network and its dysregulation may yield novel strategies for early diagnosis (INSL3, EV-miRNA signatures, mtDNA mutation burden) and targeted therapy (MSC-EVs, NAD+ precursors, TREM2 activation).
    Keywords:  extracellular vesicles; late-onset hypogonadism; leydig cells; mitochondrial transfer; reproductive aging; testicular macrophages
    DOI:  https://doi.org/10.3389/fendo.2026.1866059
  38. Clin Interv Aging. 2026 ;21 606639
    Astrocytes in Parkinson's Disease: From Guardians to Accomplices.
    Dan Gu, Yu Lei, Jiayi Lu, Wenmin Yi, Qinbin Zhang, Chuanling Wang, Zhiyou Cai.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigral dopaminergic neurons and misfolded α‑synuclein (α‑Syn) aggregation. However, increasing evidence indicates that astrocytes occupy a central position in the multifactorial pathogenesis of PD. As the most abundant glial cells in the Central Nervous System (CNS), astrocytes maintain neural homeostasis via neurotransmitter clearance, ion balance, metabolic support, synaptic regulation, and blood-brain barrier (BBB) integrity. In early PD, astrocytes exert neuroprotective effects; with disease progression, persistent pathological stimuli-including aggregated α-Syn, chronic neuroinflammation, mitochondrial dysfunction, oxidative stress, and iron dyshomeostasis-drive astrocytes into a reactive, neurotoxic state. This review systematically summarizes how astrocytes regulate α-Syn handling, mitochondrial function, neuroinflammation, and oxidative stress in PD, explaining how these pathways reshape astrocyte states across disease stages, and highlights stage-dependent dual roles of astrocytes as guardians and accomplices, with implications for astrocyte-targeted therapies.
    Keywords:  Parkinson’s disease; astrocyte; mitochondrial dysfunction; neuroinflammation; α-synuclein
    DOI:  https://doi.org/10.2147/CIA.S606639
  39. Neurosci Biobehav Rev. 2026 Jul 11. pii: S0149-7634(26)00323-4. [Epub ahead of print]189 106866
    Intranasal dopamine: Anatomical pathways, biological mechanisms and neuromodulatory potential.
    Owen Y Chao, Susanne Nikolaus, Claudia Mattern, Lih-Chu Chiou, Joseph P Huston.
      Dopamine (DA) regulates motor control, motivation, learning and memory, cognition, and social behavior, and its dysregulation underlies a wide range of neurological and psychiatric disorders. In Parkinson's disease (PD), degeneration of dopaminergic neurons in the substantia nigra depletes striatal DA, making dopaminergic restoration a central therapeutic target. Because DA does not cross the blood-brain barrier (BBB), treatment relies on its precursor L-DOPA. Intranasal (IN) administration offers a non-invasive alternative: it enables rapid absorption, avoids hepatic first-pass metabolism, and provides partial brain access via nose-to-brain pathways, positioning IN-DA as a potential tool to directly influence central dopaminergic function. This review integrates current knowledge on IN-DA. We first examine nasal anatomy, the biological and physicochemical variables governing IN delivery, and the mechanisms of nose-to-brain transport, followed by a focused synthesis of IN-DA findings. Preclinical evidence shows that IN-DA and IN-L-DOPA increase extracellular DA levels and turnover in the striatum, with IN-DA appearing to enhance dopaminergic tone through presynaptic uptake and storage. Behaviorally, IN-DA produces state-dependent improvements across cognitive, emotional, and social domains, particularly in neuropsychiatric rodent models. Although nanoparticle-based DA formulations are being developed primarily to improve delivery efficiency for PD therapy, emerging evidence suggests that IN-DA may serve more broadly as a neuromodulatory approach for disorders involving catecholamine dysregulation.
    Keywords:  ADHD; Autism; Cognitive function; Nanoparticles; Schizophrenia
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106866
  40. Rev Invest Clin. 2026 Jul 11. pii: S0034-8376(26)00017-3. [Epub ahead of print]78(4): 100050
    Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.
    Ariadna Domínguez-García, Juan Carlos Delgado-Uriarte, Amin Cervantes-Arriaga.
      Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.
    Keywords:  Antisense oligonucleotide; CAG repeat; Disease-modifying therapy; Huntingtin; Huntington's disease; Neurofilament light; Somatic instability
    DOI:  https://doi.org/10.1016/j.ric.2026.100050
  41. Mol Neurobiol. 2026 Jul 17. pii: 776. [Epub ahead of print]63(1):
    Mitochondrial-Epigenetic Crosstalk in Autism Spectrum Disorder: Linking Cellular Stress to Synaptic Dysfunction and Treatment Resistance.
    Dijie Liu, Kai Tao, Yuxia Wang, Ying Sun, Shiyong Wang.
      Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by striking heterogeneity in therapeutic outcomes, with a substantial subset of individuals showing limited or absent improvement in targeted behavioral domains following behavioral or pharmacological interventions. Traditional explanations for poor treatment response-such as receptor desensitization and pharmacokinetic variability-fail to capture the persistent, systems-level alterations underlying this phenomenon. Emerging evidence identifies mitochondrial dysfunction as a critical but underexplored contributor to persistent treatment non-response in ASD. Beyond energy failure, mitochondrial stress activates adaptive transcriptional programs (UPRmt, NRF2-ATF4) that recruit epigenetic effectors, including DNMTs, HDACs, and EZH2, leading to chromatin remodeling and repression of neuroplasticity-related genes. In parallel, mitochondrial noncoding RNAs (mt-ncRNAs) may participate in locus-specific epigenetic regulation, establishing a relatively stable transcriptional state that constrains treatment responsiveness. This review consolidates current insights into the mitochondrial-epigenetic axis in ASD, highlighting its association with synaptic dysfunction and clinical heterogeneity. We further discuss emerging strategies aimed at modulating mitochondrial stress and epigenetic repression, including mitochondria-targeted antioxidants, epigenetic modulators, and CRISPR/dCas9-based epigenome editing. By integrating recent multi-omics findings and preclinical evidence, we propose a mechanistic framework linking mitochondrial stress to epigenetic remodeling and domain-specific treatment non-response, with implications for precision therapeutics in ASD.
    Keywords:  Autism spectrum disorder; Epigenetic silencing; Mitochondrial dysfunction; Mitochondrial non-coding RNAs; Therapeutic resistance; Transcriptional repression
    DOI:  https://doi.org/10.1007/s12035-026-06035-z
  42. Neuroscience. 2026 Jul 11. pii: S0306-4522(26)00465-3. [Epub ahead of print]611 432-449
    CAPNS1 restoration partially alleviates mitochondrial dysfunction and synaptic deficits in Alzheimer's disease through the Ca2+-CaMKIIβ-MAPK-PGC-1α axis.
    Jialin Han, Shuang Wu, Xiaolin Cui, Xinyi Zhou, Qian Yu, Qian Cheng, Zhiming Lu, Shuai Zong.
      Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by brain atrophy and cognitive decline. While the amyloid cascade hypothesis remains the dominant framework, accumulating evidence indicates that mitochondrial dysfunction critically contributes to AD progression. Although improving mitochondrial function has been shown to rescue cognitive deficits in AD models, the underlying molecular mechanisms remain elusive. In this study, we identified a significant reduction in calpain small subunit 1 (CAPNS1) expression in both AD patient samples and male transgenic mouse models. Decreased CAPNS1 levels were strongly correlated with mitochondrial ultrastructural damage, reduced mitochondrial DNA (mtDNA) copy number, and progressive synaptic loss. Mechanistically, we found that CAPNS1 positively regulated mtDNA transcription and mitochondrial gene expression, and pharmacological data suggested the involvement of the Ca2+-CaMKIIβ-MAPK-PGC-1α signaling axis, a master pathway governing mitochondrial biogenesis and respiratory capacity. This activation subsequently restored cellular ATP production and reduced mitochondrial reactive oxygen species accumulation. Importantly, neuronal-specific CAPNS1 upregulation in APP/PS1 transgenic mice markedly improved mitochondrial cristae integrity, reversed hippocampal long-term potentiation deficits, increased dendritic spine density, and partially alleviated spatial memory deficits in behavioral tests. We noted that loss-of-function experiments (e.g., CAPNS1 knockdown or knockout) were not performed in this study, and the proposed Ca2+-CaMKIIβ-MAPK-PGC-1α axis should therefore be interpreted as a suggestive working model requiring further validation. Collectively, our findings indicate that CAPNS1 serves as a key regulator of mitochondrial function. By linking Ca2+ signaling to mitochondrial gene expression and synaptic integrity, CAPNS1 represents a promising therapeutic target for ameliorating synaptic loss and cognitive decline in AD.
    Keywords:  Alzheimer’sdisease; CAPNS1; Mitochondrial dysfunction; Neuron; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.07.021
  43. Int J Mol Sci. 2026 Jun 23. pii: 5668. [Epub ahead of print]27(13):
    Trends in the Engineering of Adeno-Associated Virus (AAV) for Precision Gene Delivery to the Central Nervous System (CNS).
    Sola Oloruntimehin, Alexander Malogolovkin.
      Rare genetic disorders of the central nervous system (CNS) remain some of the most complex and challenging diseases to treat for several reasons. Targeting the CNS, especially the brain, presents one of the greatest obstacles in gene therapy using adeno-associated virus (AAV) vectors. Although various AAVs have been identified for their ability to transduce different cells in the CNS, their effectiveness and efficiency are significantly limited by the presence of neutralising antibodies (NAbs) and restricted cargo capacity. Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna®), spinal muscular atrophy (SMA) (Zolgensma®), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi® and Upstaza®, which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain regions, transforming how CNS disorders are treated.
    Keywords:  AADCD; AAV; Alzheimer’s disease; CNS; Parkinson’s disease; central nervous system; neurodegenerative; spinal muscular atrophy
    DOI:  https://doi.org/10.3390/ijms27135668
  44. Cell Biochem Funct. 2026 Jul;44(7): e70261
    Thermodynamic Frontiers in Hemoglobin-Inspired Polymer Science for Diagnosis and Modulation of Neurodegenerative Diseases.
    Mohammad Edrisi, Navid Rabiee.
      The thermodynamic logic underlying hemoglobin's cooperative binding and reversible conformational transitions offers a powerful conceptual model for reimagining polymer design in neurodegenerative medicine. In this review perspective, we outline a unified thermodynamic framework that connects molecular energetics, polymer science, and pathological protein aggregation. We discuss how hemoglobin's allosteric adaptability, enthalpy-entropy compensation, and redox responsiveness can inspire polymers capable of sensing and reshaping the free-energy landscapes that govern amyloid formation. Drawing on evidence from protein thermodynamics, polymer chemistry, and neurobiological systems, we propose design principles for adaptive, hemoglobin-inspired polymers that act as artificial chaperones, materials capable of modulating aggregation equilibria, restoring proteostatic balance, and integrating diagnostic and therapeutic functions. This article defines an emerging field at the intersection of thermodynamic polymer science and neurodegeneration, where materials are not passive carriers but active regulators of molecular energy landscapes.
    Keywords:  Artificial chaperone materials; Energy landscape re‐engineering; Hemoglobin‐inspired polymers; Protein aggregation and neurodegeneration; Thermodynamic medicine
    DOI:  https://doi.org/10.1002/cbf.70261
  45. Aging Cell. 2026 Jul;25(7): e70634
    Karyopherin Dysfunction Is a Key Driver of Aging.
    Louis R Lapierre.
      Aging is often framed as the gradual erosion of proteostasis, driven by declining chaperone capacity, impaired degradation, and dysregulated protein synthesis. Yet this view implicitly assumes that proteins fail primarily because they misfold or escape clearance. Increasing evidence instead points to a more fundamental problem: aging disrupts the spatial management of the proteome. Gradually, proteins are misplaced, signaling pathways are uncoupled from their compartments, and condensates that were once dynamic become pathological. At the center of this spatial collapse lies nucleocytoplasmic protein partitioning. Nucleocytoplasmic protein transport has long been treated as a background housekeeping process, that is, essential but largely passive. However, this assumption is no longer reasonable. Karyopherins, the importins, exportins and biportins that mediate selective transport across the nuclear pore complex (NPC), are emerging as active regulators of proteostasis, phase behavior, and signaling fidelity. Rather than simply responding to cargo demand, karyopherins shape intracellular protein solubility, suppress aberrant condensation, and buffer age-associated stress. Their dysfunction therefore constitutes a primary, not secondary, driver of aging phenotypes. Here, I argue that karyopherins should be repositioned at the core of aging biology. I propose that age-dependent failure of karyopherin-mediated transport represents a unifying mechanism linking proteostasis collapse, altered gene regulation, and the emergence of age-associated diseases. This perspective redefines nucleocytoplasmic protein transport from a logistics challenge into a central regulatory layer and highlights karyopherins as emerging targets for aging interventions.
    DOI:  https://doi.org/10.1111/acel.70634
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