bims-polgdi Biomed News
on POLG disease
Issue of 2026–07–05
forty-five papers selected by
Luca Bolliger, lxBio
  1. A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.
  2. [Mitochondrial diseases].
  3. [Is it possible to generate artificial mitochondrial genome?]
  4. [Investigation of a causal relationship between mtDNA mutations and a mitochondrial respiratory dysfunction in premature aging mice].
  5. The CARE Program: An Initiative of Patient-Focused Drug Development for Rare Diseases by NMPA.
  6. The role of mitochondria in the gut-kidney axis: implications for kidney health.
  7. Multi-platform reassessment of human mitochondrial DNA methylation reveals signals consistent with technical artifacts.
  8. Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
  9. KGRD: a knowledge-graph-augmented automated reasoning framework for diagnosis and counselling of paediatric rare genetic disorders.
  10. New-born Screening for Mitochondrial Disorders is Useful for Genetic Counseling and Early Treatment when Available.
  11. Mitochondrial quality control in human ageing and longevity.
  12. Standardized Immunofluorescence Imaging of Tunneling Nanotubes and Mitochondrial Transfer Between Astrocytes and Neurons.
  13. When mitochondria lose their fold: matrix proteostasis and stress signaling.
  14. The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease.
  15. Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.
  16. FDA Gene Therapy Approvals (1998-2025): Current Status, Regulatory Evolution, and Future Directions.
  17. Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications.
  18. Transcriptomic and epigenetic characterization of paraventricular thalamic nucleus neurons in Polg1 mutant mice.
  19. Energy beats: Daily and circadian rhythms in mitochondrial biology.
  20. Advancing the monitoring of organelle contact sites in vitro and in vivo.
  21. Mitochondria-sarcoplasmic reticulum crosstalk as a modulator of skeletal muscle mass.
  22. Nano-Based Therapeutics in Rare Disease Management: Current Perspectives, Challenges, and Unmet Needs.
  23. Telomere regulation of mitochondria in porcine parthenogenetic embryos.
  24. Analysis of whole-exome sequencing data from nearly 10,000 Iranian individuals: identification of recessive mitochondrial disease variants and proposal of a population-specific carrier screening panel.
  25. Mapping the landscape of treatable inborn errors of metabolism: a systematic gene-level evaluation based on the ICIMD classification.
  26. A de novo TWNK Variant Mimicked Sporadic Chronic Progressive External Ophthalmoplegia.
  27. The mitochondrial protease, LonP1, is a potential cardioprotective target for attenuating doxorubicin-induced cardiomyocyte death.
  28. Lived Experiences of Patients With Rare Diseases and Healthcare System Barriers: A Phenomenological Study.
  29. Rare diseases in Colombia: Current situation and ideas for a better future
  30. The microbiota-mitochondria axis: linking metabolic dysfunction to neurodegeneration.
  31. Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.
  32. Concurrence of Inherited Nuclear and Mitochondrial DNA Optic Neuropathies.
  33. Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients.
  34. CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations.
  35. Kinematic-calcium loops unravel impaired excitation-contraction coupling in MELAS-affected cardioids.
  36. [Rare genetic diseases with frequent mental symptoms].
  37. Mitochondrial genome alterations in cancer: From mutations and epigenetics to targeted therapiesack.
  38. [Expansion of Targeted Protein Degradation for Targeting Aggregate-prone Proteins and Mitochondrial Proteins].
  39. Systems modelling of mitochondrial dynamics in different exercise regimes.
  40. Microfluidic-based biomimetic mitochondrial nanocomposite for targeted immunotherapy of rheumatoid arthritis via mitochondrial transplantation.
  41. Spatholobi caulis and Epicatechin amplify erythropoiesis through mitochondrial translocation of AKT and enhanced oxidative phosphorylation.
  42. Late-onset epileptic spasms: presentation, aetiology and outcome.
  43. Health service access and delivery for people living with rare disorders: a scoping review.
  44. Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression.
  45. The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.
  1. Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00080-2. [Epub ahead of print]91 102190
    A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.
    Shane Thomas Bell, Rebeca Acín-Pérez, Iffath Ghouri, Jon Meyrick, Robert Lightowlers, Oliver Russell.
      Large-scale mitochondrial DNA (mtDNA) deletions can result in deficiency of oxidative phosphorylation and subsequent mitochondrial dysfunction, ultimately leading to mitochondrial disease. To investigate effective treatments, we report a characterised heteroplasmic iPSC-derived neuronal model with a single, large scale ∼6 kb mtDNA deletion. While mtDNA heteroplasmy remains stable during iNGN2-induced neuronal differentiation from iPSCs, the presence of this mtDNA deletion results in an upregulation of mtDNA copy number and compensatory adaptation of oxidative phosphorylation (OXPHOS) machinery. Despite this increase, mitochondrial dysfunction and reduced oxygen consumption is prevalent. Furthermore, as differentiated neurons mature over time, mitochondrial supercomplexes and isolated complex II diminish, suggesting an increase of severity of the mitochondrial dysfunction. In summary, this study provides insight into a novel compensatory mechanism during iPSC differentiation to bypass mitochondrial dysfunction, and how this response exacerbates dysfunction during culture of mature neurons.
    Keywords:  Complex II; Copy number; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Mitochondrial supercomplexes; iPSC-derived neurons
    DOI:  https://doi.org/10.1016/j.mito.2026.102190
  2. Ugeskr Laeger. 2026 Jun 22. pii: V10250820. [Epub ahead of print]188(26):
    [Mitochondrial diseases].
    Simone Rask Nielsen, Elsebeth Østergaard, John Vissing, Anja Lisbeth Frederiksen.
      Mitochondrial diseases are complex conditions that can affect many organs, and patients may be seen by doctors from various clinical specialities. Currently, treatments are primarily supportive; however, this review finds that identifying the underlying genetic cause is becoming increasingly important as new targeted therapies are under development. Additionally, recent advances in reproductive technologies, such as pre-implantation testing and mitochondrial replacement therapy, may offer additional options for affected patients.
    DOI:  https://doi.org/10.61409/V10250820
  3. Nihon Yakurigaku Zasshi. 2026 ;161(4): 216-221
    [Is it possible to generate artificial mitochondrial genome?]
    Ken-Ichi Wada.
      The mitochondrial genome (mtDNA) is a circular DNA of approximately 16.5 kbp, present at several thousand copies per cell. Although mtDNA is extremely small compared with the nuclear genome, it is quite important for life system because it encodes components essential for ATP production through oxidative phosphorylation. Since mtDNA mutations are thought to be implicated in a wide range of diseases, gene therapies targeting mtDNA are expected to provide promising treatment options for such disorders; however, current methods allow only limited manipulation of mtDNA. In this article, our recent efforts toward establishing mtDNA writing, a technology that would enable unrestricted and precise manipulation of mtDNA, are introduced. We hypothesized that creation of specialized host cells that preferentially accept exogenous mtDNA would be the key to achieving mtDNA writing. We named such host cells "e-mt cells" and assumed that cells maintaining a deviated type of mtDNA in a homoplasmic state could function as e-mt cells. To create e-mt cells, we developed a novel mitochondrial transfer method using a microfluidic device. This microfluidic device allowed direct and non-invasive mitochondrial transfer between live single cells by fusing them through a micro aperture (microslit/microtunnel). Furthermore, we successfully demonstrated single-mitochondrion transfer as well as cybrid generation via mitochondrial transfer into ρ0 cells. These findings suggest that the microfluidic device has the potential to achieve homoplasmic mtDNA modification through mtDNA cloning and is therefore expected to contribute to the creation of e-mt cells.
    DOI:  https://doi.org/10.1254/fpj.25090
  4. Nihon Yakurigaku Zasshi. 2026 ;161(4): 210-215
    [Investigation of a causal relationship between mtDNA mutations and a mitochondrial respiratory dysfunction in premature aging mice].
    Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.
      The mitochondrial theory of aging has been proposed, which suggests that the accumulations of multiple in mtDNA with age induce decreased mitochondrial respiratory function, ultimately leading to aging. This hypothesis is widely accepted because mtDNA mutator mice (Polgmut/mut mice) with a homozygous proofreading-deficient mutation in Polg gene accumulate random point mutations in mtDNA, resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, the accurate mtDNA mutation frequency in Polgmut/mut mice has remained unclear, and the causal relationship between accumulation of random point mutations in mtDNA and mitochondrial respiratory dysfunction in Polgmut/mut mice has been debated. Then, we verified the exact mtDNA mutation frequency in Polg mice and experimentally varied mtDNA mutation frequency to test their correlation with mitochondrial respiratory activity. Our results showed that, regardless of mtDNA mutation frequency, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice with a heterozygous proof-reading deficient mutation in Polg and severely reduced Polgmut/mut mice. Moreover, by varying mtDNA mutation frequency, some Polg+/+ mice showed mtDNA mutation frequency equivalent to those of Polgmut/mut mice, but mitochondrial respiratory function in Polg+/+ mice was normal. These results suggest that a reduced mitochondrial function in Polg mice is correlated with Polg mutation rather than accumulation of random mutations in mtDNA. Thus, this study proposed the need to reconsider the hypothesis that accumulation of random mutations in mtDNA induces a decreased respiratory function, which form the core of the mitochondrial theory of aging.
    DOI:  https://doi.org/10.1254/fpj.25075
  5. Ther Innov Regul Sci. 2026 Jun 27.
    The CARE Program: An Initiative of Patient-Focused Drug Development for Rare Diseases by NMPA.
    Ling Tang, Songmei Xie, Lijia Yuan, Xiaowen Xu, Xing Ai, Tian Zhao, Zhimin Yang.
      "Patient-focused drug development" emphasizes multi-stakeholder collaboration and advocates for in-depth listening to patients' opinions to facilitate all stages of drug development. In the field of rare disease drug development, implementing the concept of "patient-centered" drug development, focusing on patients' perspectives, and heeding patients' voices will serve as an effective approach for pharmaceutical companies, researchers, and regulatory authorities to gain a deeper understanding of rare diseases and patients' needs, thereby enhancing the precision and efficiency of rare disease drug development. The "Care Program" is a pilot program launched by the Center for Drug Evaluation, NMPA focusing on rare diseases. Its aim is to guide pharmaceutical companies to incorporate the perspectives of rare disease patients throughout the entire drug development process and improve the scientific rigor and standardization of integrating patients' voices into the clinical development of rare disease drugs. The launch of the "Care Program" is expected to accumulate valuable experience for future regulatory work and drug development efforts.
    Keywords:  Care program; NMPA; Patient-focused drug development; Rare disease; Regulatory science
    DOI:  https://doi.org/10.1007/s43441-026-01005-y
  6. Front Pharmacol. 2026 ;17 1851705
    The role of mitochondria in the gut-kidney axis: implications for kidney health.
    Qin Hu, Hua Jin, Lan Hu, Xu Li.
      Mitochondria, multifunctional organelles that regulate cellular energy metabolism and signaling pathways, play a pivotal role in maintaining the physiological functions of the gut and kidneys, as well as influencing the progression of chronic kidney disease (CKD). Through the gut-kidney crosstalk, gut microbiota modulate gut and renal pathophysiology and also influence mitochondrial activity in intestinal and renal cells. This review explores the regulatory roles of mitochondria in preserving epithelial barrier integrity, regulating intestinal metabolism, and maintaining gut microbiota homeostasis. It also examines the contributions of mitochondrial biogenesis, dynamics, autophagy abnormalities, and mitochondrial DNA (mtDNA) damage to renal pathological progression. Moreover, we highlight the bidirectional interactions between intestinal and renal mitochondria via the microbiota-mitochondria-kidney axis and mechanisms involving inflammation, oxidative stress, and ferroptosis. Therefore, targeting mitochondrial regulation through non-pharmacological interventions such as dietary adjustments, probiotic supplementation and fecal microbiota transplantation (FMT) emerges as a promising therapeutic strategy for maintaining renal health by optimizing mitochondrial function. In conclusion, elucidating the mechanisms of mitochondrial involvement in the gut-kidney axis will lay the foundation for novel therapeutic approaches to CKD and other gut-kidney axis-related disorders.
    Keywords:  chronic kidney disease; gut microbiota; gut-kidney axis; kidney disease; mitochondria
    DOI:  https://doi.org/10.3389/fphar.2026.1851705
  7. bioRxiv. 2026 Jun 15. pii: 2026.06.10.730935. [Epub ahead of print]
    Multi-platform reassessment of human mitochondrial DNA methylation reveals signals consistent with technical artifacts.
    Salman Basrai, Alexander T Bahcheli, Djarren Tan, Philip C Zuzarte, Andrea Bevan, Theodore Chan, Kristie Ng, Bernard Lam, Andrea Arruda, Sunit Das, Mark D Minden, Jared T Simpson, Jüri Reimand, Sagi Abelson.
      The existence and functional relevance of mitochondrial DNA methylation remain controversial. Here, we systematically profiled cytosine methylation and hydroxymethylation across human brain and blood tissues spanning healthy and malignant states using orthogonal sequencing approaches that avoid chemical conversion during library preparation. While nuclear DNA exhibited canonical methylation patterns, mitochondrial DNA consistently showed negligible signal, indistinguishable from background technical noise. By mapping cytosine-guanine sites between mitochondrial DNA and nuclear-embedded mitochondrial sequences, we demonstrate the potential of these nuclear counterparts to confound not only cytosine methylation but also hydroxymethylation measurements, corroborating and extending prior findings implicating nuclear contamination as a potential source of apparent mitochondrial epigenetic signals. Additional technical factors that inflate apparent mtDNA methylation signals were identified, including sequence context biases, flow cell chemistries, and coverage-dependent discrepancies between the heavy and light strands. Collectively, these results provide convergent evidence against the presence of biologically meaningful cytosine methylation or hydroxymethylation in mitochondrial DNA. These findings caution against interpreting apparent mtDNA methylation signals in human adult tissues as meaningful without rigorous orthogonal validation and comprehensive consideration of technical and analytical confounding factors.
    DOI:  https://doi.org/10.64898/2026.06.10.730935
  8. J Biol Chem. 2026 Jun 29. pii: S0021-9258(26)02178-2. [Epub ahead of print] 113306
    Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
    Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.
      Cardiolipin (CL) is a four-acyl chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-acyl chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of IMM structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.
    Keywords:  Barth syndrome; Cardiolipin; Lipid saturation; Mitochondria; Tafazzin
    DOI:  https://doi.org/10.1016/j.jbc.2026.113306
  9. NPJ Digit Med. 2026 Jul 02.
    KGRD: a knowledge-graph-augmented automated reasoning framework for diagnosis and counselling of paediatric rare genetic disorders.
    Guiling Guo, Zhenyu Shao, Heying Luo, Ziqing Fu, Hui Xiong, Jin Li, Qingqing Qin, Xiaoqing Yang, Shuxiang Hu, Jinzhun Wu, Qiyuan Li.
      Diagnosis and counselling for paediatric rare diseases remain constrained by the sparsity of structured patient-level data and fragmented genetic knowledge, which can induce 'common-attention' bias in conventional large language models (LLMs). Here, we describe KGRD, a knowledge-graph-augmented diagnostic support framework empowered by knowledge-driven and data-driven inference over patient-level genomic and phenotypic data. KGRD consists of three specialised inference agents for deductive reasoning regarding disease aetiology, as well as a collective decision-making module that integrates multidisciplinary deliberation with multi-source verification. In a validation benchmark of 420 rare disease cases, KGRD(DS) achieved the strongest overall performance, increased the mean Bond score of the top-ranked diagnosis from 3.27 to 3.85 and raised CIE from 73.6 to 81.9%, corresponding to 35 additional cases with candidate-diagnosis Bond score ≥4. Together, these results indicate that KGRD provides effective diagnostic support for paediatric rare diseases.
    DOI:  https://doi.org/10.1038/s41746-026-02943-5
  10. J Obstet Gynaecol India. 2026 Jun;76(3): 276-277
    New-born Screening for Mitochondrial Disorders is Useful for Genetic Counseling and Early Treatment when Available.
    Josef Finsterer.
      
    Keywords:  Depletion; MPV17; Mitochondrial; MtDNA; Newborn screening
    DOI:  https://doi.org/10.1007/s13224-024-02075-4
  11. Nat Metab. 2026 Jun 29.
    Mitochondrial quality control in human ageing and longevity.
    Anna Picca, Luigi Ferrucci.
      Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.
    DOI:  https://doi.org/10.1038/s42255-026-01563-3
  12. J Vis Exp. 2026 Jun 12.
    Standardized Immunofluorescence Imaging of Tunneling Nanotubes and Mitochondrial Transfer Between Astrocytes and Neurons.
    Xiaoyan Du, Yang Deng.
      Mitochondria are essential organelles that regulate energy production, cellular signaling, and metabolic homeostasis in neural cells. Tunneling nanotubes (TNTs) are thin membranous structures that mediate long-distance intercellular communication and facilitate the transfer of cellular components, including mitochondria, between connected cells. Reliable visualization of TNTs and mitochondrial transfer requires careful sample handling because these structures are highly fragile and sensitive to fixation, washing, and imaging conditions. This protocol describes standardized procedures for the fixation, staining, and confocal imaging of TNTs in astrocytes and astrocyte-neuron coculture systems. The workflow includes membrane and cytoskeletal staining for TNT visualization, mitochondrial labeling for tracking mitochondrial localization, and immunofluorescence staining for Miro1 colocalization analysis. Critical steps for preserving TNT morphology, including gentle washing and light-protected handling, are emphasized throughout the procedure. The protocol also outlines imaging approaches for the characterization of TNTs and mitochondria in fixed-cell preparations. These methods provide a reproducible experimental framework for studying TNT formation and mitochondrial transfer between neural cells in vitro.
    DOI:  https://doi.org/10.3791/71670
  13. Front Physiol. 2026 ;17 1873221
    When mitochondria lose their fold: matrix proteostasis and stress signaling.
    Nils Bertram, Dejana Mokranjac.
      A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.
    Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3389/fphys.2026.1873221
  14. medRxiv. 2026 Jun 15. pii: 2026.06.12.26355546. [Epub ahead of print]
    The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease.
    Johan L K Van Hove, Marisa W Friederich, Roxanne A Van Hove, Jessica C Lee, Kaz M Knight, Tonia E Donovan, Lori Silveira, Rebecca D Ganetzky, Michio Hirano, Jose Abdenur, Merlin G Butler, David Cassiman, Bruce H Cohen, Sarah H Elsea, Gregory M Enns, William A Gahl, Ralitza Gavrilova, Gabrielle C Geddes, Emma E Glamuzina, Amy Goldstein, Richard H Haas, Aneal Khan, Kimberly A Kripps, Austin A Larson, April N Lehman, Uta Lichter-Konecki, Johannes A Mayr, Eva Morava, James T Peterson, Jill A Rosenfeld, Russell P Saneto, Fernando Scaglia, Emily Shelkowitz, Mariella Simon, Joél E G Smet, Wendy E Smith, Claudia Soler-Alfonso, Mark Tarnopolsky, Rudy N A Van Coster, Arnaud V Vanlander, Pieter Vermeersch, Jerry Vockley, Kristen Wigby, Lynne A Wolfe, Saskia B Wortmann, Jennifer H Yang.
      Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.
    One sentence summary: A combination of four mitochondrial functional tests to identify or confirm suspected primary mitochondrial disease in fibroblasts had good sensitivity and excellent specificity, well beyond what was perceived using enzyme assays only.
    DOI:  https://doi.org/10.64898/2026.06.12.26355546
  15. Mol Syndromol. 2026 Apr 29.
    Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.
    Ibrahim Bingol, Ozge Umur, Sare Guntulu Sık, Tonguc Utku Yilmaz, Remzi Emiroglu, Agop Citak.
       Introduction: Valproic acid (VPA)-induced acute liver failure (ALF) is a severe and potentially fatal complication, particularly in pediatric patients with mitochondrial dysfunction. Mutations in the polymerase gamma (POLG) gene, especially those associated with Alpers-Huttenlocher syndrome, significantly increase susceptibility to VPA hepatotoxicity.
    Case Presentation: We report a previously healthy 17-year-old girl who developed ALF after 1 month of VPA therapy prescribed for refractory focal seizures. Despite prompt discontinuation of VPA, she developed progressive jaundice, coagulopathy, hyperammonemia, and hepatic encephalopathy. Liver biopsy revealed microvesicular steatosis and centrilobular necrosis, consistent with drug-induced liver injury. Her condition deteriorated with hypertension, refractory seizures, and radiological features of posterior reversible encephalopathy syndrome (PRES). Whole-exome sequencing identified a NM_002693.3(POLG):c.2243G>C (p.Trp748Ser; p.W748S). Due to worsening hepatic function and neurological status, she underwent emergency orthotopic liver transplantation. Post-transplantation, liver function normalized, and seizures became intermittently controllable with levetiracetam and topiramate.
    Conclusion: This case is notable for its late adolescent onset, homozygous POLG c.2243G>C (p.Trp748Ser) genotype, association with PRES, and successful emergency liver transplantation, thereby expanding the clinical spectrum of POLG-related VPA-ALF. These findings underscore the importance of POLG testing prior to VPA exposure in patients with suspected mitochondrial disease, even beyond early childhood.
    Keywords:  Acute liver failure; Liver transplantation; Mitochondrial disease; POLG mutation; Valproic acid
    DOI:  https://doi.org/10.1159/000552241
  16. J Clin Pharmacol. 2026 Jul;66(7): e70226
    FDA Gene Therapy Approvals (1998-2025): Current Status, Regulatory Evolution, and Future Directions.
    Charles Oo, Xiaofa Qin, Sherwin Kb Sy.
      FDA approvals of gene therapies began slowly and were concentrated within a few early modalities, but recent years have seen a marked acceleration across RNA-based agents, viral and non-viral in vivo platforms, and ex vivo genetically modified cell therapies. This expansion reflects the maturation of gene therapy into a diverse therapeutic class while revealing scientific, regulatory, and economic challenges that traditional development paradigms cannot fully accommodate. In response, FDA has introduced platform-aligned, risk-based initiatives-including the plausible mechanism framework, CMC flexibility initiative, and advanced manufacturing technologies program-to support individualized, mechanistically targeted, and potentially curative products. Persistent issues such as high upfront costs, manufacturing complexity, and payer constraints underscore the need for sustainable development and access models. Mechanistic and model-informed drug development, increasingly supported by AI/ML-enabled analytics, is becoming central to dose selection, safety evaluation, and durability prediction. These scientific, regulatory, and clinical-pharmacology perspectives define the evolving landscape of FDA gene therapy approvals and outline future directions needed to ensure durable benefit, equitable access, and long-term safety as genetic medicines expand into broader patient populations.
    Keywords:  FDA approvals; advanced manufacturing; biologics license applications (BLAs); drug development strategy; gene therapy; genetic‑medicine platforms; genome editing; regulatory science
    DOI:  https://doi.org/10.1002/jcph.70226
  17. Mol Psychiatry. 2026 Jul 03.
    Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications.
    Yu Wang, Ji-Tao Li, Lin-Lin Zhu, Yan-Kun Wu, Yun-Ai Su, Tian-Mei Si.
      Despite its high prevalence, the precise mechanisms underlying major depressive disorder (MDD) remain incompletely understood. Growing evidence identifies mitochondrial dysfunction, including abnormalities in mitochondrial DNA, impaired bioenergetics, disrupted quality control, and redox imbalance, as a central pathological feature of MDD. Beyond deficits in energy production, mitochondria function as upstream regulators of neuroinflammation. Mitochondria derived damage associated molecular patterns and excessive reactive oxygen species activate innate immune signaling, while inflammatory challenges in turn compromise mitochondrial integrity. This bidirectional and self-reinforcing interaction between mitochondrial dysfunction and inflammation may contribute to disease onset, progression, and clinical heterogeneity. Preclinical and clinical studies indicate that conventional antidepressants gradually restore mitochondrial function while suppressing oxidative and inflammatory stress, whereas rapid-acting agents such as ketamine induce acute metabolic reprogramming and mitophagy, enabling swift functional recovery. Mechanistically distinct interventions, including mitochondria targeted antioxidants, metabolic modulators, and psychedelic compounds, further highlight the therapeutic potential of targeting mitochondrial pathways. By integrating current evidence, this review delineates mitochondrial-inflammation crosstalk in MDD and supports mitochondrial regulation as a promising target for novel antidepressant strategies.
    DOI:  https://doi.org/10.1038/s41380-026-03732-y
  18. Neurosci Res. 2026 Jul 03. pii: S0168-0102(26)00076-3. [Epub ahead of print] 105089
    Transcriptomic and epigenetic characterization of paraventricular thalamic nucleus neurons in Polg1 mutant mice.
    Emilie Kristine Bagge, Mie Kubota-Sakashita, Noriko Fujimori-Tonou, Takaoki Kasahara, Tadafumi Kato.
      How damaged mitochondrial DNA (mtDNA) affects gene expression in mtDNA-related diseases is not well understood. Here, we investigated the changes in the transcriptome and chromatin modifications associated with the accumulation of mtDNA mutations in a proof-reading-deficient mitochondrial DNA polymerase transgenic mouse (Polg1 mutant mice), which accumulate mtDNA mutations preferentially in the paraventricular thalamic nucleus (PVT) and exhibit depressive-like episodes. We examined PVT neurons that were positive or negative for cytochrome oxidase (COX) in the mutant mice in depressive-like or euthymic states. The genes that were upregulated in the COX-negative PVT neurons during the depressive-like state were enriched for mitophagy or interferon signalling pathways. We observed no differentially accessible regions between WT and Polg1 mutant mice by ATAC (Assay for Transposase-Accessible Chromatin), but the loss of H3K27Ac signal in Polg1 mutant mice was associated with a higher number of ATAC tags. The change in H3K27Ac signal was seen only in brain regions that accumulate mtDNA mutations. In addition, we found that mtDNA, especially partially deleted mtDNA, was released from mitochondria upon opening of the mitochondrial permeability transition pore. These findings altogether suggest that mutated mtDNA molecules are released from mitochondria, which may contribute to the depression-specific transcriptomic alterations in the PVT neurons of the mood disorder animal model. (186 words).
    Keywords:  chromatin; cytochrome oxidase; gene expression; histone acetylation; mitochondrial DNA; mitochondrial permeability transition pore; paraventricular nucleus of the thalamus
    DOI:  https://doi.org/10.1016/j.neures.2026.105089
  19. Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00081-4. [Epub ahead of print] 102191
    Energy beats: Daily and circadian rhythms in mitochondrial biology.
    Nadia Ceccato, Milena Damulewicz, Gabriella Margherita Mazzotta.
      Circadian rhythms orchestrate a wide array of behavioral and physiological functions, coordinating cellular and organismal processes on an approximately 24-h cycle through an intrinsic timekeeping system. Among the many processes subject to this temporal regulation, mitochondrial function has emerged as a critical and dynamic target of circadian control. Mitochondria, far from being static organelles, undergo continuous morphological remodeling through cycles of fusion and fission, collectively termed mitochondrial dynamics, that are essential for maintaining metabolic homeostasis, energy production, and cellular quality control. Disruptions in circadian rhythmicity, such as those arising from sleep disturbances or irregular feeding patterns, have been associated with impaired glucose tolerance, insulin resistance, and increased risk of metabolic syndrome, diabetes, and cardiovascular disease. Emerging evidence suggests that the circadian clock and mitochondrial dynamics are engaged in a bidirectional interplay, whereby clock-controlled gene expression shapes mitochondrial morphology and function, while mitochondrial metabolic states in turn feedback to influence circadian timing. This review explores the evolutionary origins of mitochondrial rhythmicity, synthesizes current evidence on how the circadian clock regulates mitochondrial dynamics, and examines the physiological and pathological implications of their interconnection. A particular focus is placed on how disruptions in this circadian-mitochondrial axis may contribute to the development of common diseases, including neurodegenerative disorders, metabolic diseases, and cancer, highlighting novel avenues for chronobiologically informed therapeutic strategies.
    Keywords:  Circadian clock; Circadian misalignment; Clock-mitochondria interplay; Mitochondrial rhythmicity
    DOI:  https://doi.org/10.1016/j.mito.2026.102191
  20. Biochem Soc Trans. 2026 Jul 29. 54(7): 887-899
    Advancing the monitoring of organelle contact sites in vitro and in vivo.
    Lucia Barazzuol, Caterina Peggion, Marisa Brini, Yusuke Nasu, Tito Calì.
      Organelle contact sites are highly dynamic and specialized regions where distinct organelles come into proximity, enabling direct inter-organelle communication. These structures play fundamental roles in cellular homeostasis by coordinating the exchange of lipids, metabolites, and ions, as well as regulating key processes such as organelle dynamics, mitochondrial fission, autophagy, and metabolic integration. Alterations in contact site architecture and function have been increasingly associated with a wide range of human diseases, including neurodegeneration, metabolic disorders, and cancer. Despite their biological relevance, the nanoscale nature and dynamic behaviour of contact sites have historically posed significant challenges for their accurate detection and functional characterization. Here, we provide a comprehensive overview of the methodologies currently available to study organelle contact sites, ranging from classical approaches such as electron microscopy and biochemical fractionation to advanced imaging techniques and genetically encoded reporters. We discuss recent developments in high-resolution and live-cell microscopy that have improved the spatial and temporal resolution of contact site analysis, as well as emerging tools designed to selectively label, quantify, and manipulate these interfaces. Attention is given to the next generation of engineered reporters capable of sensing molecular and ionic exchanges at contact sites, thereby moving beyond structural description toward functional interrogation. By critically evaluating the strengths and limitations of existing approaches, we aim to provide a framework for selecting appropriate tools and to highlight future directions in the field. Ultimately, advancing our ability to monitor and dissect organelle contact sites will be essential for understanding their contribution to cellular physiology and disease.
    Keywords:  Organelle contact sites; SPLICS; genetically encoded reporters
    DOI:  https://doi.org/10.1042/BST20250371
  21. J Physiol Biochem. 2026 Jun 30. pii: 60. [Epub ahead of print]82(1):
    Mitochondria-sarcoplasmic reticulum crosstalk as a modulator of skeletal muscle mass.
    Rafael A Casuso.
      Preservation of skeletal muscle mass and function is a key feature of healthy ageing and relies on the tight coordination between protein synthesis and breakdown to maintain proteostatic balance. These processes impose a substantial energetic demand, highlighting the importance of mitochondrial function in skeletal muscle homeostasis. Increasing evidence indicates that mitochondria and the sarcoplasmic reticulum are functionally interconnected. Effective crosstalk between these organelles contributes to the integration of bioenergetic supply, Ca²⁺ handling, and proteostasis. Disruption of this communication network may impair adaptive stress responses, compromise protein quality control, and favour the development of anabolic resistance during ageing. This review synthesizes current evidence on mitochondria-sarcoplasmic reticulum communication. It further discusses how disruption of this crosstalk may promote anabolic resistance and skeletal muscle atrophy, with particular emphasis on its implications for age-related muscle decline.
    Keywords:  Atrophy; Calcium; Endoplasmic reticulum; Organelle crosstalk; Sarcopenia; Unfolded protein response
    DOI:  https://doi.org/10.1007/s13105-026-01198-8
  22. Curr Neuropharmacol. 2026 Jun 24.
    Nano-Based Therapeutics in Rare Disease Management: Current Perspectives, Challenges, and Unmet Needs.
    Ankit Sahoo, Faisal H Altemani, Omar Awad Alsaidan, Faisal Alsenani, Alhussain Aodah, Majed Alrobaian, Waleed Hassan Almalki, Salem Salman Almujri, Jonathan A Lal, Janhvi Singh, Mahfoozur Rahman.
      Rare diseases, affecting approximately 8% of the global population, remain among the most underserved areas in modern medicine due to their low prevalence, complex genetic origins, and limited commercial incentives for drug development. Rare neurological disorders, in particular, pose formidable challenges owing to their progressive nature and the difficulty of delivering thera-peutics across the blood-brain barrier. This review explores the emerging role of nanomedicine in transforming rare disease management through precision-targeted drug delivery, enhanced bioavail-ability, and the ability to bypass biological barriers. Nanoparticles (NPs)-including PEGylated NPs, lipid-based NPs, polymeric NPs, and hybrid formulations-are being engineered to deliver therapeu-tic agents for gene therapy, enzyme replacement, and RNA interference. These platforms have shown promise in treating conditions such as Krabbe disease, Niemann-Pick type C1, spinocerebel-lar ataxia type 1, and prion diseases. Additionally, nanotherapeutics are being investigated for pulmonary and congenital lung disorders, including cystic fibrosis and idiopathic pulmonary fibro-sis, with improved tissue penetration and reduced systemic toxicity. The review also highlights the potential of AI-integrated diagnostics and personalized nanomedicine to address disease heterogene-ity and improve patient outcomes. Despite these advances, significant barriers remain, including regulatory complexity, high development costs, and limited clinical models. The manuscript calls for collaborative innovation across academia, industry, and regulatory bodies to accelerate clinical translation and ensure equitable access. By bridging molecular innovation with patient-centric care, nanotherapeutics offer a paradigm shift in the diagnosis and treatment of rare diseases, potentially redefining therapeutic landscapes and improving the quality of life for affected individuals.
    Keywords:  Rare disease; gene therapy; nanomedicine; nanoparticles; neurological disorders; personalized medicine.
    DOI:  https://doi.org/10.2174/011570159X444151260430113548
  23. Theriogenology. 2026 Jul 01. pii: S0093-691X(26)00257-8. [Epub ahead of print]265 118067
    Telomere regulation of mitochondria in porcine parthenogenetic embryos.
    Masamune Hayashi, Yuya Suzuki, Asuka Kamio, Yuki Inoue, Komei Shirasuna, Hisataka Iwata.
      Mitochondrial DNA copy number (mt-cn) and telomere length (TL) are considered secondary markers of embryonic quality. The present study investigated the relationship between mt-cn and TL in parthenogenetically activated porcine embryos. Oocytes collected from gilt ovaries were matured and subsequently activated. Presumptive zygotes were then cultured until blastocyst stage. In none treated embryos, the mt-cn increased consistently during embryonic development, whereas telomere elongation was observed between the oocyte and 4-cell stages. Mt-cn and TL showed significant correlations at both the 4-cell and blastocyst stages. In the second experiment, embryos were cultured in medium containing the telomerase inhibitor TMPyP4 or vehicle (water) until the blastocyst stage. TMPyP4 treatment shortened TL at both the 4-cell and blastocyst stages and reduced mt-cn in blastocysts. Immunostaining revealed that TMPyP4 treatment increased G-quadruplex (G4) expression at the 4-cell stage, increased p53 expression, and decreased the expression levels of PGC1 and TFAM at both 4-cell and blastocyst stage embryos. TMPyP4 treatment also increased mitochondrial membrane potential and ATP content in embryos. RNA-seq analysis of blastocysts indicated that mitochondria are a major target of TMPyP4 treatment. In addition, microinjection of a TERT plasmid elongated TL and increased mt-cn in blastocysts. In conclusion, these findings suggest that although TMPyP4 may directly affect mitochondrial function, TL plays a regulatory role in mitochondrial homeostasis during embryonic development.
    Keywords:  Embryos; Mitochondrial DNA copy number; Pigs; Telomere; p53 and PGC a
    DOI:  https://doi.org/10.1016/j.theriogenology.2026.118067
  24. Hum Genomics. 2026 Jun 30.
    Analysis of whole-exome sequencing data from nearly 10,000 Iranian individuals: identification of recessive mitochondrial disease variants and proposal of a population-specific carrier screening panel.
    Mohadeseh Fathi, Parvaneh Karimzadeh, Farzad Ahmadabadi, Damoun Nashta Ali, Narjes Jafari, Raheleh Tangestani, Shadab Salehpour, Toktam Moosavian, Soudeh Ghafouri-Fard, Mohammad Miryounesi.
       BACKGROUND: Mitochondrial diseases, often stemming from recessive nuclear gene mutations, represent a heterogeneous group of disorders with significant morbidity and mortality. Carrier screening for these conditions is population-specific, yet data on the pathogenic variant burden in the Iranian population remain limited. This study aimed to analyze whole-exome sequencing (WES) data from 9989 Iranian individuals to identify the spectrum and frequency of recessive mitochondrial disease variants and to develop a population-specific carrier screening panel.
    METHODS: We analyzed WES data from 9989 unrelated Iranian individuals. Variants in 1,564 nuclear genes associated with mitochondrial function were filtered for rarity (minor allele frequency < 0.01 in public databases), predicted pathogenicity, and recessive inheritance patterns (homozygous or compound heterozygous). Clinically relevant variants were manually curated, and carrier frequencies for significant recessive mitochondrial conditions were calculated.
    RESULTS: Our analysis identified variants across 15 groups of mitochondrial-related nuclear genes in 345 individuals recognized as carriers. Of these, 123 variants (35.6%) were classified as Pathogenic, and 154 variants (44.6%) were classified as Likely Pathogenic according to ACMG guidelines.
    CONCLUSIONS: This study provides the first large-scale WES-derived assessment of recessive mitochondrial disease carrier burden in the Iranian population. The high estimated carrier rate supports implementing population-specific preconception screening. The results of this study can be used for design of targeted panels of nuclear mitochondrial genes to identify at-risk couples, facilitating genetic counseling and reproductive decision-making in Iran.
    Keywords:  Carrier frequency; Mitochondrial disorders; Whole exome sequencing
    DOI:  https://doi.org/10.1186/s40246-026-01011-z
  25. Orphanet J Rare Dis. 2026 Jul 03.
    Mapping the landscape of treatable inborn errors of metabolism: a systematic gene-level evaluation based on the ICIMD classification.
    Tabeer Fatima, Jalal Khan, Fatma Al-Jasmi, Hiba Alblooshi.
       BACKGROUND: Inborn errors of metabolism (IEMs) are among the most clinically actionable groups of rare genetic diseases, yet therapeutic knowledge remains distributed across multiple databases, complicating consistent identification of treatable IEMs.
    METHODS: In this study, we performed a cross-database analysis to characterize the current therapeutic landscape of IEM genes using GeneReviews as a clinical reference. Gene symbols from GeneReviews, Metabolic Treatabolome, Treatable ID, and the Drug Database for Inborn Errors of Metabolism (DDIEM) were harmonized to HGNC nomenclature and mapped to the International Classification of Inherited Metabolic Disorders (ICIMD). IEM genes were categorized as associated with targeted or supportive treatment based on a GeneReviews-derived benchmark.
    RESULTS: Among 656 ICIMD-defined IEM genes in GeneReviews, 155 (23.6%) were associated with targeted therapies and 501 (76.4%) with supportive treatment. Cross-database comparison demonstrated limited concordance, with only 36 genes associated with targeted therapy shared across Metabolic Treatabolome, Treatable ID, and DDIEM, reflecting heterogeneous representation of treatable IEMs across databases. Targeted therapies were more common in intermediary metabolic pathways, including fatty acid, tetrapyrrole, and vitamin/cofactor metabolism, whereas mitochondrial and complex cellular disorders were predominantly associated with supportive management. Moreover, 53% of the ICIMD-defined IEM genes remain unrepresented in structured databases.
    CONCLUSIONS: Our study defines a set of IEM genes for which targeted therapies are available and demonstrates that treatment information is largely fragmented across databases. This set of IEM genes may facilitate the interpretation of genomic findings and aid the prioritization of IEMs for genomic screening and clinical decision-making.
    Keywords:  DDIEM; ICIMD; IEMbase.; Inborn errors of metabolism; Inherited Metabolic Disorders; Metabolic Treatabolome; Rare diseases; Targeted therapy; Treatable ID; Treatable IEMs
    DOI:  https://doi.org/10.1186/s13023-026-04486-0
  26. Intern Med. 2026 Jun 27.
    A de novo TWNK Variant Mimicked Sporadic Chronic Progressive External Ophthalmoplegia.
    Chiharu Yoshida, Akatsuki Kubota, Norifumi Kawamoto, Kensuke Takahashi, Satoka Yano, Shogo Komaki, Meiko Maeda, Hiroya Naruse, Takashi Matsukawa, Masashi Hamada, Wataru Satake, Tatsushi Toda.
      Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, with most sporadic cases caused by a single large mitochondrial DNA (mtDNA) deletion. We report the case of a 54-year-old woman with ptosis, external ophthalmoplegia, and proximal muscle weakness without any relevant family history. A muscle biopsy supported the diagnosis of sporadic CPEO. However, a muscle DNA analysis revealed multiple mitochondrial DNA (mtDNA) deletions. Whole-exome sequencing identified a heterozygous pathogenic TWNK variant [c.1121G>A (p.Arg374Gln)] absent in her parents, suggesting a de novo origin. Although TWNK pathogenic variants typically cause autosomal dominant CPEO, this case mimicked a sporadic form, thus highlighting the importance of a nuclear gene analysis in such cases.
    Keywords:  TWNK; chronic progressive external ophthalmoplegia; de novo variant; mitochondrial disease
    DOI:  https://doi.org/10.2169/internalmedicine.7395-26
  27. J Transl Med. 2026 Jul 02.
    The mitochondrial protease, LonP1, is a potential cardioprotective target for attenuating doxorubicin-induced cardiomyocyte death.
    Kienan P O'Dwyer, Perry E Bauer, Sebastian A Dziadowicz, Subhankhi Pal, Mark Eminhizer, Aishwarya Bandaru, Emma Myers, Maan Awad, Abdulrahman Murshid, Matthew Santer, Lei Wang, Gangqing Hu, Kathleen Brundage, Evan DeVallance, John M Hollander, Brijesh Patel, Sundararajan Venkatesh.
       BACKGROUND: Doxorubicin (DOX), a first-line chemotherapeutic agent, has been linked to severe off-target cardiotoxicity in the clinic. Previous works suggest that mitochondria are key mediators of this cardiotoxicity. Leakage of mitochondrial contents after DOX treatment, including mitochondrial DNA (mtDNA), is thought to activate apoptotic and inflammatory signaling pathways implicated in cardiomyocyte cell death. Whether the master mitochondrial protease, LonP1, can dampen these pathways and improve cardiomyocyte viability following DOX treatment remains unknown.
    METHODS: Human cardiac cells (AC-16) and primary (1°) human cardiomyocytes were subjected to DOX treatment, followed by bulk RNA-Seq, RT-qPCR, qPCR, and immunoblotting to assess apoptotic signaling, inflammatory signaling, mtDNA release, and LonP1 expression, respectively. Lentivirus transduction of AC-16 cells was used to generate both knockdown (KD) and overexpression (OE) LonP1 cell lines to determine the effects of altered LonP1 levels on DOX-induced apoptosis and mtDNA release. Further, levels of mitochondrial DNA (mtDNA) were measured using qPCR from serum samples obtained from patients undergoing DOX treatment to assess the clinical relevance of released mtDNA as a potential biomarker for the development of DOX cardiotoxicity.
    RESULTS: DOX treatment of AC-16 cells, as well as 1° human cardiomyocytes, upregulated both apoptotic and inflammatory signaling in both cell models. Increased LonP1 levels were also observed under DOX treatment in AC-16 cells and 1° human cardiomyocytes. Likewise, DOX increased mtDNA release from both cell lines, both prior to, and as a sequel to cell death. Decreasing LonP1 levels exacerbated DOX-mediated apoptotic signaling and mtDNA release, whereas overexpression of LonP1 attenuated these effects. Furthermore, DOX treatment in cancer patients increases plasma mtDNA levels.
    CONCLUSIONS: These findings suggest LonP1 plays a protective role in the heart following DOX treatment, supporting LonP1 as a potential novel therapeutic target for prevention of DOX cardiotoxicity. Patterns of mtDNA release within patients undergoing DOX treatment also highlight the potential of mtDNA as a potential biomarker and target for prevention of DOX cardiotoxicity, justifying the need for more extensive, prospectively monitored cohort studies to expand upon these findings and statistically model mtDNA release patterns.
    Keywords:  Apoptosis; Cardiotoxicity; Doxorubicin; Inflammation; LonP1; Mitochondria; TLR9; cGAS-STING; mtDNA
    DOI:  https://doi.org/10.1186/s12967-026-08537-9
  28. J Nurs Manag. 2026 ;2026(1): e6754802
    Lived Experiences of Patients With Rare Diseases and Healthcare System Barriers: A Phenomenological Study.
    Pedro Soriano-Martin, Cristofer Ruiz-González, Antonio Javier Alias-Castillo, Pablo Roman, Adrian Martinez-Ortigosa, Daniel Bertini-Pérez, Isabel Font Jímenez.
       AIM: To explore the lived experiences and perceptions of patients with rare diseases (RD) in relation to the disease process and its management by the healthcare system.
    BACKGROUND: Although each RD individually affects fewer than 0.05% of the population, collectively RD affect between 3.5% and 5.9% of the global population, representing approximately 400 million people worldwide. Most RD are chronic, progressive, and debilitating, with 80% having a genetic origin. Despite advances, diagnosing RD remains complex, often taking 4 to 8 years, worsening patient outcomes and increasing healthcare costs. Furthermore, 95% of RD lack approved treatments, presenting significant challenges for both patients and healthcare systems.
    METHODS: An interpretative phenomenological qualitative study following Gadamer's hermeneutic framework was conducted. Semistructured, in-depth interviews were conducted between February 2022 and January 2024. Seventeen patients with RD were recruited using purposeful sampling. ATLAS.ti v.9 software was used solely to organize and manage the data during the analysis process.
    RESULTS: Two main interpretive themes emerged: (1) RD: a desperate struggle against abstraction and hindrance, describing the emotional burden, diagnostic delays, and social consequences faced by patients with RD and (2) management and handling of RD by the healthcare system, highlighting professional unpreparedness, lack of coordination, and the key role patients and caregivers play in guiding care and sharing knowledge, alongside the emergence of peer support, digital tools, and social media as facilitators.
    CONCLUSION: This study highlights the significant barriers patients with RD face, from diagnosis to treatment. Healthcare systems struggle with insufficient knowledge and resources, hindering effective care. It is essential for professionals to acquire specialized skills and for resource allocation to improve in order to address RD as a public health concern.
    IMPLICATIONS FOR NURSING MANAGEMENT: As part of an interprofessional team, nursing professionals play a vital role in supporting patients with RD throughout the diagnostic journey, treatment, and management. This study highlights the need for nurses to address not only clinical but also psychosocial and informational challenges, including guiding patients in the safe and effective use of social media as a source of support, information, and empowerment.
    PATIENT AND PUBLIC CONTRIBUTION: Patients contributed as participants in the study by sharing their lived experiences through in-depth interviews. No patients or members of the public were involved in the design, conduct, reporting, or dissemination plans of this research.
    Keywords:  disease management; health information management; healthcare disparities; rare diseases
    DOI:  https://doi.org/10.1155/jonm/6754802
  29. Biomedica. 2026 06 01. 46(2): 175-178
    Rare diseases in Colombia: Current situation and ideas for a better future
    Luis Alejandro Barrera.
      
    Keywords:  enfermedades huérfanas
    DOI:  https://doi.org/10.7705/biomedica.8507
  30. Metab Brain Dis. 2026 Jun 29. pii: 146. [Epub ahead of print]41(1):
    The microbiota-mitochondria axis: linking metabolic dysfunction to neurodegeneration.
    Sedighe Yosefi, Ali Babaeizad, Seyed Soheil Tabibian, Aisa Bahar, Majid Eslami.
      The interplay between gut microbiota and mitochondria represents a dynamic relationship that profoundly impacts host physiology, ranging from maintaining intestinal homeostasis to regulating systemic metabolic and neurological functions. Microbial metabolites such as short-chain-fatty-acids, bile acids, and amino acid derivatives serve as pivotal modulators of mitochondrial bioenergetics, oxidative stress management, and fission-fusion processes. These interactions are vital for preserving epithelial integrity, supporting energy metabolism, shaping immune responses, and managing inflammatory signaling pathways. Disruptions within this microbiota-mitochondria axis are associated with various pathologies, including non-alcoholic fatty liver disease, obesity, type 2 diabetes, and chronic inflammatory conditions like inflammatory bowel disease. Additionally, growing evidence connects gut dysbiosis and mitochondrial dysfunction to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, highlighting the importance of this bidirectional relationship in maintaining neuronal health. On a mechanistic level, pathways involving AMPK, sirtuins, and PGC-1α govern mitochondrial biogenesis and adaptive responses to microbial signals. Dysregulation of these pathways can heighten oxidative stress, hinder mitophagy, and contribute to systemic inflammation. Emerging therapeutic strategies aim to target this axis through dietary modifications, probiotics and engineered microbes, FMT, and mitochondria-specific pharmacological treatments. These interventions focus on restoring metabolic stability, enhance resilience against oxidative damage, and slowing disease progression. By integrating insights from fields such as metabolism, immunology, and neuroscience, this review positions the microbiota-mitochondria axis as a critical area of focus in biomedical research. A deeper understanding of this communication network offers promising opportunities for precision therapies aimed at addressing metabolic, inflammatory, and neurodegenerative diseases.
    Keywords:  Gut microbiota; Inflammation; Metabolic disorders; Mitochondria; Neurodegeneration; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s11011-026-01914-9
  31. medRxiv. 2026 Jun 24. pii: 2026.06.22.26356227. [Epub ahead of print]
    Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.
    Dan E Arking, Tryggvi McDonald, Wen Shi, Daniela Puiu, Jeremy V Arking, Sergiu Pasca, Yun Soo Hong, Lukasz Gondek.
      Mitochondrial DNA (mtDNA) heteroplasmy, the coexistence of multiple mtDNA variants within cells, accumulates with age and is associated with hematological malignancies and mortality. However, whether predicted deleterious heteroplasmies causally contribute to cancer or merely represent passenger mutations remains unresolved. Here, leveraging ∼36,000 first-degree relative pairs from the UK Biobank and All of Us Research Program cohorts, we deconvolute overall heteroplasmy metrics into those that are shared across family members (representing inherited variants) and those that are not (representing de novo variants) to establish a Mendelian randomization framework for assessing causality. We show that shared heteroplasmies exhibit strong purifying selection, with reduced predicted deleteriousness compared to not shared variants, and that 90% of an individual's deleterious heteroplasmy burden is somatically acquired. Critically, shared deleterious heteroplasmy burden, fixed at conception and thus temporally upstream of potential confounders, is significantly associated with hematological malignancies (RR=2.81, 95% CI 1.29-6.13), with effect sizes concordant with the not shared heteroplasmy burden. Furthermore, shared deleterious heteroplasmy specifically associates with high-risk clonal hematopoiesis of indeterminate potential (CHIP), particularly spliceosome mutations, suggesting mitochondrial dysfunction promotes clonal expansion of specific CHIP subtypes. Finally, we identify ultra-rare individual mtDNA variants associated with hematological malignancies, a hallmark of driver mutations. These findings establish mtDNA heteroplasmies, including inherited variants, as causal contributors to hematological malignancy risk and demonstrate that most disease-relevant burden is acquired during life, identifying potential opportunities for prevention and therapeutic intervention in individuals at elevated risk for hematological cancer, particularly of myeloid origin.
    DOI:  https://doi.org/10.64898/2026.06.22.26356227
  32. J Neuroophthalmol. 2026 Jul 02.
    Concurrence of Inherited Nuclear and Mitochondrial DNA Optic Neuropathies.
    Benson S Chen, Benjamin I Meyer, Nancy J Newman.
      
    DOI:  https://doi.org/10.1097/WNO.0000000000002466
  33. NPJ Genom Med. 2026 Jun 29.
    Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients.
    Dream Lok Sze Chan, Helen Ying Fung Tam, Amy Hin Yan Tong, Wei Ma, Chak Sing Lau, Ho Ming Luk, Shirley Yin Yu Pang, Shirley Sze Wing Cheng, Yuan Gao, Lai Ting Leung, Denis Long Him Yeung, Claudia Ching Yan Chung, Steve Tsz Fung Chan, Shirley Pik Ying Hue, Anson Man Chun Xi, Dicky Or, Steve Cheuk Yiu Yeung, Jamie Sui Lam Kwok, Nattily Sum Yin Tai, Carol Ching Fun Lau, Wai Lap Wong, Raven Yan Wah Lee, Janice Kai Ning Wong, Hong Kong Genome Project, Annie Tsz Wai Chu, Brian Hon Yin Chung.
      Genetic neurological disorders are highly heterogeneous, and many are driven by complex variants that challenge short‑read genome sequencing (srGS). Long‑read genome sequencing (lrGS) has recently shown promise, but head‑to‑head evaluations are limited. A direct comparison study of srGS and lrGS was performed for 310 families with undiagnosed neurological disorders from the Hong Kong Genome Project to assess their diagnostic performance, technical capabilities and costing. Genome sequencing showed an overall diagnostic yield of 22.6% (n = 70/310, 77 variants). lrGS and srGS showed comparable variant detection rates at 92.2% (n = 71/77) and 96.1% (n = 74/77), respectively. lrGS solely confirmed three repeat expansions with phased methylation data and enhanced accuracy in two complex structural variants. srGS detected six variants in homopolymeric regions that were missed by lrGS. Costing analysis revealed a comparable unit cost per sample for srGS and lrGS with USD1,545.97 and USD1,580.00, respectively. This study demonstrated that srGS excels in detecting variants near homopolymers while lrGS offers better resolution for complex variants and enables the simultaneous analysis of methylation and phasing. Although lrGS is not yet capable of fully replacing srGS, we anticipate that the continued technical improvement would position lrGS as the first‑tier genomic test for neurological disorders.
    DOI:  https://doi.org/10.1038/s41525-026-00593-w
  34. Front Mol Biosci. 2026 ;13 1861303
    CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations.
    Zheng Tai Kuai, Xiao Min Zheng, Yue Yue Li, Tian Qi Wang.
      Mitochondrial bioenergetic competence critically depends on cristae architecture, which is organized and stabilized by the mitochondrial contact site and cristae organizing system (MICOS) complex. As a core MICOS subunit, CHCHD3 (also known as MIC19) contributes to assembly of the mitochondrial intermembrane space bridging (MIB) supercomplex and regulates cristae morphology, endoplasmic reticulum-mitochondria contact sites, and cellular metabolic homeostasis. Aberrant CHCHD3 expression or functional deficiency is implicated in the pathogenesis of neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and cancers. Notably, CHCHD3 function is governed by a dose-dependent "Goldilocks" principle, wherein both insufficient and excessive expression-as well as preserved abundance with impaired functional integrity-can compromise mitochondrial homeostasis, underscoring the need for context-specific therapeutic modulation. Here, we systematically summarize CHCHD3 molecular characteristics and post-translational modification networks, with emphasis on its roles in energy metabolism, organelle crosstalk, and apoptosis. We further examine the mechanistic links between CHCHD3 dysregulation and disease pathogenesis, evaluate current targeting strategies and their pharmacological limitations, and identify remaining controversies and knowledge gaps to guide future research toward clinical translation.
    Keywords:  CHCHD3; MIC19; MICOS complex; apoptosis; energy metabolism; mitochondrial contact sites; mitochondrial cristae
    DOI:  https://doi.org/10.3389/fmolb.2026.1861303
  35. J Physiol. 2026 Jul 01.
    Kinematic-calcium loops unravel impaired excitation-contraction coupling in MELAS-affected cardioids.
    Margherita Burattini, Annalinda Pisano, Maria Gemma Pignataro, Giulia d'Amati, Silvana Pinelli, Minh Long Hoang, Francesco Paolo Lo Muzio, Michele Miragoli.
      Impaired Ca2+ handling, and in particular leakage from the sarcoplasmic reticulum, is a critical mechanism in metabolic diseases affecting the heart. Phase-plane loop analysis provides an integrated assessment of excitation-contraction coupling (ECC) by capturing the dynamic relation between Ca2 + transients and mechanical contraction, exceeding standard time analysis limitations. Here, we investigated how mitochondrial encephalopathy, lactic acidosis and stroke-like episodes metabolic disorder (MELAS) impairs the ECC using cardiac spheroids from diseased human induced pluripotent stem cells (m3243A>G mutation) and matched control (mtDNA mutation <10%). High-speed dual-mode imaging at 200 fps enabled simultaneous acquisition of Ca2 + dynamics and spheroid kinematics. To uncover disease-specific mechanisms, supra-threshold electric field stimulation was applied to simulate increased energy demand. After signal extraction, we built our interpretation of phase-plane loops, comprising kinematic-calcium (Ki-Ca) loops, to quantify ECC efficiency. Time-domain analysis demonstrated that MELAS cardiac spheroids showed significant reduction in beat duration at kinematics (1.068 ± 0.066 s vs. 0.775 ± 0.094 s), as well as decreased Ca2+ transient duration (0.984 ± 0.049 s vs. 0.664 ± 0.042 s). Critically, Ki-Ca loop analysis provided a more complete picture where MELAS samples displayed visibly different loops and a significant reduction of their area compared to controls (0.129 ± 0.056 vs. 0.082 ± 0.163). These findings demonstrate that Ki-Ca loops provide a sensitive and integrative metric for detecting ECC dysfunction in human in vitro cardiac models. This approach offers mechanistic insight into how mitochondrial metabolic disorders, such as MELAS, compromise the coupling between Ca2 + cycling and contractility. KEY POINTS: Phase-plane Ki-Ca loops effectively contribute to understanding the excitation-contraction coupling (ECC) efficiency. Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes metabolic disorder (MELAS) impairs ECC in cardioid models. Cardiac challenge pacing protocol highlights beating anomaly in MELAS spheroids, uncovering ECC failure.
    Keywords:  Ki‐Ca loops; MELAS; calcium signalling; computer vision; excitation–contraction coupling; hiPSCs; kinematics
    DOI:  https://doi.org/10.1113/JP290473
  36. Nervenarzt. 2026 Jul;97(4): 323-325
    [Rare genetic diseases with frequent mental symptoms].
    Urs Heilbronner, Jürgen Deckert, Eva C Schulte.
      
    DOI:  https://doi.org/10.1007/s00115-026-01981-4
  37. Biochem Biophys Res Commun. 2026 Jun 30. pii: S0006-291X(26)00982-4. [Epub ahead of print]829 154218
    Mitochondrial genome alterations in cancer: From mutations and epigenetics to targeted therapiesack.
    Sachin Shetty, Nisarga M Padmasali, Divya Adiga, Shama Prasada Kabekkodu.
      Mitochondria play a central role in cellular energetics, metabolism, and apoptosis, and their dysfunction is increasingly recognized as a hallmark of cancer. The mitochondrial genome encodes essential subunits of oxidative phosphorylation (OXPHOS) complexes, tRNAs, and rRNAs, which are critical for mitochondrial functions. However, mitochondrial DNA (mtDNA) lacks protective histones and efficient repair mechanisms, rendering it highly susceptible to mutations and epigenetic changes. This review examines the role of mitochondrial-encoded genes (MEGs) in cancer progression, emphasizing the molecular mechanisms through which alterations in these genes contribute to tumorigenesis. We discuss how microsatellite instability, somatic mutations, and epigenetic modifications, such as methylation and non-coding RNA interactions, disrupt mitochondrial function, leading to defective OXPHOS, metabolic reprogramming (including the Warburg effect), elevated reactive oxygen species (ROS) production, and evasion of apoptosis. Furthermore, we highlight the tissue-specific and stage-dependent alterations in MEGs across various cancers, including breast, colorectal, lung, and ovarian malignancies, and explore their potential as diagnostic, prognostic, and therapeutic biomarkers. Finally, we evaluate emerging therapeutic strategies targeting MEGs, including mitochondrial gene editing, allotopic expression, and nanocarrier-based delivery systems, offering insights into future directions in precision oncology. We also discuss how MEG alterations contribute to the Warburg effect, chemoresistance, and tumor metastasis, which are critical barriers to effective cancer treatment. This synthesis highlights the pivotal role of mitochondrial genetics in cancer biology and positions MEGs as promising targets for innovative anticancer therapies.
    Keywords:  Cancer research; Epigenetics; Microsatellite instability; Mitochondrial-encoded genes; OXPHOS; Precision medicine; Targeted cancer therapy; mtDNA mutations
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154218
  38. Yakugaku Zasshi. 2026 ;146(7): 625-630
    [Expansion of Targeted Protein Degradation for Targeting Aggregate-prone Proteins and Mitochondrial Proteins].
    Shusuke Tomoshige.
      Targeted protein degradation (TPD), a technology that induces the degradation of a protein of interest (POI) by a chemical degrader, is a major trend in drug discovery research. Proteolysis targeting chimeras (PROTACs) are representative degraders that induce the ubiquitination of a POI, leading to its proteasomal degradation. Following the report of PROTAC efficacy in animals approximately a decade ago, TPD research continues to flourish. Unlike the occupancy-driven mechanism of traditional inhibitors, TPD employs an event-driven mechanism. Consequently, TPD is a highly anticipated technology capable of addressing therapeutic targets previously considered "undruggable." Against this backdrop, our group is actively pursuing research focused on the targeted degradation of undruggable proteins. This symposium review summarizes our studies. It focuses on two distinct areas: the targeted degradation of aggregation-prone proteins for the development of neurodegenerative disorder treatments, and the targeted degradation of mitochondrial matrix-localized proteins for mitochondria-related diseases.
    Keywords:  mitochondria; neurodegenerative disorder; targeted protein degradation
    DOI:  https://doi.org/10.1248/yakushi.25-00183-2
  39. J Physiol. 2026 Jul 01.
    Systems modelling of mitochondrial dynamics in different exercise regimes.
    Ali Khalilimeybodi, Lingxia Qiao, Allen Leung, Andrew D McCulloch, Simon Schenk, Padmini Rangamani.
      Exercise stimulates skeletal muscle signalling and mitochondrial metabolism. Emerging evidence shows that mitochondrial dynamics (i.e. fission and fusion) could be regulated by exercise. Yet, key gaps remain in identifying (i) the signals that drive fission vs. fusion; (ii) how energy status and reactive oxygen species (ROS) shift control between dynamin-related protein 1 (DRP1) and mitofusin (MFN)/optic atrophy 1 (OPA1); and (iii) which intensity-duration combinations yield similar cytosolic signals but different mitochondrial remodelling. Therefore, we developed an integrative computational framework connecting exercise regimens to mitochondria fission-fusion machinery by linking blood-myofibre energetics in cytosol and mitochondria to signalling pathways. The influence of sprint, resistance and endurance exercise regimens on mitochondrial fission and fusion has been simulated. Classified qualitative validation of the signalling network model achieved 80% accuracy. The model predicts regimen-specific dynamics starting with an acute DRP1-driven fission during exercise followed by MFN1/2-OPA1-mediated re-fusion as energy stress declines, consistent with a cyclical triage-then-rebuild paradigm. Changes are most pronounced and sustained with endurance, sharp but brief with sprint, and minimal with resistance. Global sensitivity analysis identified AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1α→MFN1/2 as dominant fusion drivers, ROS and AMPK→mitochondrial fission factor/DRP1 as primary fission switches, and Ca2 +-calmodulin, extracellular-signal-regulated kinase and liver kinase B1/AMPK as shared regulators. The model predicts that an endurance base, augmented with one or two weekly high intensity interval training/sprint interval training sessions could maximize AMPK-ROS pulses and mitochondrial fission-fusion. This framework unifies muscle's signalling logic with energetic state to explain how intensity-volume combinations, bout spacing and kinase modulation tune mitochondrial remodelling, yielding testable predictions for optimizing training and adjuvant therapies to enhance mitochondrial quality and performance. KEY POINTS: Different exercise regimes such as sprint, resistance, and endurance can trigger different signalling pathways. Exercise also triggers mitochondrial remodelling in skeletal muscle. Using a systems biology model, we developed a systems biology model for skeletal muscle signalling and mitochondrial metabolism for exercise. Our model predicts the dynamics of mitochondrial fusion and fission in different exercise regimes and identifies which signalling pathways dominassste these remodelling mechanisms.
    Keywords:  ROS‐mediated signalling; exercise regime; metabolic signalling; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1113/JP290424
  40. Mater Today Bio. 2026 Aug;39 103371
    Microfluidic-based biomimetic mitochondrial nanocomposite for targeted immunotherapy of rheumatoid arthritis via mitochondrial transplantation.
    Nengjie Yang, Chen Dong, Rui Zhao, Mei Yang, Shiwen Ni, Yi Jin, Qingshui Wen, Cong Xu, Zhifeng Gu, Yujuan Zhu, Chi Sun.
      Rheumatoid arthritis (RA) is a common chronic autoimmune disease and has recently been reported to be closely related to mitochondrial dysfunction. Mitochondrial dysfunction can promote the occurrence and development of rheumatoid arthritis (RA) through increased cellular ROS production, activation of immune cells and production of autoantibodies. Although the mechanism of mitochondrial dysfunction remains uncertain, it offers potential therapeutic strategies for rheumatoid arthritis. Mitochondrial transplantation is an emerging treatment method, aiming to restore the normal function of tissues by replacing abnormal mitochondria in tissues or cells. Here, we propose a novel biomimetic mitochondrial nanocomposite (Mito@G3K) based on microfluidic chips, which can be used for intravenous RA targeted immunotherapy. Based on microfluidic chips, Mito@G3K were efficiently generated by taking advantage of the charge capture effect between mitochondria and cationic peptide dendritic macromolecules. Due to the naturally derived peptide components, the synthetic Mito@G3K have very high biological activity. Even more attractive is that by customizing Mito@G3K with a higher surface charge density, they can achieve rapid targeting ability, high accumulation volume and long-lasting effect in inflamed joints. In vitro experiments have shown that it can effectively inhibit the inflammation caused by pro-inflammatory macrophages. In addition, Mito@G3K have shown good therapeutic effects in the CIA mouse model and can effectively alleviate inflammation in the joint area. Mouse synovial transcriptome sequencing shows that the therapeutic effect may be achieved by improving mitochondrial metabolism.
    Keywords:  Biomimetic mitochondrial nanocomposite; Dendritic polylysine; Microfluidic chip; Mitochondrial transplantation; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103371
  41. Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00076-0. [Epub ahead of print]91 102186
    Spatholobi caulis and Epicatechin amplify erythropoiesis through mitochondrial translocation of AKT and enhanced oxidative phosphorylation.
    Tsai-Ju Chien, Qian-Wen Huang, Pei-Hsin Chuang, Chia-Ying Wu, Ming-Chung Lee, Yu-Ni Hsu, Yu-Ling Su, Shuoh-Wen Chen, Yu-Xuan Wu, Min-Hui Chen, Chen Kuo, Xin-Yun Han, He-Yi Yang, Hsin-Yu Chang, Chiao-Hsin Chang, Yuan-I Chang.
      Erythroid differentiation requires a metabolic shift to oxidative phosphorylation (OXPHOS). We investigated the effects of Spatholobi Caulis (SC) and its active flavonoid, epicatechin (EC), on erythropoiesis. Both SC and EC significantly amplified erythroid differentiation in vitro and in vivo. Mechanistically, SC and EC further triggered differentiation-induced AKT activation and its mitochondrial translocation, leading to upregulation of mitochondrial DNA-encoded respiratory chain genes and enhanced OXPHOS capacity. Notably, this functional enhancement occurred without changes in mitochondrial mass or mtDNA copy number, indicating a biogenesis-independent mechanism. Both PI3K/AKT signaling and intact OXPHOS function were essential, as pharmacological inhibition of either pathway abolished SC's pro-erythropoietic activity. Our findings establish an AKT-mitochondrial axis that couples proliferative signaling to bioenergetics, offering a therapeutic strategy for anemias involving mitochondrial dysfunction.
    Keywords:  AKT; Epicatechin; Erythropoiesis; Mitochondria; Spatholobi caulis
    DOI:  https://doi.org/10.1016/j.mito.2026.102186
  42. Brain Commun. 2026 ;8(4): fcag224
    Late-onset epileptic spasms: presentation, aetiology and outcome.
    Sameer Dal, Emma Macdonald-Laurs, Simone Mandelstam, Rachel Kerr, Eunice K Chan, Kathryn Santamaria, Wirginia Maixner, Alison Wray, Colleen D'Arcy, Ramja Kokulan, Jacquie A Wrennall, Joseph Yuan-Mou Yang, Bonnie Alexander, Sila Genc, Sarah M Barton, Matthew Coleman, Paul J Lockhart, Richard Leventer, Jeremy L Freeman, Sarah E M Stephenson, Katherine B Howell, A Simon Harvey.
      Late-onset epileptic spasms (LOES) are epileptic spasms (ES) commencing after age 12 months, often misdiagnosed and having uncertain relationship to infantile spasms. Previous studies of mostly small LOES cohorts frequently reported 'cryptogenic' aetiologies. We studied the presentations, aetiologies, treatment responses and outcomes in a large LOES cohort, evaluated with modern neuroimaging and genomic testing. In this retrospective cohort study, 62 children with video-confirmed epileptic spasms, diagnosed between 2011 and 2021, were included. All had epileptiform activity on EEG, but none had hypsarrhythmia. Median age at epileptic spasms onset was 23 months (range 1-15 years) and median delay to diagnosis was 8 months (interquartile range: 3-15). Only 24% children were correctly diagnosed at presentation, common misdiagnoses being myoclonic epilepsies and non-epileptic phenomenon. Aetiology was identified in 95%. Structural-malformative aetiologies were present in 63% (most commonly focal cortical dysplasia and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy). Other aetiologies were structural-acquired in 13% (mostly postnatal stroke and CNS infections), genetic in 13% (mostly intragenic variants and chromosomopathies) and oncological in 6% (history of leukaemia, two with CNS involvement). Children with structural aetiologies often had normal development prior to onset of epileptic spasms, a later median age of epileptic spasms onset and were more likely to have asymmetric or subtle epileptic spasms and additional seizures prior to epileptic spasms. Epileptic spasms ceased in 29% children treated with prednisolone, most having genetic aetiologies and in 35% treated with vigabatrin, all having structural-malformative aetiologies. Apart from clobazam, which was effective in 17% of children, all other antiseizure medications, vagus nerve stimulation and ketogenic diet therapy were ineffective. Epileptic spasms ceased in 86% (18/21) of children who underwent epilepsy surgery. At median follow-up of 10.3 years, 53% children were free of all seizures and 76% were free of epileptic spasms. More children with unilateral structural-malformative aetiologies achieved seizure freedom than other aetiologies, most commonly following surgery but occasionally following treatment with vigabatrin or clobazam. Impairment of cognitive function or adaptive behaviour (formally assessed in 90%) was significantly more common in children with genetic than structural aetiologies, and in children with ongoing seizures than seizure freedom. Among children who underwent epilepsy surgery, 62% achieved average or low-average adaptive functioning or normal intellectual capacity. This study highlights the importance of prompt recognition of epileptic spasms in older children for improved seizure and developmental outcomes. Brain malformations and insults are the predominant causes of LOES, and when unilateral, respond best to epilepsy surgery.
    Keywords:  cognitive outcome; developmental and epileptic encephalopathy; diagnostic delay; infantile spasms; neuroimaging
    DOI:  https://doi.org/10.1093/braincomms/fcag224
  43. Orphanet J Rare Dis. 2026 Jun 27.
    Health service access and delivery for people living with rare disorders: a scoping review.
    Tara N Officer, Michael Roguski, Lucy Bennett, Bruce C Officer, Lisa Ye, Gretchen Good, Karen McBride-Henry.
       BACKGROUND: Rare disorders contribute significant collective health system costs; individuals living with rare disorders frequently encounter diagnostic, treatment, and management barriers. Despite international recognition of these challenges, there remains limited research addressing systemic health service delivery and access barriers for those with rare disorders, or identification of how such research impacts policymaking.
    METHODS: Dimensions, PubMed, Scopus, ProQuest, CINAHL, and Ovid platform databases were employed in a search of qualitative research documenting the health service experiences of people living with rare disorders and their primary support networks. A total of 4,615 studies were screened by title, keywords, and abstract. Seventy-eight studies met the inclusion criteria after full text screening, these were then reviewed. Policy impact in the form of citations was determined by whether an Overton search identified a link between the reviewed studies and policy documents.
    FINDINGS: Two primary findings were identified. (1) Health service access and delivery barriers are pervasive. People living with rare disorders and their support networks manage emotional, financial, and social challenges. There is an urgent need for improved service delivery, including better access, education, psychological, and peer support. (2) Reviewed studies, covering only a small subset of the over 10,000 identified rare disorders, are published by specialised rare disorders journals often failed to adopt inclusive methods, and have negligible policy reach.
    INTERPRETATION: Despite growing awareness, health systems fall short of addressing structural barriers faced by people living with rare disorders. The findings support consideration of a global coordinated action plan for rare disorder management. For researchers, this could include adoption of inclusive research methods. For policymakers, there is a need for stronger inclusion of equity-priority populations and coordinated policy frameworks that recognise the collective impact of disparate and poorly managed care. Critical to supporting change is investment in the upskilling of the health workforce and clinicians' active engagement in diagnosis, coordination, long-term management, and treatment.
    Keywords:  Health service delivery; Healthcare access; Healthcare experiences; Qualitative methods; Rare diseases; Rare disorders; Scoping review
    DOI:  https://doi.org/10.1186/s13023-026-04455-7
  44. bioRxiv. 2026 Jun 17. pii: 2026.06.15.731916. [Epub ahead of print]
    Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression.
    Niansheng Ren, Liuyang Wang, Rajesh K Dutta, David S Umbaugh, Qiaojuan Zhang, Seh Hoon Oh, Dennis C Ko, Ming Song, Anna Mae Diehl, Kuo Du.
       Background & Aims: Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis.
    Methods & Results: Using dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3-SCO1-MT-CO1-CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis.
    Conclusions: Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.
    DOI:  https://doi.org/10.64898/2026.06.15.731916
  45. Commun Med (Lond). 2026 Jul 03.
    The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.
    Walter Endrizzi, Flavio Ragni, Stefano Bovo, Avinash Chandra, Monica Moroni, Giuseppe Jurman, Venet Osmani.
       BACKGROUND: The rising global burden of neurodegenerative diseases underscores an urgent need for advanced research in diagnosis, prognosis, and treatment. Artificial Intelligence (AI) methods, particularly when applied to multimodal data, offer a powerful tool to address these challenges. However, a comprehensive overview and critique of the current landscape of AI methods is lacking.
    METHODS: 4,685 records of peer-reviewed, primary research articles were screened and 1,956 articles reviewed in full text, yielding 1,186 included studies. For each included study, clinical objectives, disease focus, data modalities, modelling approach, evaluation strategy, and reporting practices were extracted.
    RESULTS: Fewer than 5% of studies integrated pharmacological treatments into their predictive models, limiting the extent to which models can directly inform clinical decision-making. Neuroimaging was the predominant input modality, while integration of other clinically relevant data types was relatively rare. Reproducibility rates remain critically low at 35%, and external validation practices fail to use geographically and demographically diverse datasets.
    CONCLUSIONS: Overall, AI research in neurodegenerative diseases suffers from significant limitations in reproducibility, data inclusivity, and clinical translatability. We provide a set of recommendations that can be adopted to address these issues and improve reliability and downstream clinical utility.
    DOI:  https://doi.org/10.1038/s43856-026-01669-5
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