bims-polgdi Biomed News
on POLG disease
Issue of 2026–06–14
43 papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
  2. Targeting Mitochondria in Aging-Related Diseases: Therapeutic Potential and Obstacles.
  3. Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.
  4. Effects of an indole chemical, mitochonic acid 5, in a mouse model of mitochondrial disease onset.
  5. Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
  6. Mitophagy: an emerging therapeutic target in mitochondrial diseases.
  7. Mitochondrial transfer between tumor and immune cells: a nexus of metabolic adaptation and immune dysfunction.
  8. Mitochondrial Dysfunction as a Driver of Neurodegeneration in Parkinson's and Huntington's Disease: Molecular Insights and Emerging Interventions.
  9. Elucidating the Neural Basis of Bipolar Disorder - Secondary Publication.
  10. Integrative Literature Review on the Lived Experiences of Parents of Children with a Rare Disease.
  11. Mitochondrial capsules mitigate mitochondrial dysfunction.
  12. Rare disease nomenclature and coding: challenges, systems, and policies in the global context.
  13. Mitochondrial Dysfunction in Parkinson's Disease: Diagnostic and Therapeutic Advances.
  14. Size Does Matter! Prioritizing Rare Diseases for Luck Egalitarian Reasons.
  15. G.AI: an AI-driven platform for phenotype standardization, variant interpretation and structured clinical reporting in rare disease genomic diagnosis.
  16. Expanding the MRPS34 Genotype-Phenotype Correlation: Two Novel Cases and a Cohort Review.
  17. Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
  18. The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.
  19. DJ-1 in the Neuro-cutaneous Aging Axis: Unifying Pathways of Parkinson's Disease Neurodegeneration, Progression, and Redox-Based Therapeutic Strategies for Healthy Longevity.
  20. CRISPR-Based Gene Therapy for Brain Disease.
  21. Mechanisms by Which Exercise Delays Brain Aging Through Regulation of the Mitochondrial Quality Control System.
  22. Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.
  23. Clinical outcomes of mitochondrial-enhancing nutraceutical supplementation in psychiatric disorders: A systematic review.
  24. Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
  25. Editorial: Repurposing for small population needs.
  26. Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.
  27. Main Recommendations for Developing Education and Awareness Strategies for Rare Diseases: Scoping Review.
  28. Mitochondria tethered to the nucleus secure its energy supply.
  29. Mitophagy-mediated immune evasion: Shared strategies of pathogens.
  30. Associations between adverse childhood experiences, mitochondrial DNA copy number and atopic disease in children.
  31. Mitochondrial dysfunction in pulmonary fibrosis: from mechanisms to therapeutic opportunities.
  32. Mitochondrial complex I deficiency-associated diseases and models.
  33. Genetically supported drug target prioritization for rare diseases.
  34. Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome.
  35. "If I go down, if I crumble, then everybody does" - identity crisis and emotional strain in parents of children with rare and undiagnosed conditions: a qualitative study.
  36. Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial.
  37. National Rare Disease Registration Project in the Republic of Korea: Current Status and Policy Directions.
  38. Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review).
  39. Oocyte aging, the mitochondrial downward spiral, and the path to responsible innovation.
  40. Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
  41. Cerebellar Ataxia and Chorea: Genetic Etiologies and Key Considerations for Diagnosis and Management.
  42. Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
  43. Targeted degradation of intracellular organelles: Strategies and implications.
  1. Free Radic Biol Med. 2026 Jun 06. pii: S0891-5849(26)00857-9. [Epub ahead of print]253 749-769
    Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
    Samantha Corrà, Luke Young, Anthony L Moore, Carlo Viscomi.
      Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and metabolic conditions. Mitochondrial diseases are genetically heterogeneous disorders caused by mutations in nuclear or mitochondrial DNA that impair oxidative phosphorylation (OXPHOS), resulting in reduced ATP production and cellular energy failure. Despite a shared bioenergetic defect, these diseases display marked clinical variability, and the mechanisms underlying this heterogeneity remain poorly understood. At present, no curative therapies are available, although several metabolic and experimental approaches have shown promise in preclinical models. Mitochondrial dysfunction is commonly associated with altered redox homeostasis and increased production of reactive oxygen species (ROS), which can damage mitochondrial components, including mitochondrial DNA, and further impair respiratory chain function. At the same time, ROS also act as context-dependent signalling molecules, with effects that vary according to concentration, localization, and cell type complicating their interpretation in disease mechanisms and therapy development. In this review, we summarize current concepts in mitochondrial disease pathophysiology focusing on unresolved questions that limit mechanistic understanding and clinical translation. We critically evaluate the role of ROS in disease progression and signalling, discuss how the alternative oxidase (AOX) has emerged as a valuable experimental tool to dissect ROS-related mechanisms and reveal unexpected aspects of mitochondrial dysfunction and disease variability.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.013
  2. MedComm (2020). 2026 Jun;7(6): e70790
    Targeting Mitochondria in Aging-Related Diseases: Therapeutic Potential and Obstacles.
    Zijie Xiang, Yu Chen, Xishui Liu, Haowen Lu, Yuqing Yang, Lei Xing, Yu Zhang, Chuandong Lang, Siming Zhang, Shixiang Zhao, Youzhi Hong, Jiaxiang Bai, Yusen Qiao.
      Aging is a complex biological process characterized by the functional decline of multiple cellular organelles, with mitochondrial dysfunction emerging as a predominant hallmark. Alterations in mitochondria within senescent cells primarily encompass two interrelated aspects: intrinsic mitochondrial dysfunction and compromised mitochondrial quality control systems, including mitophagy, dynamics, and biogenesis. However, a comprehensive synthesis that bridges mechanistic insights into mitochondrial dysfunction with an analysis of therapeutic obstacles remains lacking. Here, we systematically summarized the pathways leading to mitochondrial dysfunction in aging and deeply analyzed how this dysregulation, including mitochondrial DNA instability and mitochondria driving inflammation through the cGAS-STING pathway, contributed to the etiology of aging-related diseases, including muscle, bone, neurodegeneration, cardiovascular, and metabolic diseases. Additionally, we analyzed a series of mitochondrial targeted treatment strategies, from metabolism and kinetic regulation to disease-specific intervention and emerging technologies, such as mitochondrial transplantation and mitochondrial DNA base editing. Finally, we emphasized the key obstacles that must be overcome for clinical transformation, including tissue-specific mitochondrial heterogeneity. By combining the basic mechanism with the development of treatment and its potential challenges, this review provides a key perspective for promoting the emerging field of mitochondrial medicine to intervene in aging-related pathology more accurately and effectively.
    Keywords:  aging; mitochondria; therapy
    DOI:  https://doi.org/10.1002/mco2.70790
  3. Int J Mol Sci. 2026 May 30. pii: 4966. [Epub ahead of print]27(11):
    Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.
    Hanna Bynum, Kristin S Edwards.
      Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS-STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts.
    Keywords:  endocrine disorders; estrogen; immunometabolism; mitochondria; mitochondrial dynamics; mitochondrial reactive oxygen species; oxidative phosphorylation; sex differences; sex hormones; testosterone
    DOI:  https://doi.org/10.3390/ijms27114966
  4. Sci Rep. 2026 Jun 10.
    Effects of an indole chemical, mitochonic acid 5, in a mouse model of mitochondrial disease onset.
    Emi Ogasawara, Haruna Tani, Chitose Suzuki, Yuji Owada, Masaki Ogata, Naotada Ishihara, Takaaki Abe, Kazuto Nakada.
      This study tested the effects of mitochonic acid 5 (MA-5) using a mouse model of mitochondrial disease onset (mito-mice∆), with disease resulting from the accumulation of pathogenic mitochondrial DNA harboring a large deletion (∆mtDNA). Administration of MA-5 to mito-mice∆ inhibited the progression of clinical symptoms, such as low body weight and lactic acidosis. In the kidneys, MA-5 protected against mitochondrial respiration defects and subsequent renal failure, even when ∆mtDNA accumulated to > 80%. In the heart, MA-5 also resolved the mitochondrial respiration defects. Our findings suggested that administration of MA-5 would be effective in delaying the progression of some mitochondrial diseases caused by mutant mtDNA and especially in mitochondrial-mediated renal failure.
    Keywords:  Mitochondria; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Mitochonic acid 5 (MA-5); Mouse model; Respiratory chain
    DOI:  https://doi.org/10.1038/s41598-026-57342-3
  5. Fundam Res. 2026 May;6(3): 1893-1912
    Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
    Yu Zhang, Xishui Liu, Zijie Xiang, Yuqing Yang, Lei Xing, Yu Chen, Siming Zhang, Shixiang Zhao, Youzhi Hong, Yusen Qiao, Jiaxiang Bai.
      Mitochondria have complex functional and information-processing networks that play key roles in both health regulation and disease progression. However, the multiple properties and complex thresholds of mitochondrial dysfunction and quality control make the contribution of mitochondria to bone aging elusive. These factors prevent mitochondria from being among the most important precision therapies. Currently, many strategies that target mitochondrial homeostasis have entered clinical trials. In mitochondria, mitochondrial DNA (mtDNA) and its associated proteins are potential therapeutic agents for immunometabolic diseases and tissue injury, with the aim of enhancing mitochondrial function. Here, we comprehensively review the intrinsic mechanisms of mitochondrial dysfunction and quality control leading to bone aging and summarize current strategies for the treatment of skeletal aging disorders and the clinical translation of relevant agents in terms of unraveling dysfunctional pathways and developing precision therapies. In this review, we offer a general overview of the progress of clinical application in the treatment of skeletal senescence diseases, and we also provide prospects for the challenges associated with the role of mitochondrial dysfunction in bone senescence in clinical application and future trends in this field.
    Keywords:  Bone aging; Clinical application; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Precision therapy; Quality control
    DOI:  https://doi.org/10.1016/j.fmre.2025.12.021
  6. Biochem J. 2026 Jul 08. 483(7): 1193-1220
    Mitophagy: an emerging therapeutic target in mitochondrial diseases.
    Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.
    Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins
    DOI:  https://doi.org/10.1042/BCJ20260161
  7. Biomark Res. 2026 Jun 11.
    Mitochondrial transfer between tumor and immune cells: a nexus of metabolic adaptation and immune dysfunction.
    Jianqiang Yang, Yunqi Li, Soumya Vijaya Kumar, Nabil F Saba, Chloe Shay, Yong Teng.
      The tumor microenvironment (TME) is a dynamic and highly interactive ecosystem that fuels cancer progression through coordinated cellular crosstalk. Recent studies have uncovered intercellular mitochondrial transfer as a critical adaptive mechanism within this niche. Here, we synthesize current evidence supporting a paradigm in which mitochondria function as "shared organelles", whose bidirectional trafficking reshapes tumor and immune cell states. We discuss the mechanisms by which cancer cells acquire functional mitochondria from stromal compartments to enhance bioenergetic fitness, metabolic plasticity, and resistance to therapy. Conversely, we highlight the transfer of damaged or dysfunctional mitochondria from tumor cells to immune populations, a process that contributes to immune suppression and impaired anti-tumor responses. We further delineate the molecular and cellular networks regulating mitochondrial exchange, including tunneling nanotubes, extracellular vesicles, and cytoskeletal dynamics. Finally, we evaluate emerging therapeutic strategies aimed at disrupting mitochondrial trafficking and reprogramming TME metabolism. Collectively, this review positions mitochondrial transfer as a fundamental driver of tumor progression and a promising, yet underexplored, target for cancer therapy.
    Keywords:  Antitumor therapy; Mitochondrial transfer; TME; Tumor immunity; Tumor-stromal cell interactions
    DOI:  https://doi.org/10.1186/s40364-026-00955-7
  8. Mol Neurobiol. 2026 Jun 10. pii: 685. [Epub ahead of print]63(1):
    Mitochondrial Dysfunction as a Driver of Neurodegeneration in Parkinson's and Huntington's Disease: Molecular Insights and Emerging Interventions.
    Omkar Kumar Kuwar, Sarila Khan, Ayushi Maloo, Chetna Singh, Mansi Sharma, Kousik Maparu, Mamta Sachdeva Dhingra, Vipul Sharma.
      Mitochondrial dysfunction has emerged as a central contributor to the pathogenesis of major neurodegenerative disorders, such as Parkinson's and Huntington's disease. In Parkinson's disease, mitochondrial abnormalities are often linked to mutations in genes like PINK1 and Parkin, which regulate mitochondrial quality control, while α-synuclein aggregation further exacerbates mitochondrial damage. In Huntington's disease, mutant huntingtin protein impairs mitochondrial dynamics, transport, and ATP production, contributing to selective neuronal vulnerability. The convergence of mitochondrial impairments across both diseases highlights a common pathological axis that can be therapeutically targeted. This review critically examines the molecular underpinnings of mitochondrial dysfunction in PD and HD and explores emerging strategies to restore mitochondrial function. These include antioxidants, metabolic modulators, mitophagy activators, and gene therapy approaches. Despite promising preclinical findings, several translational challenges remain, underscoring the need for continued investigation. Understanding the shared and unique mitochondrial-related mechanisms in PD and HD will be essential for developing targeted, disease-modifying therapies that may improve outcomes and quality of life for affected individuals.
    Keywords:  Antioxidants; Huntington’s disease; Mitochondrial dysfunction; Neuroinflammation; Neuronal loss; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-026-05991-w
  9. JMA J. 2026 May 15. 9(3): 602-605
    Elucidating the Neural Basis of Bipolar Disorder - Secondary Publication.
    Tadafumi Kato.
      Bipolar disorder is a mental disorder characterized by recurrent episodes of mania/hypomania and depression, with a strong genetic contribution and substantial functional burden. Recent genomic studies implicate multiple risk variants converging on intracellular calcium (Ca2+) signaling and synaptic function, while neurons derived from induced pluripotent stem cells of patients with bipolar disorder demonstrate altered neuronal excitability and lithium-responsive phenotypes. Building on early neuroimaging and postmortem observations, accumulating evidence supports the mitochondrial dysfunction hypothesis, which proposes that impaired mitochondrial Ca2+ buffering disrupts neuronal Ca2+ homeostasis and contributes to mood instability. Diverse findings align with this framework: altered brain energy metabolism, increased mitochondrial DNA (mtDNA) deletions, elevated lactate, reduced mitochondrial gene expression and complex I proteins, enrichment of deleterious de novo and mosaic variants in Ca2+ signaling- and mitochondrial/endoplasmic reticulum-related genes, and a higher prevalence of the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)-associated m.3243A>G mutation in individuals with bipolar disorder. Animal models further strengthen causal inference. Neuron-specific Ant1 knockout mice exhibit reduced mitochondrial Ca2+ uptake and serotonergic hyperexcitability, while mice with neuron-specific mutant Polg accumulate mtDNA deletions and show recurrent depression-like episodes responsive to lithium and switch-like manic behaviors following treatment with a tricyclic antidepressant, indicating construct, face, and predictive validity. To identify the critical brain substrate, mtDNA deletions were mapped and found to accumulate most prominently in the paraventricular thalamic nucleus (PVT), a serotonergic-recipient hub projecting to limbic circuits involved in emotional salience. Human postmortem single-nucleus analyses reveal marked reductions of PVT neurons and prominent gene expression changes in the PVT, including enrichment of GWAS (genome-wide association study) signals among downregulated genes, as well as neuropathological alterations such as granulovacuolar degeneration in the PVT in late-onset cases. These convergent data suggest that genetically driven Ca2+ dysregulation and mitochondrial vulnerability promote circuit-level dysfunction-particularly within the serotonin-PVT-limbic pathway-leading to dysregulated emotion-cognition balance and mood swings.
    Keywords:  bipolar disorder; calcium; depression; hyperexcitability; lithium; mitochondria; paraventricular nucleus of the thalamus
    DOI:  https://doi.org/10.31662/jmaj.2026-0004
  10. Healthcare (Basel). 2026 May 22. pii: 1437. [Epub ahead of print]14(11):
    Integrative Literature Review on the Lived Experiences of Parents of Children with a Rare Disease.
    Assunta Guillari, Keti Ballfusha, Chiara Palazzo, Maurizio Di Martino, Vincenza Giordano.
       BACKGROUND/OBJECTIVES: Rare diseases have a substantial impact not only on affected individuals but also on their families, particularly parents who assume primary caregiving roles. Despite increasing attention to rare conditions, parents' experiences remain fragmented across the literature. This integrative review aimed to synthesise existing evidence on the experiences and multidimensional impact of caring for a child with a rare disease on parents.
    METHODS: An integrative review was conducted following Whittemore and Knafl's methodology and reported according to PRISMA 2020 guidelines. A systematic search was performed across MEDLINE, CINAHL, PsycINFO, PsycARTICLES, and Scopus from 1 November 2025 to 31 January 2026. Twenty-two studies (qualitative, quantitative, mixed-methods, and reviews) were included. Data were analysed using thematic synthesis.
    RESULTS: Three interrelated themes were identified: (1) the diagnostic journey, characterised by prolonged uncertainty, fragmented care, and the pivotal role of communication; (2) multidimensional caregiving burden, encompassing emotional, social, economic, and physical impacts, with notable gender differences; and (3) adaptive trajectories, involving dynamic coping processes, parental upskilling, and meaning-making. Across studies, caregiving burden emerged as a cumulative and system-influenced phenomenon, while adaptation was found to coexist with ongoing uncertainty rather than representing a linear resolution.
    CONCLUSIONS: Caring for a child with a rare disease profoundly affects parents across multiple domains. The findings highlight the need for integrated, family-centred care models, improved diagnostic communication, and sustained psychosocial support.
    IMPLICATIONS FOR NURSING PRACTICE: Nurses play a key role in recognising caregiver burden, supporting adaptive processes, and promoting effective communication throughout the diagnostic and care trajectory.
    Keywords:  caregiving burden; coping; diagnostic odyssey; family-centred care; integrative review; parents; rare diseases
    DOI:  https://doi.org/10.3390/healthcare14111437
  11. Nat Genet. 2026 Jun;58(6): 1200
    Mitochondrial capsules mitigate mitochondrial dysfunction.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-026-02651-6
  12. Arch Med Res. 2026 Jun 11. pii: S0188-4409(26)00088-3. [Epub ahead of print]57(8): 103466
    Rare disease nomenclature and coding: challenges, systems, and policies in the global context.
    Ashray Vohora, Sylvie Maiella, Caterina Lucano, Kurt Kirch, Carina Thomas, Stefanie Weber, Ana Rath.
      Rare diseases (RD) collectively affect millions of people worldwide yet remain poorly represented in generic coding terminologies. This lack of representation impedes patient visibility in health systems, in turn engendering downstream consequences such as negatively impacting patient outcomes, clinical research, and RD policy. This review evaluates the intricacies of the common coding systems currently employed to capture RD, and surveys the coding practices and policies in select countries as they pertain to RD. We analyse published literature, mappings between terminologies, and results from recent European projects to assess the applicability of generic and specific coding standards in clinical and registry settings. Globally, RD coding practices are demonstrated to be inconsistent and highly variable, although often rely on generic terminologies (ICD variations and other broad terminologies). Major drivers include heterogeneous national policies and the reliance on legacy standards. Furthermore, our findings reveal that generic classifications, due to their intended use for statistical purposes, provide limited and uneven coverage for RD and lack mechanisms to flag RD patients who have not yet received a diagnosis. In contrast, the Orphanet nomenclature (ORPHAcodes) offers coverage of all RD in the Orphanet knowledge base, a dedicated code for undiagnosed cases, and mappings to major terminologies, thereby improving patient visibility and data interoperability. We propose that the routine use of ORPHAcodes alongside generic classifications, supported by legal frameworks, governance, and implementation support, will enhance RD outcomes and facilitate RD research and policymaking. Coordinated stakeholder collaboration will be essential to realise these benefits to the RD community.
    Keywords:  Codification policy; Health data; Health information systems; Medical terminology; Rare Disease
    DOI:  https://doi.org/10.1016/j.arcmed.2026.103466
  13. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Mitochondrial Dysfunction in Parkinson's Disease: Diagnostic and Therapeutic Advances.
    Gang Wu, Xiao-Lin Dong, Rui Li, Fu-Rong Jin, Jing-Ting Lu, Lian-Bing Lin.
      Parkinson's Disease (PD) is a neurodegenerative disorder in which mitochondrial dysfunction plays a central role in pathogenesis. This review summarizes key mitochondrial abnormalities involved in PD, including respiratory chain impairment, dysregulation of mitochondrial dynamics, defective mitophagy, and mitochondrial DNA (mtDNA) damage. It further examines how these processes interact with α-synuclein (α-syn) pathology, contributing to increased vulnerability of dopaminergic neurons. In addition, current diagnostic approaches are transitioning from isolated biomarkers to an integrated Mitochondrial Health Index (MHI) for improved early detection. Finally, a critical appraisal of therapeutic interventions is presented, emphasizing the shift from monotherapies to multifaceted combination strategies. This review delineates a strategy for transformative PD therapies.
    Keywords:  Parkinson's disease; biomarkers; mitochondrial; neuroimaging; therapeutics strategies
    DOI:  https://doi.org/10.2174/0118715273454275260601070029
  14. Bioethics. 2026 Jun 06.
    Size Does Matter! Prioritizing Rare Diseases for Luck Egalitarian Reasons.
    Didde Boisen Andersen, Andreas Brøgger Albertsen, Sarah Wadmann, Mickael Bech.
      Rarity provides a challenging case for contemporary priority setting. On the one hand, many philosophers and economists argue that rarity has no inherent moral value, and thus that rare diseases merit no special treatment in priority setting decisions simply because they are rare. On the other hand, existing priority-setting practices demonstrate a higher willingness to pay for rare disease treatments. We argue that special priority for rare diseases might be justified on egalitarian grounds. Specifically, we develop and defend what we call the "bad numbers luck" argument for prioritizing rare diseases. This is a variant of the luck egalitarian idea of bad price luck. We conclude by discussing how higher willingness to pay, adjusted priority-setting processes, and a broader societal focus on rare diseases could address such injustices. Recognising bad numbers luck clarifies the relationship between fairness and efficiency in health care priority setting.
    Keywords:  Justice; bad price luck; formal equality; luck egalitarianism; orphan drugs; priority setting; rare diseases
    DOI:  https://doi.org/10.1111/bioe.70136
  15. J Transl Med. 2026 Jun 06.
    G.AI: an AI-driven platform for phenotype standardization, variant interpretation and structured clinical reporting in rare disease genomic diagnosis.
    Zhinong Wang, Xiaoning Chen, Liuqing Tang, Xiaokai Wu, Aiyu Huang, Hao Zhang.
       BACKGROUND: The diagnosis of rare diseases increasingly relies on the interpretation of high-throughput next-generation sequencing (NGS) data. As sequencing volume expands, the analytical burden grows substantially, and manual workflows become increasingly difficult to scale and prone to inconsistency. To address these challenges, we developed G.AI, an interpretable and traceable artificial intelligence (AI)-assisted genomic analysis platform that integrates automated phenotype standardization, variant pathogenicity ranking, and structured clinical reporting.
    METHODS: The platform uses a modular architecture comprising data parsing, AI-driven inference, and structured report generation. Performance was assessed using 39,156 multicenter whole-exome sequencing (WES)/ parent-child trio sequencing (WES Trio) cases from China, including 7,097 confirmed pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs) positive cases. Key evaluation metrics included phenotype-model concordance, Top-1, Top-3 and Top-20 variant pathogenicity ranking accuracy and workflow efficiency.
    RESULTS: The AI-Human Phenotype Ontology (HPO) phenotype standardization model achieved 94% concordance with manual review. The pathogenicity-ranking model reached Top-1 95%, Top-3 98%, and Top-20 99.6% accuracy among positive cases, with metabolic disorders achieving 100% Top-3 accuracy. Additional analysis on non-diagnostic cases demonstrated low false prioritization rates and good model specificity. Total analysis time decreased from 4 to 6 h to 48 ± 12 min, demonstrating a significant improvement in efficiency.
    CONCLUSION: By integrating automated phenotype processing, variant annotation, and AI-driven pathogenicity evaluation, G.AI substantially enhances the accuracy, consistency, and scalability of rare disease variant interpretation. Its transparent and traceable workflow provides a robust foundation for large-scale clinical genomic applications.
    Keywords:  AI-assisted genomic interpretation; HPO phenotype standardization; NGS data analysis; Rare diseases; Variant pathogenicity ranking
    DOI:  https://doi.org/10.1186/s12967-026-08368-8
  16. JIMD Rep. 2026 Jul;67(4): e70089
    Expanding the MRPS34 Genotype-Phenotype Correlation: Two Novel Cases and a Cohort Review.
    Alberte Aspaas Lundquist, Sumit Parikh, Thomas van Overeem Hansen, Flemming Wibrand, Elsebet Østergaard.
      MRPS34 encodes a mitoribosomal protein essential for mitochondrial translation. Biallelic pathogenic variants in MRPS34 cause Combined Oxidative Phosphorylation Deficiency 32 (COXPD32), a rare mitochondrial disorder within the Leigh syndrome spectrum (LSS), ranging from fatal in infancy to adult survival. The objective is to describe two new individuals with MRPS34-related disease and expand the clinical, genetic, and phenotypic spectrum of COXPD32. Clinical, radiological, biochemical, and molecular evaluations were conducted in two individuals with Leigh Syndrome (LS). Exome and genome sequencing identified presumed biallelic MRPS34 variants. A systematic review of all previously reported cases was performed to assess possible genotype-phenotype correlations (n = 11). Individual 1, who died in infancy with LS, was presumed compound heterozygous for a novel splice-site variant (c.364 + 2 T>C, p.(?)) and a nonsense variant (c.94C>T, p.(Gln32*)). Individual 2 survived into mid childhood and was homozygous for the hypomorphic variant c.322-10G>A, p.(?). Among 11 individuals, key features included developmental delay (100%), lactic acidosis (91%), brainstem lesions (91%), and metabolic acidosis (83%). Homozygosity for c.322-10G>A, p.(?) correlated with longer survival. MRPS34-related disease presents with multisystemic features and genotype-dependent severity. Accurate genetic diagnosis is essential for prognosis and therapeutic strategies.
    Keywords:  MRPS34; combined oxidative phosphorylation deficiency 32; genotype–phenotype correlation; hypomorphic splice variant; leigh syndrome spectrum; mitochondrial disease
    DOI:  https://doi.org/10.1002/jmd2.70089
  17. Curr Neuropharmacol. 2026 Jun 08.
    Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
    Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.
    Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.
    DOI:  https://doi.org/10.2174/011570159X473929260605103158
  18. Int J Mol Sci. 2026 May 29. pii: 4932. [Epub ahead of print]27(11):
    The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.
    Yoo Been Chang, James D Baleja.
      The ketogenic diet, a high-fat and low-carbohydrate diet, has potential therapeutic effects on various neurological and psychiatric disorders. The diet shifts the body's energy production in the form of adenosine triphosphate from using glucose to fats. The increased fatty acid β-oxidation results in the production of ketone bodies. This metabolic adaptation changes cellular bioenergetics, especially in the brain, which is highly reliant on energy metabolism. Schizophrenia, a psychotic disorder, and bipolar disorder, a mood disorder, are distinct psychiatric illnesses that can both involve disturbances in mood, cognition, and perception. These disturbances differ in prominence and clinical significance between the two conditions. Although the underlying mechanisms behind each disorder vary, they share some common pathophysiology, such as imbalances in the neurotransmitter system, mitochondrial dysfunction, and oxidative stress. Alzheimer's disease, a neurodegenerative disorder marked by progressive cognitive decline, shares similar cellular disruptions, along with additional pathological features such as neuroinflammation and neuronal death. Recent studies suggest that the ketogenic diet may exert therapeutic effects by modulating underlying biochemical pathways. Its ability to reduce oxidative stress, improve mitochondrial function, and stabilize neurotransmitter balance may help alleviate symptoms and potentially slow disease progression.
    Keywords:  Alzheimer’s disease; bipolar disorder; brain energy metabolism; ketogenic diet; mitochondrial dysfunction; neurotransmitter dysregulation; oxidative stress; schizophrenia
    DOI:  https://doi.org/10.3390/ijms27114932
  19. Mol Neurobiol. 2026 Jun 08. pii: 683. [Epub ahead of print]63(1):
    DJ-1 in the Neuro-cutaneous Aging Axis: Unifying Pathways of Parkinson's Disease Neurodegeneration, Progression, and Redox-Based Therapeutic Strategies for Healthy Longevity.
    Azhagu Madhavan Sivalingam.
      Sleep and circadian disturbances precede motor symptoms in Parkinson's disease (PD), acting as early neurodegeneration indicators. Disrupted rhythms, mitochondrial dysfunction, neuroinflammation, and neurotransmitter imbalance create a self-reinforcing cycle that accelerates progression. DJ-1 (PARK7), a redox-sensitive protein, provides central neuroprotection by preserving mitochondrial integrity, mitigating oxidative stress, and curbing neuroinflammation. DJ-1 loss or mutation weakens antioxidant defences, promotes α-synuclein aggregation, and worsens dopaminergic neuron loss, positioning it as a key biomarker and therapeutic target. Oxidative stress, mitochondrial impairment, chronic inflammation, and telomere attrition link neurodegeneration to systemic and skin aging via a "neuro-cutaneous aging axis." Similar mechanisms include mitochondrial dysfunction, ferroptosis, and redox imbalance energy Alzheimer's cognitive decline. Chronotherapy, NRF2 activators, phytochemicals, nanozymes, and postbiotics offer promise in restoring redox balance and halting progression. Telomere dysfunction and genomic instability further connect neural and skin aging, modulated by environment, diet, and lifestyle. Micro physiological systems, predictive analytics, and personalized medicine enhance mechanistic insights and therapy development. Targeting interconnected pathways of redox regulation, mitochondrial function, proteostasis, and telomere maintenance provides a unified approach to combat neurodegeneration and aging. DJ-1-focused therapies, paired with antioxidants and mitochondrial interventions, hold strong potential for disease modification and healthy aging.
    Keywords:  DJ-1 (PARK7); NRF2 pathway; Neurodegeneration; Oxidative stress; Skin aging
    DOI:  https://doi.org/10.1007/s12035-026-05981-y
  20. Mol Neurobiol. 2026 Jun 10. pii: 686. [Epub ahead of print]63(1):
    CRISPR-Based Gene Therapy for Brain Disease.
    Fatemeh Khajouei, Asma Ghaemi, Khalil Abnous, Seyed Mohammad Taghdisi, Mohammad Ramezani, Mona Alibolandi.
      Neurological disorders are complex and often very challenging for patients. Many of these conditions result from mutations in genes that are essential for normal function. Most existing treatments only alleviate symptoms, highlighting the urgent need for more effective therapeutic strategies. In the current drug development landscape, gene therapy offers hope as a promising approach. Specifically, CRISPR-Cas9 technology enables precise gene editing across diverse cell types and organisms. An increasing number of research groups are investigating innovative therapies and the molecular mechanisms behind neurological diseases. This review highlights the use of CRISPR-based gene therapies for various brain diseases, including multiple sclerosis, Alzheimer's, Parkinson's disease, epilepsy, stroke, and brain tumors. It consistently recognizes significant challenges in clinical applications, including overcoming the blood-brain barrier (BBB), managing off-target effects, ensuring efficient delivery, and addressing immunogenicity and ethical concerns.
    Keywords:  CRISPR-Cas9; Gene editing; Neurodegenerative disorders; Neurological disorders
    DOI:  https://doi.org/10.1007/s12035-026-05966-x
  21. Biology (Basel). 2026 May 29. pii: 854. [Epub ahead of print]15(11):
    Mechanisms by Which Exercise Delays Brain Aging Through Regulation of the Mitochondrial Quality Control System.
    Xinyi Zhu, Lei Shi, Yahong Dong, Yingjie Sun, Qiguan Jin.
      Brain aging is a complex biological process characterised by progressive neuronal and synaptic decline, in which disruption of mitochondrial quality control plays a central role. This system encompasses multiple synergistic components, including mitochondrial biogenesis, dynamic equilibrium, autophagic clearance, and energy metabolism. Aging induces dysfunction across these processes, precipitating mitochondrial fragmentation, functional decline, and energy crises, ultimately driving cognitive deterioration. Exercise is a promising non-pharmacological intervention for preserving brain health during aging, and its benefits may be mediated, at least in part, through modulation of mitochondrial quality control. Specifically, exercise has been shown to activate key signaling pathways such as AMPK/SIRT1/PGC-1α, thereby promoting mitochondrial biogenesis and metabolic adaptation. It may also regulate mitochondrial dynamics and mitophagy via pathways including cAMP/PKA/Drp1 and AMPK/mTOR. In addition, emerging evidence indicates that exercise may influence brain mitochondrial function through activity-dependent regulation of mitochondrial gene expression and systemic signaling factors. Furthermore, this review discusses potential differences between exercise modalities and highlights future directions for personalised intervention strategies, providing a theoretical basis for the application of exercise in delaying brain aging and preventing neurodegenerative diseases.
    Keywords:  brain aging; exercise intervention; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial quality control; neuromuscular axis
    DOI:  https://doi.org/10.3390/biology15110854
  22. Front Neurosci. 2026 ;20 1846384
    Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.
    Julie E V Offerdahl, Danielle E Mor.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders (ND) globally, disproportionately affecting the elderly population. Traditionally viewed as distinct diseases, AD is defined by symptoms of cognitive impairment and dementia with amyloid-β and tau protein pathologies, while PD is defined by motor symptoms and eventual dementia with α-synuclein (α-syn) protein pathology. However, these pathologies are not unique to either disease, with a large fraction of AD patients displaying α-syn inclusions and PD patients displaying abnormal tau. Emerging evidence indicates that pathological tau and α-syn not only frequently coexist in AD and PD, but may engage in synergistic interactions that promote mitochondrial dysfunction, accelerate neurodegeneration, and worsen cognitive decline in both disorders. This review aims to provide both the prevailing views of AD and PD, as well as a detailed discussion of their commonalities with a focus on how tau and α-syn toxicities intersect at the mitochondrial level. Common features of mitochondrial impairment in AD and PD are discussed, including complex I deficiency, oxidative stress, impaired axonal transport, altered mitochondrial dynamics, and mitochondrial DNA damage. While prior reviews have often examined AD and PD independently, this review specifically focuses on the convergent and potentially synergistic interactions between tau and α-syn at the level of mitochondrial dysfunction, highlighting a shared mechanistic framework that may inform unified therapeutic strategies. By studying and understanding the mutual mechanisms underlying neurodegeneration in AD and PD, common treatment strategies can be identified.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondria; tau; α-synuclein
    DOI:  https://doi.org/10.3389/fnins.2026.1846384
  23. Gen Psychiatr. 2026 Jun;39(3): e70023
    Clinical outcomes of mitochondrial-enhancing nutraceutical supplementation in psychiatric disorders: A systematic review.
    Juan Tortajada, Bengisu Kevser Bulduk, Belén Alfonso-Landete, Paula Alcaide-Barriga, Bernat Ballvé-Gelonch, Glòria Garrabou, Elisabet Vilella, Yolanda Alonso, Alba Valiente-Pallejà, Lourdes Martorell.
       Background: Nutraceutical supplementation targeting mitochondrial function has been proposed as a beneficial therapeutic strategy to improve physical and mental health in psychiatric patients.
    Aims: To summarise the results of studies evaluating nutraceutical supplementation targeting mitochondrial function in patients with psychiatric disorders.
    Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed, Embase and Scopus databases from 1 January 2007 to 30 April 2024. Reports were included if they evaluated outcomes of nutraceutical supplementation in patients with psychiatric disorders or related conditions. Additionally, we performed a risk-of-bias analysis of the studies compatible with the RoB2 tool.
    Results: Of the 2061 records identified, 122 studies met the inclusion criteria, evaluating vitamin D3, N-acetylcysteine, acetyl-L-carnitine, coenzyme Q10, alpha-lipoic acid, magnesium, vitamin B6, vitamin B7, folic acid, vitamin B12, vitamin E, vitamin A, vitamin C and vitamin B3. The most studied nutraceuticals were vitamin D3 (27.05%) and N-acetylcysteine (15.6%). Among randomised controlled clinical trials (RCTs), vitamin D3 was the most extensively investigated and accounted for the highest number of trials reporting improvements in clinical outcomes, although findings were heterogeneous. Notably, 14.8% of the studies evaluated combinations of three or more nutraceuticals. Dietary supplements were extensively evaluated for autism spectrum disorder (28 studies), schizophrenia spectrum disorder (27 studies), major depressive disorder or related depressive symptoms (22 studies), attention-deficit hyperactivity disorder (9 studies) and bipolar spectrum disorder (6 studies). A substantial proportion of studies were not RCTs but open-label single-arm trials or case reports. Significant heterogeneity was observed in the nutraceutical components used, treatment duration and the outcomes assessed. Overall, the risk of bias was high, and the methodological quality was generally low.
    Conclusions: Promising findings in nutraceutical studies for psychiatric disorders face challenges, including small sample sizes, short follow-up periods and a lack of treatment standardisation. Future research requires robust RCTs with standardised protocols and validated biomarkers of efficacy.
    Keywords:  N‐acetylcysteine; dietary supplements; mental disorders; mitochondria; vitamin D3
    DOI:  https://doi.org/10.1002/gps3.70023
  24. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
    Shalini Singh, Anisha Sharma, Ravi Kumar Rajan, Manodeep Chakraborty, Ananya Bhattacharjee.
       INTRODUCTION: Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD). PINK1-Parkin-mediated mitophagy is a quality-control system for mitochondria that protects neurons by getting rid of damaged mitochondria. The OMA1-DELE1-HRI axis has recently been recognized as a vital regulatory checkpoint that limits excessive mitophagy and prevents metabolic failure during mitochondrial stress. The aim of this review is to analyze the mechanistic interplay between the PINK1-Parkin pathway and the OMA1-DELE1-HRI signaling axis. This study aims to synthesize current research on the influence of the stress-response pathway on the initiation of mitophagy, maintenance of mitochondrial homeostasis, and neuronal survival in PD.
    METHODS: A comprehensive literature review was conducted of molecular, genetic, and pharmacological studies on OMA1, DELE1, and HRI. A thorough analysis of data from kinome-wide screening assays, genetic knockdown experiments, multi-omics profiling, and structural biology studies was performed to elucidate the regulatory interactions between HRI and PINK1 under mitochondrial stress conditions.
    RESULT: The OMA1-DELE1-HRI pathway stops PINK1 from being stable by controlling how mitochondria make proteins and how they respond to stress. This inhibition serves as a metabolic safeguard that regulates mitophagy levels, preventing harmful overactivation. HRI seems to change PINK1-dependent mitophagy while having little effect on other pathways that clear things at the same time. This suggests that HRI has different substrate preferences and signaling specificity.
    DISCUSSION: The OMA1-DELE1-HRI axis is an important negative regulator of mitophagy that PINK1 and Parkin mediate. It stops too much mitochondrial clearance and metabolic failure in Parkinson's disease. This mechanism preserves bioenergetic homeostasis and promotes neuronal survival, suggesting that HRI is a promising therapeutic target. Inhibitors like ISRIB or heme mimetics may selectively restore mitophagy, thereby enhancing neuroprotection and enabling precision therapies guided by biomarkers such as phosphorylated eIF2.
    CONCLUSION: The OMA1-DELE1-HRI axis is a distinctive regulatory mechanism for mitochondrial quality control, significantly impacting neuroprotection in Parkinson's disease. Understanding its dual role in controlling mitophagy and maintaining bioenergetic homeostasis opens new possibilities for targeted drug development. Subsequent research should focus on structural and pharmacological modifications of HRI to enhance mitophagy while preventing mitochondrial depletion.
    Keywords:  DELE1; HRI (heme-regulated inhibitor kinase); ISR (integrated stress response); OMA1; PINK1; Parkin; Parkinson’s Disease (PD).; mitophagy
    DOI:  https://doi.org/10.2174/0118715273469080260515103009
  25. Front Med (Lausanne). 2026 ;13 1836851
    Editorial: Repurposing for small population needs.
    Viviana Giannuzzi, Christine Fetro, Cécile Ollivier, Oscar Della Pasqua.
      
    Keywords:  orphan medicines; pediatric medicines; rare diseases; repurposing; therapeutic needs
    DOI:  https://doi.org/10.3389/fmed.2026.1836851
  26. Metab Brain Dis. 2026 Jun 10. pii: 132. [Epub ahead of print]41(1):
    Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.
    Mahsa Asadi Anar, Mohammad Amin Fathollahi, Fereshteh Zare, Zahra Farrokhi, Elham Habibzadeh, Saina Hasany, Majid Mirmazloumi, Melika Arab Bafrani, Fatemeh Abedian Kenari, Marjan Falahati, Kamyar Khorsand, Amirali Zakavi, Yasaman Asadollah Salmanpour, Elham Yadegarifard, Farbod Khosravi, Parsa Goudarzi.
      Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by profound disturbances in cerebral energy metabolism. Mitochondrial dysfunction has long been implicated in AD pathophysiology; however, the specific contribution of mitochondrial enzymes in human disease remains fragmented across heterogeneous studies. Enzymes regulating carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, and redox balance represent key metabolic control points whose dysfunction may contribute to neuronal vulnerability. To systematically synthesize human evidence on mitochondrial enzyme alterations in Alzheimer's disease and to evaluate the feasibility of quantitative meta-analysis based on current reporting practices. A systematic literature search was conducted in PubMed, Scopus, and Web of Science from database inception through January 2026 in accordance with PRISMA 2020 guidelines. Studies were included if they investigated mitochondrial enzymes in human postmortem brain tissue, human-derived cellular models, or peripheral biospecimens. Risk of bias was assessed using the ROBINS-I tool. The feasibility of meta-analysis was evaluated based on the availability and comparability of group-level summary statistics. Fifteen studies met the eligibility criteria and were included in the final synthesis. Mitochondrial enzymes involved in carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, redox regulation, and neurotransmitter-linked mitochondrial metabolism were the most frequently investigated targets. Direct enzyme-activity evidence most consistently implicated selected metabolic control points, particularly PDHC and αKGDHC, whereas additional studies supported mitochondrial impairment through protein or post-translational modification changes, respiratory dysfunction, redox alterations, or RNA-regulatory mechanisms. Quantitative meta-analysis was not feasible due to heterogeneous assay methodologies, variable normalization strategies, and inconsistent reporting of group-level summary statistics. Human evidence consistently implicates mitochondrial enzyme dysfunction as a central metabolic feature of Alzheimer's disease. However, progress toward cumulative quantitative synthesis remains limited by methodological heterogeneity and incomplete reporting of enzyme activity outcomes. Standardized measurement and reporting of mitochondrial enzyme alterations will be essential to advance mechanistic understanding and enable future meta-analytic integration.
    Keywords:  Alzheimer’s disease; Mitochondrial enzymes; Neurodegeneration; Oxidative phosphorylation; Tricarboxylic acid cycle
    DOI:  https://doi.org/10.1007/s11011-026-01895-9
  27. JMIR Med Educ. 2026 Jun 12. 12 e79027
    Main Recommendations for Developing Education and Awareness Strategies for Rare Diseases: Scoping Review.
    Diego Bettiol Yamada, Tatiana Takahasi Komoto, Vinícius Costa Lima, Julio Souza, Michele de Souza Seixas, Victor Cassão, Victor Evangelista de Faria Ferraz, Bibiana Mello de Oliveira, Têmis Maria Félix, Domingos Alves.
       BACKGROUND: According to the World Health Organization, education and awareness are essential components of public health promotion strategies. In the context of rare diseases (RDs), these actions are particularly critical because of persistent stigma, fragmented knowledge, and the frequent absence of consolidated clinical and organizational protocols. These gaps often result in inappropriate referrals, inefficient care pathways, unnecessary procedures, and delays in diagnosis, negatively affecting health outcomes and quality of life.
    OBJECTIVE: This study aimed to identify and systematize the main recommendations for health education and awareness in the field of RDs, supporting the development of health care programs, public policies, and strategic initiatives.
    METHODS: We formulated the research question using the Population, Concept, and Context framework. This scoping review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines to ensure methodological transparency. Eligible records included peer-reviewed research articles of any design and official documents published in Portuguese, English, or Spanish, with no time restrictions. Records that did not address the research question, lacked sufficient rigor, or focused exclusively on specific subgroups of RDs were excluded. Searches were performed in PubMed/MEDLINE, Scopus, Embase, Web of Science, as well as gray literature. Study selection and data extraction were conducted by the research team, with disagreements resolved and the included sources reviewed by an RDs expert. Data were thematically categorized by consensus, and descriptive statistics were used to summarize findings.
    RESULTS: A total of 58 sources of evidence were included. Among the identified recommendations related to education and awareness, most sources focused on professional education and training (49/58, 84.4%), followed by public policies and intersectoral integration (36/58, 62%), education and awareness for the general population (28/58, 48.2%), digital technologies (27/58, 46.5%), emotional support and experience sharing (20/58, 34.4%), and awareness events and dates (8/58, 13.7%). Percentages exceed 100% because individual sources could report multiple recommendations. Overall, the literature emphasizes integrating RDs content into educational initiatives and strengthening professional competencies, intersectoral collaboration, digital technologies, and broader awareness strategies.
    CONCLUSIONS: This scoping review systematically mapped and organized recommendations from diverse sources of evidence on strategies for health education and awareness related to RDs. It synthesizes heterogeneous evidence using a structured approach to provide a comprehensive overview of strategies in this field, consolidating dispersed knowledge into a coherent body of evidence. The findings may inform improvements in health services, as well as professional and managerial practices, and initiatives aimed at supporting patients, families, and advocacy groups involved in RDs, with potential implications for strengthening diagnostic processes, referral coordination, and more equitable access to information and care.
    Keywords:  educational strategies; health awareness; health education; public health recommendations; rare diseases
    DOI:  https://doi.org/10.2196/79027
  28. Nature. 2026 Jun;654(8119): 605-606
    Mitochondria tethered to the nucleus secure its energy supply.
    Philippa Clarke, Sophie Trefely.
      
    Keywords:  Cell biology; Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01587-5
  29. Redox Biol. 2026 Jun 05. pii: S2213-2317(26)00245-4. [Epub ahead of print]95 104247
    Mitophagy-mediated immune evasion: Shared strategies of pathogens.
    Jun Li, Weijian Li, Dan Wang, Yulan Liu.
      Mitophagy selectively eliminates dysfunctional mitochondria, playing a pivotal role in mitochondrial quality control and cellular homeostasis. Emerging evidence reveals that certain pathogens exploit mitophagy to evade host immune defenses. Here, we provide novel insights into the regulatory mechanisms of mitophagy by integrating it with mitochondrial dynamics, and systematically review the mechanisms by which intracellular bacteria, viruses, and parasites utilize mitophagy to subvert host innate immunity. Notably, some pathogens dynamically regulate mitophagy at different infection stages to facilitate their survival, and the mitophagy show a positive correlation with mitochondrial fission/fragmentation. This review further summarizes four therapeutic strategies to counteract pathogen-induced immune evasion via mitophagy: 1) pharmacological modulation of mitophagy pathways; 2) mitochondria-targeted nanomaterials delivery systems; 3) mitochondria transplantation; 4) nanoengineered mitochondria. Moreover, two core mechanistic questions that remain to be addressed: (1) The mechanisms of time-dependent mitophagy-mediated immune evasion during infection, and (2) the mechanistic connection between mitochondrial dynamics and mitophagy. Future studies could employ label-free holographic tomography microscopy combined with artificial intelligence to visualize and quantify pathogen-induced subcellular alterations, enhancing our understanding of how mitophagy is manipulated, particularly through stage-specific regulation. These insights may open new avenues for treating infections resistant to conventional therapies.
    Keywords:  Immune evasion; Mitophagy; Pathogen infection; Therapy
    DOI:  https://doi.org/10.1016/j.redox.2026.104247
  30. Psychoneuroendocrinology. 2026 Jun 09. pii: S0306-4530(26)00196-4. [Epub ahead of print]191 107936
    Associations between adverse childhood experiences, mitochondrial DNA copy number and atopic disease in children.
    Laura M Díaz, Neeta Thakur, Samantha C Lewis, Morgan Ye, David J X González, Nicole R Bush, Dayna Long, Danielle Hessler, Rosemarie de la Rosa.
       BACKGROUND: Exposure to adverse childhood experiences (ACEs) chronically activates the neuroendocrine stress response, which can perturb mitochondrial DNA and may drive risk of atopic disease among children. We sought to examine the association between ACEs and mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial DNA abundance, and to characterize associations between mtDNAcn and atopic disease (atopic dermatitis, rhinitis and asthma) in a pediatric population.
    METHODS: We performed cross-sectional analyses in a sample of 226 children enrolled in the Pediatric ACEs Screening and Resiliency Study who were recruited during well-child visits. Caregivers reported whether their child was exposed to ACEs or ever diagnosed with asthma, atopic dermatitis, or allergic rhinitis. MtDNAcn was measured in buccal swabs using qPCR. Multivariate linear and logistic regression analyses were used to measure associations with ACEs, mtDNAcn and atopic disease.
    RESULTS: Children in our study were predominantly non-Hispanic Black, female, with a mean age of 5.6 years (SD = 3.6), and most caregivers had completed high school. We found that greater ACEs exposure was associated with a decrement in children's mtDNAcn. We also observed mtDNAcn was inversely associated with odds of children having atopic dermatitis but not associated with asthma or allergic rhinitis.
    CONCLUSION: Our results suggest that greater exposure to ACEs is associated with lower mtDNAcn in children, and that having lower mtDNAcn is associated with greater odds of atopic dermatitis. Future work should measure other biomarkers of mitochondrial stress to understand this potential mechanistic relationship between adverse childhood experiences and atopic disease in children.
    Keywords:  Atopic dermatitis; Atopic disease; Childhood adversity; Eczema; Mitochondrial DNA; Psychosocial stress
    DOI:  https://doi.org/10.1016/j.psyneuen.2026.107936
  31. Biochem Pharmacol. 2026 Jun 12. pii: S0006-2952(26)00501-0. [Epub ahead of print] 118164
    Mitochondrial dysfunction in pulmonary fibrosis: from mechanisms to therapeutic opportunities.
    Xingyu Jin, Le Sang, Jiayi Zhu, Zuoqaun Zhong, Jian Sun.
      Pulmonary fibrosis (PF) is a progressive and often fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible remodeling of lung architecture. Although current antifibrotic therapies can slow disease progression, they remain unable to halt or reverse fibrosis, underscoring the need for a deeper mechanistic understanding and new therapeutic strategies. Mitochondria are increasingly recognized as central regulators of PF pathogenesis, extending beyond their canonical role in energy production. Emerging evidence indicates that mitochondrial dysfunction contributes to epithelial injury, fibroblast activation, immune dysregulation, and the persistence of a profibrotic microenvironment. Alterations in mitochondrial biogenesis, dynamics, mitophagy, redox homeostasis, and oxidative phosphorylation constitute interconnected processes that converge on mitochondrial quality control (MQC) failure. These defects may establish self-amplifying pathogenic circuits that sustain fibrotic progression. Notably, mitochondrial dysfunction in PF shows clear cell type-dependent features, supporting the concept that mitochondrial dysregulation operates within a multicellular network rather than as an isolated cellular defect. Therapeutically, targeting mitochondrial pathways-including enhancement of biogenesis, correction of dynamic imbalance, restoration of mitophagy, and redox modulation-has demonstrated antifibrotic potential in experimental models. However, key questions remain regarding causality, stage-specific roles, and the long-term safety of mitochondrial modulation. This review summarizes recent advances in understanding mitochondrial dysfunction in PF, highlights its integration across metabolic and signaling networks, and discusses emerging mitochondria-targeted interventions. A systems-level perspective on mitochondrial quality control may help refine future research directions and support the development of more precise antifibrotic therapies.
    Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.bcp.2026.118164
  32. Cell Mol Life Sci. 2026 Jun 10. pii: 249. [Epub ahead of print]83(1):
    Mitochondrial complex I deficiency-associated diseases and models.
    Lena Jentsch, Natascia Ventura.
      Mitochondrial complex I is the first and largest enzyme of the mitochondrial respiratory chain and thus plays a crucial role in cellular energy metabolism. Defects in the mitochondrial respiratory chain, and in particular CI deficiency, are the primary cause of human mitochondrial associated diseases, which most often presents as severe neurometabolic disorders with fatal outcome. Up to this date the diagnosis and treatment of CI deficiency-associated diseases is challenging, only limited symptomatic therapies exist and no cures are available. This review aims at summarizing current knowledge on the genetic basis of CI deficiency-associated diseases and available experimental disease models. Most common human disorders caused by CI deficiency range from Leigh syndrome to MELAS and LHON, all characterized by genetic and symptomatic heterogeneity. So far, in vivo studies on non-mammalian organisms and mouse models, as well as in vitro studies on patient derived fibroblasts, cybrids and human-induced pluripotent stem cells have mainly facilitated the research of CI deficiency. These model systems provide insights on molecular mechanisms in mitochondrial disease and approaches for potential therapeutic intervention strategies. However, current research is limited by translational relevance of existing disease models, varying degrees of heteroplasmy and tissue specific effects characteristic of mitochondrial diseases, so that basic disease mechanisms still remain poorly understood. To overcome these challenges there is an urgent need for in vivo and in vitro human relevant models to aid the development of effective therapeutic interventions and potential cures of CI deficiency-associated diseases.
    Keywords:  Mammalian cell models; Mitochondrial complex I; Mitochondriopathies; Model organisms
    DOI:  https://doi.org/10.1007/s00018-026-06169-2
  33. Genome Med. 2026 Jun 11. pii: 83. [Epub ahead of print]18(1):
    Genetically supported drug target prioritization for rare diseases.
    Robert Chen, Áine Duffy, Matthew Mort, David N Cooper, Ghislain Rocheleau, Daniel M Jordan, Ron Do.
      RareGPS is a machine-learning framework prioritizing drug targets for rare and uncommon diseases, integrating 11 genetic, clinical, and experimental evidence sources. It uses the full distribution of genetic associations across allele-frequency bins in an allelic-series model. Across 161 phenotypes, RareGPS outperforms existing resources for predicting drug indications and clinical trial progression; top 1% targets show 58-fold higher likelihood of advancing from nonindicated to phase IV and 8-fold from phase I to IV versus the middle 50%. We validated RareGPS using prescriptome analyses in two million patients and an independent literature evaluation tool (AMELIE). We publish predictions for 3,021,965 gene-phenotype pairs.
    Keywords:  Drug Discovery; Electronic Health Records; Genetic Association Studies; Machine Learning; Off-Label Use; Rare Diseases
    DOI:  https://doi.org/10.1186/s13073-026-01671-5
  34. JCI Insight. 2026 Jun 09. pii: e196134. [Epub ahead of print]
    Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome.
    Katharina B Kuentzel, Ana Vranešević, Samuel Aj Trammell, Fabian Finger, Jesper F Havelund, Yvette L Schooneveldt, Ivan Bradić, Nicoline R Andersen, Anna S Hassing, Katja T Michler, Martin R Larsen, Zachary Gerhart-Hines, Steven M Claypool, Jonas T Treebak, Andreas M Fritzen, Matthew P Gillum, Steen Larsen, Nils Færgeman, Trisha J Grevengoed.
      The composition of mitochondrial membrane lipids is crucial to cellular respiration, as seen in Barth syndrome (BTHS), a rare disease affecting skeletal muscle, heart, and neutrophils. In BTHS, mutations in the tafazzin (TAZ) gene reduce remodeling of the mitochondrial phospholipid, cardiolipin, causing mitochondrial dysfunction in skeletal muscle and heart. Here, we investigated effects of altering polyunsaturated fatty acid content in cardiolipin using preclinical models of BTHS. In vitro, the absence of TAZ did not impair omega-3 fatty acid incorporation into cardiolipin and resulted in increased turnover of these acyl chains. To examine this in a functional model, we generated a muscle-specific knockout mouse of TAZ (TAZ MKO), which recapitulated the human phenotype in skeletal muscle. Supplementing the diet of TAZ MKO with fish-oil-derived omega-3 fatty acids prevented lean mass loss, improved mitochondrial respiration, altered mitochondrial structure, and revealed moderate improvements in the stress response. Surprisingly, no diet-induced changes to cardiolipin species were observed in the TAZ MKO, but other phospholipids were altered by both genotype and diet, revealing complex regulation and potential compensation. Overall, this work provides evidence that omega-3 fatty acid supplementation is beneficial in muscle lacking TAZ to improve quality of life when added to current BTHS treatments.
    Keywords:  Lipidomics; Metabolism; Mitochondria; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.196134
  35. Orphanet J Rare Dis. 2026 Jun 09.
    "If I go down, if I crumble, then everybody does" - identity crisis and emotional strain in parents of children with rare and undiagnosed conditions: a qualitative study.
    Tara Maria Hoffmann, Bettina Friedrich, Celine Lewis.
       BACKGROUND: Caring for a child with a rare condition can significantly impact parents' emotional health, yet research on the emotional impact is limited. This qualitative interview study sought to investigate the lived experiences of parents who are experiencing higher psychological burden. Participants were parents of undiagnosed children undergoing whole genome sequencing (WGS) through the Genomic Medicine Service (GMS) across multiple NHS sites in England. Parents were purposively sampled to select those scoring poorly on validated measures of anxiety, family impact and/or resilience (GAD-7, PedsQL family functioning, BRS). We interviewed 24 parents after testing but prior to the return of WGS results. Questions focused on understanding their lived experience, in particular the emotional impact of their child's condition and how they coped day-to-day.
    RESULTS: Semi-structured interviews were transcribed and analysed using reflexive thematic analysis, leading to the generation of the central organising concept: "The construction of a caregiver identity: Torn between being a 'hero(ine)' and being a parent." Parents' experiences as caregivers often involved a significant re-evaluation of their parental role, as they sought to provide love and support while also adjusting to changes in their envisioned family life. Societal expectations, along with the complex challenges of navigating the health and social care systems, contributed to emotional strain. In particular, mothers often adapted their personal identities to embody a 'heroic' caregiving role. The anxiety caused by the uncertainty surrounding their child's condition was also found to affect parents' mental health. Areas for psychological interventions and recommendations to support parents' mental health are identified.
    CONCLUSIONS: Further research is needed to explore how the return of genomic sequencing results impacts parents' emotional wellbeing, and whether and which psychological counselling modalities throughout the journey might reduce emotional distress.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Emotional wellbeing; Family dynamics; Genomic sequencing; Mental health; Parent caregivers; Psychological counselling; Psychosocial insights; Rare condition; Uncertainty; Undiagnosed condition
    DOI:  https://doi.org/10.1186/s13023-026-04384-5
  36. Int J Mol Sci. 2026 Jun 05. pii: 5127. [Epub ahead of print]27(11):
    Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial.
    Lucia Chico, Piervito Lopriore, Giulia Cecchi, Adriana Meli, Clara Bernardini, Linda Balestrini, Maico Polzella, Vincenzo Montano, Michelangelo Mancuso.
      Primary mitochondrial diseases (PMD) are rare disorders with limited therapeutic options. Coenzyme Q10 (CoQ10) supplementation is widely used, although formulation differences can affect absorption and efficacy. This open-label pilot feasibility trial evaluated a food for special medical purposes (FSMP) containing high-dose CoQ10 (250 mg per capsule) in patients with PMD. Ten patients (mean age: 55.5 ± 8.6 years) were enrolled. Serum/plasma biomarkers, including CoQ10, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), ferric-reducing antioxidant power (FRAP), total sulfhydryl groups (t-SH), and advanced oxidation protein products (AOPP), were assessed at baseline (T0, after ≥30 days of conventional ubidecarenone) and after 30 days of FSMP administration (T1). Fatigue severity scale (FSS) and 5-times sit-to-stand test (5xSST) were evaluated at both timepoints. FSMP was administered at 250 or 500 mg/day. Twenty sex- and age-matched healthy controls were included for CoQ10 comparison. Absolute CoQ10 concentrations remained stable overall at T1, with all patients maintaining levels above 390 ng/mL (100% vs. 60% at T0), although concentrations remained lower than in healthy controls (p < 0.01). Dose-normalized CoQ10 exposure was significantly higher with FSMP versus conventional ubidecarenone (p < 0.001, Cohen's d = 7.31). FGF21, GDF15, AOPP, and t-SH remained unchanged, whereas FRAP increased at T1 (p < 0.01). No significant changes were observed in 5xSST and FSS. Exploratory analyses indicated inter-individual variability in functional responses. FSMP was associated with higher dose-normalized systemic CoQ10 exposure, more consistent circulating CoQ10, and increased FRAP levels. Its simplified dosing regimen may support long-term adherence. Larger studies are warranted to validate these preliminary findings.
    Keywords:  antioxidants; coenzyme Q10; food for special medical purposes; mitochondrial diseases
    DOI:  https://doi.org/10.3390/ijms27115127
  37. Public Health Wkly Rep. 2026 ;19(21): 898-920
    National Rare Disease Registration Project in the Republic of Korea: Current Status and Policy Directions.
    Jeong-Hyeon Ha, Do-Hyeon Park, Jee-Young Kim.
       Objectives: Rare diseases are characterized by having a small number of patients with the given condition and the frequent absence of established diagnostic and therapeutic guidelines, which makes it difficult to build the evidence base that is necessary for patient management and policy development. In response to this, the Korea Disease Control and Prevention Agency (KDCA) launched the National Rare Disease Registration Project, which is intended to systematically collect and analyze data on patients' diagnostic and treatment status as well as the characteristics of the disease.
    Methods: This study evaluated the achievements and limitations of the project drawing on the implementation results of the pilot and main phase, on-site assessments, and international case studies.
    Results: The project achieved key milestones through the establishment of an operational framework, the development of a registry management system, and links it with related institutional systems to facilitate data collection and analysis. However, certain challenges remain, including the limited amount of data coverage due to institutional workload and lack of dedicated personnel, the need for standardized registration criteria, and the expansion of linked administrative and clinical data.
    Conclusions: Moving forward, the KDCA aims to establish a systematic and standardized data collection foundation to secure reliable, large-scale datasets and strengthen the institutional framework for data utilization, contributing to the development of evidence-based rare disease management policies.
    Keywords:  Policy; Rare disease; Rare disease registry; Specialized rare disease institutes; Statistics
    DOI:  https://doi.org/10.56786/PHWR.2026.19.21.2
  38. Int J Mol Med. 2026 Aug;pii: 216. [Epub ahead of print]58(2):
    Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review).
    Yaping Wu, Hao Yu, Ling Xia, Li Yang, Yu Zhou, Qian Yu.
      Metabolic reprogramming is fundamental to immune cell function, yet the spatial architecture that organizes these metabolic states remains incompletely defined. Rather than functioning as isolated bioenergetic units, mitochondria act as spatial hubs embedded within dynamic organelle networks that coordinate immuno‑metabolic signaling. In the present review, the structural and functional basis of mitochondrial organelle interfaces were delineated, including membrane contact sites and vesicular trafficking pathways, with the endoplasmic reticulum, lysosomes, peroxisomes, lipid droplets and the nucleus. It was discussed how these interfaces generate specialized microdomains for the localized exchange of calcium, lipids and redox signals, thereby shaping innate and adaptive effector programs. It was further highlighted how mitochondria‑derived vesicles and mitochondria‑containing extracellular vesicles extend this regulatory axis, linking intracellular organelle crosstalk directly to systemic tissue homeostasis. Crucially, maladaptive decoupling of these interface circuits emerges as a recurrent feature of infection, sepsis, cancer, autoimmunity and chronic inflammation diseases. Finally, emerging interface‑targeted therapeutic strategies were evaluated and the technical methodologies required to validate nanoscale interactions were critically assessed. By conceptualizing immunometabolism as a spatially coordinated process, the prsent review provides a comprehensive landscape for decoding immune signaling and identifies tractable avenues for precision immunotherapy.
    Keywords:  cancer immunity; immunometabolism; inflammation; innate immunity; mitochondria; mitochondria-associated membrane; vesicle trafficking
    DOI:  https://doi.org/10.3892/ijmm.2026.5887
  39. Hum Reprod. 2026 Jun 11. pii: deag091. [Epub ahead of print]
    Oocyte aging, the mitochondrial downward spiral, and the path to responsible innovation.
    Sebastiaan Mastenbroek, Geert Hamer.
      
    Keywords:  IVF; aging; embryo culture media; innovation; mitochondria
    DOI:  https://doi.org/10.1093/humrep/deag091
  40. Biochim Biophys Acta Mol Cell Res. 2026 Jun 09. pii: S0167-4889(26)00069-8. [Epub ahead of print] 120171
    Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
    Ahram Ahn, Seungwoo Hong, Michele Brischigliaro, Flavia Fontanesi, Antoni Barrientos.
      Mammalian mitochondrial gene expression operates within an unusually compact genomic architecture in which most regulatory information must be encoded within or immediately adjacent to protein-coding sequences. In this context, mitochondrial mRNAs function not merely as templates for translation but as structured molecules whose folding landscape contributes to multiple stages of gene expression. Recent advances in chemical probing, mutational profiling, and mitoribosome profiling have begun to disclose the human mitochondrial mRNA structurome in its native organellar context, revealing a transcriptome that is broadly accessible yet punctuated by localized structural elements and alternative conformational states. These studies indicate that RNA structure contributes to translation initiation on leaderless transcripts, elongation kinetics, translational coupling across bicistronic junctions, and dynamic remodeling during membrane protein synthesis. They also highlight the role of RNA-binding proteins, including LRPPRC-SLIRP and related factors, in maintaining a translation-competent folding environment. In this review, we discuss the structural organization of mitochondrial mRNAs, the experimental approaches that enabled its analysis, and emerging mechanistic links between RNA folding, translational regulation, and respiratory chain biogenesis. We further discuss how alterations in mt-mRNA structure may represent an underappreciated determinant of mitochondrial disease and consider implications for future diagnostic and therapeutic strategies.
    Keywords:  Bicistronic transcripts; Mitochondrial RNA folding; Mitochondrial RNA processing; Mitochondrial RNA structurome; Mitochondrial gene expression; Mitochondrial translation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120171
  41. Mov Disord Clin Pract. 2026 Jun 08.
    Cerebellar Ataxia and Chorea: Genetic Etiologies and Key Considerations for Diagnosis and Management.
    Adolfo Ramirez-Zamora, Mallory Eisel, Anson Wang, Matthew Vasquez, Matthew Burns, Lauren Fanty, Bhavana Patel, E Lee Kugelmann, Matthew Farrer, Shannon Chiu, S H Subramony, Michael S Okun, Takashi Tsuboi.
       BACKGROUND: The differential diagnosis of progressive ataxia is broad. Multiple degenerative, inherited, and acquired causes of ataxia must be considered. The presence of chorea as part of the clinical phenotype provides invaluable clinical information which may help to narrow the differential.
    OBJECTIVES: There are a limited number of conditions with both prominent chorea and cerebellar ataxia, and it is essential for clinicians to recognize these disorders to direct early disease-specific treatment. We aim to identify these conditions and propose a diagnostic approach.
    METHODS: We conducted a literature search on PubMed from January 2000 to January 2025 using search terms including "ataxia," "cerebellar ataxia," "chorea," and "ataxia-chorea syndromes."
    RESULTS: We identify and examine the key clinical features of several inherited disorders with this unique clinical phenotype, including spinocerebellar ataxias, Huntington's disease, dentatorubral-pallidoluysian atrophy, ataxia telangiectasia, disorders of brain iron metabolism, Wilson's disease, Niemann-Pick disease type C, ataxia with oculomotor apraxia, glucose transporter type 1 deficiency, mitochondrial cytopathies, along with other rare genetic and metabolic disorders. We provide insight into diagnostic approach and genetic testing with focus on identifying treatable conditions.
    CONCLUSIONS: Features unique to each disorder are discussed, along with current treatment and diagnostic considerations.
    Keywords:  ataxia; chorea; movement disorders; spinocerebellar ataxia
    DOI:  https://doi.org/10.1002/mdc3.70689
  42. bioRxiv. 2026 Jun 07. pii: 2026.06.03.729837. [Epub ahead of print]
    Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
    Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Ushodaya Mattam, Omar Chaudhry, Karleigh G Porter, Saanvi Maadaadi, Dina Secic, Megan Bischoff, Karthickeyan Chella Krishnan, Rhett Kovall, Tom Cunningham, Maria Czyzyk-Krzeska, Katherine E Vest.
      Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 induced prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a critical assembly protein for both COX copper cofactors, or by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is rescued by copper supplementation or expression of an SLC25A3 variant that transports copper but not phosphate. Taken together these data support a model wherein copper transport by SLC25A3 and copper delivery to COX is critical for survival in mature myotubes.
    DOI:  https://doi.org/10.64898/2026.06.03.729837
  43. J Control Release. 2026 Jun 06. pii: S0168-3659(26)00484-0. [Epub ahead of print] 115081
    Targeted degradation of intracellular organelles: Strategies and implications.
    Yifei Lu, Yunting Zhang, Keran Wang, Renhe Liu, Yao Fu.
      Organelle dysfunction is increasingly recognized as a primary driver of neurodegeneration, metabolic disorders, and cancer. The selective elimination of these organelles is primarily mediated by the autophagy-lysosome pathway. Targeted organelle degradation (TOD) has thus emerged as a powerful strategy to harness and redirect this machinery, enabling the selective clearance of organelles through engineered cargo recognition and lysosomal delivery. In this review, we aim to establish a mechanism-driven classification framework for TOD. We comprehensively survey current strategies and systematically integrate representative modalities, including autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), nanoparticle-based organelle targeting chimeras (NanoTACs), and related platforms within this framework. Key experimental strategies for assessing degradation efficiency are critically compared, with a particular focus on mitochondria and lipid droplets as well-developed case studies. Finally, we discuss the potential for expanding TOD to other organelles such as the endoplasmic reticulum and Golgi apparatus, and we highlight key challenges and future directions to drive continued advancement in the field.
    Keywords:  ATTEC; AUTAC; Lipophagy; Mitophagy; NanoTAC; Selective autophagy; Targeted organelle degradation
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115081
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