bims-polgdi 2026-06-07 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2026–06–07
thirty-six papers selected by
Luca Bolliger, lxBio

Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?
Emerging therapeutic strategies for mitochondrial DNA-related diseases.
Consequences of defective mitochondrial protein import: From targeting signals to pathology.
Regulation of mitochondrial protein translocases.
Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset.
Orphan Designation for Drugs Approved in the United States and European Union: A Comparative Analysis.
Mitochondrial donation and human reproduction: Clinical, ethical and legal aspects.
Functional specialization within the mitochondrial network: Are all mitochondria created equal?
Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?
Mitochondria across the globe: Diverse voices, shared energy.
In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan.
Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson's disease.
POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.
Mutations Causative of CPEO Differentially Engage Innate Immunity Sensors.
The "China model" for rare disease governance: Policy framework, local implementation, and pathways for optimization.
Adjunctive transcranial DC stimulation in the management of refractory drug-resistant focal epilepsy in POLG mitochondrial disease: A case series.
Clinical pharmacology insights from recent cell and gene therapy approvals relevant to pediatrics.
Deubiquitinases at organelle quality control bottlenecks in neurodegeneration.
Modelling Human Proteostasis and Organelle Homeostasis Disorders in Yeast and Its Application in Drug Discovery.
Cognitive and behavioral clinical outcome assessments in children with developmental and epileptic encephalopathies: Issues and instruments.
Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
Evolving insights into mitochondrial presence in RBC in sickle cell disease: Red blood cell and reticulocyte pathophysiology, therapeutic strategies, and future directions.
Policy lessons regarding medical security for rare diseases inChina: Insights from Zhejiang Province through the multiplestreams framework.
Genotype before phenotype? Reversing the diagnostic odyssey in genomic medicine.
A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia.
Mitochondria across the globe: Diverse voices, shared energy.
Altered mitochondrial functionality in metabolic disorders: insights from Drosophila studies.
COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
Gene Editing Technologies for Hereditary Hearing Loss: Prospects and Challenges.
Mitochondrial transplantation as an immunomodulatory strategy: Modulating polymorphonuclear leukocytes for functional tissue regeneration.
Ketogenic diet in children with epilepsy: A bibliometric and science mapping analysis of global research.
Identifying and targeting abnormal mitochondrial localization associated with psychosis.
The Biobank Rare Variant consortium powers the discovery of rare genetic associations through global collaboration.
Circadian Rhythms, NRF2 Signalling and Redox Homeostasis: A Holy Grail for a Healthy Life Course?
Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.

Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00152-X. [Epub ahead of print]38(6): 1079-1080

Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?

Jirair K Bedoyan, Jerry Vockley.

After decades without approved pharmacotherapies, mitochondrial disease care is shifting. Two FDA approvals emerged in 1 year, elamipretide (Forzinity) for Barth syndrome and deoxynucleoside therapy (Kygevvi) for TK2 deficiency, with another under review. Zink et al.1 suggest sildenafil (Viagra) could treat Leigh syndrome, highlighting drug repurposing for severe pediatric mitochondrial disease.

DOI: https://doi.org/10.1016/j.cmet.2026.04.014
Cell Rep Med. 2026 Jun 02. pii: S2666-3791(26)00258-2. [Epub ahead of print] 102841

Emerging therapeutic strategies for mitochondrial DNA-related diseases.

Rubing Shi, Micol Falabella, Jana Aref, Michael G Hanna, Michal Minczuk, Carlo Viscomi, Robert D S Pitceathly.

  Primary mitochondrial diseases (PMDs) are among the most common inherited metabolic disorders, affecting approximately 1 in 4,300 individuals. They result from pathogenic variants in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that disrupt oxidative phosphorylation and lead to multisystem disease. Although advances in genomic testing have significantly improved diagnostic rates in PMDs, effective disease-modifying therapies remain limited. Therapeutic development increasingly focuses on mtDNA-targeted approaches because mtDNA variants are a major cause of disease and may offer opportunities for targeted intervention. Current strategies include allotopic expression, mitochondria-targeted nucleases, and next-generation base editors, which reduce or correct pathogenic mtDNA variants. Other emerging approaches include pharmacological modulation of heteroplasmy, reproductive techniques such as mitochondrial donation, and therapeutic strategies based on mitochondrial transplantation. This review summarizes advances in gene editing, pharmacological approaches, and reproductive and mitochondrial transplantation strategies for mtDNA-related PMDs, highlighting progress toward more targeted interventions.

Keywords:  gene therapy; mitochondrial DNA; mitochondrial replacement therapy; primary mitochondrial diseases

DOI:  https://doi.org/10.1016/j.xcrm.2026.102841
Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546

Consequences of defective mitochondrial protein import: From targeting signals to pathology.

Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.

  Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.

Keywords:  Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex

DOI:  https://doi.org/10.1016/j.bbamem.2026.184546
Protein Sci. 2026 Jul;35(7): e70662

Regulation of mitochondrial protein translocases.

Lea Bertgen, Agnieszka Chacinska.

  Mitochondria are essential for cellular health, and their function is underlain by the plasticity of the mitochondrial proteome. Most mitochondrial proteins are nuclear encoded, synthesized in the cytosol, and require precise import into mitochondrial subcompartments to fulfill their proper functions. Multimeric mitochondrial translocases ensure accurate protein localization and membrane integration. Recent work has begun to reveal how translocase activity and composition are dynamically regulated within mammalian cells. This review discusses regulatory mechanisms, including phosphorylation and protein degradation, that emerge as important players in adjusting the capacity and/or selectivity of the mitochondrial translocase to metabolic demands. Particular emphasis will be placed on the TIM23 complex as an emerging regulator of the inner membrane and matrix proteome composition.

Keywords:  TIM23 complex; TOM complex; mitochondria; mitochondrial biogenesis; proteases; protein translocases; protein turnover

DOI:  https://doi.org/10.1002/pro.70662
bioRxiv. 2026 May 19. pii: 2026.05.15.725546. [Epub ahead of print]

Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset.

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium

Rare disease research and diagnosis rely on the integration of genomic and phenotypic data generated across diverse clinical sites; however, the absence of widely adopted standards for representing genomic data and associated metadata has limited data interoperability, reuse, and cross-study analysis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was established to investigate challenging rare disease cases and evaluate emerging multi-omic technologies for clinical translation. To support coordinated data integration across distributed research sites, we developed a common Consortium Data Model in partnership with domain experts to standardize the capture of participant-, family-, phenotype- and assay-level metadata, with a particular emphasis on using a modular architecture to support linking of multiple data versions from multiple omic technologies to a single individual and attribution of a genetic finding to the specific technology used for its initial discovery. Adoption of the GREGoR Data Model has enabled continued generation and public release of a harmonized, analysis-ready Consortium Dataset. The most recent release includes phenotypic, family and multi-omic data from 12,292 participants in 5,029 families. Other rare disease data sharing efforts are beginning to adopt this data model which will facilitate cross consortium analyses and empower rare disease research. This work demonstrates that a collaborative, flexible, and scalable data model can enable large-scale rare disease research, facilitate cross-center data harmonization, and enable data interoperability.

DOI: https://doi.org/10.64898/2026.05.15.725546
Clin Pharmacol Ther. 2026 May 31.

Orphan Designation for Drugs Approved in the United States and European Union: A Comparative Analysis.

Enrico Costa, Joseph S Ross, Aaron S Kesselheim.

Rare disease drugs represent a significant portion of new drug approvals, but the United States and European Union (EU) have differing approaches to Orphan Drug designations, impacting application fees and market exclusivity. This cross-sectional study analyzed the first rare disease drug approvals in the United States and EU from 2011 to 2020 using data from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) databases, describing similarities and differences in how both regions grant Orphan Drug designations. Out of 344 rare disease drug approvals, 336 (97.7%) were licensed by the FDA with Orphan Drug designations, 139 (40.4%) by the EMA with Orphan Drug designations; 131 (38.1%) were licensed with Orphan Drug designations by both the FDA and EMA, while 103 (29.9%) were approved in the EU without this designation. Additionally, 110 (32.0%) had approval from one agency only, with 102 (29.7%) by the FDA and 8 (2.3%) by the EMA. Both agencies were most consistent in granting Orphan Drug designations for advanced therapies (75.0%) and genetic diseases (55.4%). EMA approvals were lacking for tropical diseases (12.7%), while EU designations were often absent for diseases not considered distinct entities, such as subsets of cancers or pediatric indications of prevalent diseases. These findings reflect the differing regulatory frameworks and practices between the United States and the EU. Policymakers seeking to improve rare disease drug approval could prioritize incentives for the development of treatments for truly rare diseases as opposed to subsets of more common conditions for which incentives have already been established or create pathways that tackle scientific and societal challenges.

DOI: https://doi.org/10.1002/cpt.70349
Mitochondrion. 2026 Jun 02. pii: S1567-7249(26)00065-6. [Epub ahead of print]91 102175

Mitochondrial donation and human reproduction: Clinical, ethical and legal aspects.

Roberto Piergentili, Gianluca Montanari Vergallo, Enrico Marinelli, Elisabetta Pelagatti, Stefano Sechi, Maria Lucia Furnari, Giuseppe Gullo, Simona Zaami.

  Women carriers of a disease caused by changes in mitochondrial DNA (mtDNA) seeking to achieve motherhood, currently have three options: (i) prenatal testing, via CVS or amniocentesis for women aiming to conceive naturally and test the health of the fetus during development; (ii) preimplantation genetic testing (PGT), which allows for the selection of embryos without mtDNA mutations or with the lowest possible chance of pathogenic mtDNA presence, and (iii) egg donation. The United Kingdom and Australia have approved two methods for replacing mutant mtDNA: maternal spindle transfer (MST) and pronuclear transfer (PNT). In MST, the maternal nuclear DNA is transferred from the patient's oocyte into an enucleated donor oocyte from which the maternal spindle has been removed. The reconstituted egg would then be fertilized by the intended father's sperm and the newly formed embryo implanted in the intended mother. In PNT, first mother's eggs are fertilized using the intended father's sperm, then the pronuclei of the embryo are transferred to a recipient embryo, from which the pronuclei have been removed. This paper will illustrate the basis of mtDNA-related diseases and the approaches to minimize transmission to offspring. Then, it will focus on the main ethical and legal/regulatory complexities as to various types of nuclear transfer to prevent mtDNA diseases, the risks to the child and future generations, and the issues related to germline changing. Our conclusion is that the two main methods developed to replace pathogenic mtDNA variants are morally approvable because they afford the newborn child quality of life.

Keywords:  Human reproduction; Legal and ethical implications; Mitochondrial disease; Regulatory frameworks; maternal spindle transfer (MST); pronuclear transfer (PNT)

DOI:  https://doi.org/10.1016/j.mito.2026.102175
Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00184-1. [Epub ahead of print]38(6): 1089-1092

Functional specialization within the mitochondrial network: Are all mitochondria created equal?

Jessica B Spinelli.

Mitochondria are classically viewed as a uniform ATP-producing network; however, a growing body of evidence suggests distinct subpopulations exist within tissues and even single cells. Here, I highlight evidence supporting the presence of functionally distinct mitochondria and propose mechanisms by which these subpopulations are formed and regulated.

DOI: https://doi.org/10.1016/j.cmet.2026.04.019
Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00155-5. [Epub ahead of print]38(6): 1081-1084

Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?

Gwang-Bum Im, Juan M Melero-Martin.

Intercellular mitochondrial transfer has emerged as a key mode of metabolic communication across tissues. Its outcomes are context dependent, spanning from therapeutic benefits to pathological risks.

DOI: https://doi.org/10.1016/j.cmet.2026.04.017
Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00153-1. [Epub ahead of print]38(6): 1075-1078

Mitochondria across the globe: Diverse voices, shared energy.

Ichitaro Abe, Alejandro Failde Fiestras, Maia Hjerting Ekstrand, Nahid A Khan, Kenneth Bowitz Larsen, Jason Maynes, Agata M Rudolf, Francois Singh.

Like mitochondria themselves, research on the organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology & Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.

DOI: https://doi.org/10.1016/j.cmet.2026.04.015
bioRxiv. 2026 May 23. pii: 2026.05.21.726892. [Epub ahead of print]

In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan.

Devin Raine Everaldo Cortes, Sean Hartwick, Thomas Becker-Szurszewski, Kristina Elsa Schwab, Cody Ruck, Shanim Manzoor, Noah William Coulson, Dalton West, Margaret Caroline Stapleton, Samuel Wyman, Cecilia Wen-Ya Lo, Sivakama Bharathi, Eric S Goetzman, Anthony G Christodoulou, Yijen Lin Wu.

Mitochondria are essential for cellular energy production and are particularly critical for brain development and function. Neurons rely predominantly on oxidative phosphorylation for energy production, rendering the brain highly vulnerable to mitochondrial dysfunction. Consequently, impaired mitochondrial function contributes to a broad spectrum of neurological and systemic disorders, making mitochondria attractive therapeutic targets. Despite this importance, there is currently no non-invasive, spatially resolved method to assess mitochondrial function in the intact living brain. Here, we establish a non-invasive functional MRI approach-4D Oxy-wavelet MRI-to probe in vivo mitochondrial electron transport chain (ETC) function in a spatially specific manner across the lifespan, from fetal to adult brains. This method employs a low-rank k -t sub-Nyquist acquisition strategy to achieve simultaneous structural and functional imaging with high spatial (78 μm) and temporal (∼14 ms) resolution, enabling motion-robust imaging in multi-fetal mouse pregnancies. Mitochondrial ETC function is interrogated by measuring oxygen homeostasis responses to brief hypoxic challenges, analyzed using computational time-frequency wavelet profiling. We validate this approach in mouse models of mitochondrial respiratory chain disease and late-onset Alzheimer's disease, from in utero fetuses to adults, and demonstrate reproducibility and specificity using pharmacological hyperemia and ETC complex I inhibition. We further show parallel wavelet responses in placenta and fetal brain, enabling multi-organ interrogation of the placenta-brain axis. Finally, we present first-in-human feasibility data, supporting translational potential for non-invasive assessment of mitochondrial function in living brains across the lifespan.

DOI: https://doi.org/10.64898/2026.05.21.726892
NPJ Aging. 2026 Jun 03.

Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.

Jiahui Yang, Jianfeng Li, Xintong Hou, Yifei Zheng, Zeyu Zhao, Ting Zhou, Tongwei Jing, Jiming Kong, Guohui Zhang, Ying Guo.

Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41514-026-00424-3
J Neurol. 2026 May 30. pii: 350. [Epub ahead of print]273(6):

The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson's disease.

Yu-Lin Liang, Feng-Ge Yang, Qiang Tang.

  Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, characterized primarily by motor symptoms such as resting tremor, rigidity, and bradykinesia, accompanied by non-motor symptoms (NMS) including constipation and depression. The underlying mechanisms of PD are multifaceted, driven by a complex interaction between genetic and environmental factors that remain to be entirely understood. In recent years, an increasing body of evidence has confirmed that the abnormal aggregation of α-synuclein (α-Syn), mitochondrial dysfunction, and neuroinflammatory activation are not isolated pathological events; rather, they constitute the core driving mechanism of PD pathogenesis and progression through complex networked interactions. This narrative review examines the independent mechanisms of these three pathological components, provides an in-depth analysis of their regulatory interaction networks, and summarizes therapeutic targets and synergistic treatment strategies for the pathological axes, aiming to provide theoretical support for disease-modifying therapy and early intervention in PD.

Keywords:  Interaction; Mitochondrial dysfunction; Neuroinflammation; Parkinson’s disease; Therapeutic strategies; α-Synuclein

DOI:  https://doi.org/10.1007/s00415-026-13900-3
Mol Genet Metab Rep. 2026 Jun;47 101322

POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.

Fuad Al Mutairi, Faisal Joueidi, Ziyad A Al Mutairi, Maha Alshalan, Wafaa Eyaid, Aziza M Mushiba, Malak AlGhamdi, Brahim Tabarki, Abdulaziz AlGhamdi, Ruqaiah AlTassan, Hamad Alzaidan, Abubakar Sharif, Hesham Aldhalaan, Muhammad Umair, Majid Alfadhel.

   Background: POLG-related disorders are a group of mitochondrial diseases caused by variants in the POLG gene, which is essential for mitochondrial DNA replication and repair. These disorders encompass a wide spectrum of clinical manifestations, ranging from severe, early-onset conditions to milder, adult-onset syndromes.
Methods: We conducted a retrospective study of 19 molecularly confirmed cases with POLG-related disorders from 16 unrelated families in six different referral centers. Clinical, radiological, and molecular analysis were performed following standard methods.
Results: Most of the patients in this study presented with variable neurological symptoms before the age of 12 years (80%); commonly, these symptoms included developmental delay and encephalopathy (63%), seizures (58%), ataxia and dysphagia (42% each). Molecular analysis revealed eight different disease-causing variants in the POLG gene. The most frequently observed variant was c.3286C > T; p.(Arg1096Cys). Notably, the POLG c.1957G > A; p.(Glu653Lys) variant has not been reported in the literature previously, and might impact protein folding and stability.
Conclusion: Despite the management of these conditions remaining largely supportive, advances in understanding the molecular mechanisms of POLG-related disorders offer promise for future therapeutic strategies targeting mitochondrial function and stability. This study highlights the complexity of POLG-related disorders and underscores the need for continued research into their pathophysiology and treatment.

Keywords:  Developmental delay; Mitochondrial depletion; Mitochondrial replication; Myopathy; POLG; Seizures

DOI:  https://doi.org/10.1016/j.ymgmr.2026.101322
bioRxiv. 2026 May 25. pii: 2026.05.24.727547. [Epub ahead of print]

Mutations Causative of CPEO Differentially Engage Innate Immunity Sensors.

Joshua Okletey, Megan Muench, Chenxiao Yu, Alessandra Maresca, Valerio Carelli, Marco Tigano.

Chronic Progressive External Ophthalmoplegia (CPEO) is a primary mitochondrial disorder (PMD) caused by mutations in nuclear genes encoding mitochondrial DNA (mtDNA) maintenance proteins. CPEO is characterized by mtDNA depletion and deletions, and patients primarily present with ocular and muscular features (isolated CPEO). However, additional encephalomyopathy, neurological complications, and Parkinsonism can drive a more severe disease form, CPEO-plus. The evolution from isolated CPEO to CPEO-plus remains poorly understood. Inflammatory and innate immune processes are emerging as strong disease modifiers and may underlie this heterogeneity. Instability of mitochondrial DNA is a major driver of organellar stress and release of mitochondrial contents into the cytosol. Mutations in several genes involved in mtDNA replication and maintenance have been implicated in triggering the escape of mitochondrial nucleic acids from the mitochondrial matrix. Once exposed to cytosolic innate immune sensors, mtDNA and mitochondrial double-stranded RNA (mt-dsRNA) act as potent immunogens, with more than 10 innate immune sensors capable of recognizing them. Therefore, mtDNA and mt-dsRNA release are likely pathological mechanisms in CPEO, yet the list of CPEO-related genes that can trigger inflammatory processes is far from complete. Here, we use patient-derived fibroblasts from individuals with CPEO carrying mutations in RNASEH1 and Twinkle, and provide - for the first time - evidence that their mutations drive innate immune activation through the release of different mitochondrial nucleic acids. RNASEH1 mutations lead to the accumulation and subsequent release of mt-dsRNA, while mtDNA remains protected. On the other hand, mutations in Twinkle cause the release of mtDNA without triggering mt-dsRNA production, or leakage. Supporting this notion, the POLRMT inhibitor IMT-1, and the STING inhibitor H-151, reduced interferon stimulated genes expression downstream of RNASEH1 and Twinkle mutations, respectively. Further, when we analyzed a unique compound patient line carrying mutations in both genes simultaneously, we detect both species of nucleic acids in its cytosol, indicating that both pathways can be engaged simultaneously in the same cell. Lastly, we show that cytosolic sensing triggers paracrine signaling to activate bystander microglia - the resident macrophages of the retina and brain - with potential implications to the neurological progression of CPEO. Overall, our findings reveal a new role for RNASEH1 and Twinkle in driving aberrant innate immunity and paracrine inflammation in CPEO. Our data support a model in which innate immunity is a universal feature of mutations causing mtDNA instability; yet different mutations engage distinct sensing pathways, and in complex scenarios multiple pathways can be triggered at the same time. Given the clinical heterogeneity observed in patients with PMDs, our findings that different signaling pathways are triggered in patient-specific manners might have direct implications for precision medicine approaches aimed at targeting specific innate immunity.

DOI: https://doi.org/10.64898/2026.05.24.727547
Intractable Rare Dis Res. 2026 May 31. 15(2): 120-128

The "China model" for rare disease governance: Policy framework, local implementation, and pathways for optimization.

Xiumei Zhang, Jing Luan, Yan Mu, Keke Zhang, Zhiyan Han, Jinxiang Han.

  Globally, the prevention and treatment of rare diseases is still constrained by limited diagnostic and therapeutic capacity, restricted drug accessibility, and disparities in medical security systems. In response, China has developed a distinct "China Model" of rare disease governance, characterized by national policy leadership and coordinated local implementation. This study systematically reviews policies issued between 2009 and 2026 and it analyzes five domains: i) prevention and screening, ii) list-based governance, iii) clinical diagnosis and treatment systems, iv) drug accessibility, and v) payment guarantees. Shandong Province is examined as a representative case. Findings show that the central government has established unified standards through two nationally endorsed rare disease lists covering 207 conditions, supported by clinical guidelines and a national collaborative network for diagnosis and treatment of those diseases. Regulatory incentives for drug review and approval have facilitated the inclusion of 126 treatments for patients with rare diseases in the National Basic Medical Insurance reimbursement list, forming an integrated policy framework spanning identification, diagnosis, treatment, and financial protection. At the provincial level, Shandong is aligned with national directives by integrating its case registration system with the national platform, enhancing quality control across its clinical network and developing a multilevel payment mechanism. The core of the "China Model" is the enhancement of clinical capacity through standardized systems and networked organizations, combined with multilevel risk-sharing mechanisms. However, governance challenges persist, including weak inter-organizational policy coordination, barriers to drug accessibility, fragmented coverage schemes, and an underdeveloped data governance infrastructure. Addressing these challenges requires enhanced end-to-end policy implementation and institution of effective local practices at the national level.

Keywords:  China model; case registration; collaborative network for diagnosis and treatment; drug accessibility; medical security; rare diseases

DOI:  https://doi.org/10.5582/irdr.2025.01060
Seizure. 2026 May 09. pii: S1059-1311(26)00139-1. [Epub ahead of print]

Adjunctive transcranial DC stimulation in the management of refractory drug-resistant focal epilepsy in POLG mitochondrial disease: A case series.

Katrin A Bangel, Yi Ng, Albert Lim, Naomi J P Thomas, Stephan R Jaiser, H Ming Lai, Gráinne S Gorman, Rhys R Thomas, Douglass M Turnbull, Venkateswaran Ramesh, Andrew M Schaefer, Robert McFarland, Mark R Baker.

   BACKGROUND: Pathogenic POLG variants produce an age-related progressive multi-system mitochondrial disorder, with neurologic manifestations that include focal onset seizures, stroke-like episodes, cerebellar ataxia, sensory neuronopathy, complex ophthalmoplegia and myopathy. Focal onset status epilepticus or epilepsia partialis continua (EPC) frequently occurs in patients with paediatric and early adulthood onset disease.
METHODS: Between 2014 and 2020, we treated 15 episodes of drug-refractory focal epileptic status (epilepsia partialis continua) in 5 patients with POLG-related mitochondrial disease with cathodal transcranial direct current stimulation (tDCS). Here we describe the management of each episode of EPC, including the application of tDCS.
RESULTS: Transcranial DCS, delivered for 20 min at 2 mA, once daily (minimum 3 days; maximum 14 days), as an adjunct to optimal standard medical care, was associated with a significant reduction (93% of episodes after 4.3 sessions) or a cessation of seizures (63% of episodes after 8.4 sessions). No major side effects of tDCS were noted.
CONCLUSION: Our findings support further exploration of tDCS as a potential adjunctive therapy for complex neurological challenges in mitochondrial disorders.

Keywords:  Cathodal transcranial direct current stimulation (tDCS); Drug-refractory epilepsy; Epilepsia partialis continua (EPC); Focal onset status epilepticus; Mitochondrial disorder; POLG

DOI:  https://doi.org/10.1016/j.seizure.2026.05.009
Pediatr Res. 2026 Jun 03.

Clinical pharmacology insights from recent cell and gene therapy approvals relevant to pediatrics.

Sahana Kunanayagam, Michelle C Wang, Catrina M Loucks, Facundo Garcia-Bournissen, Ruud H J Verstegen, Tamorah Lewis.

The United States Food and Drug Administration has approved 44 cell and gene therapies as of May 2025, including 14 for pediatric use (excluding cord blood). This signifies an advancement in the treatment of diseases and conditions that, as of yet, cannot be effectively managed with available small-molecule drugs and therapeutic proteins. This review explores the pharmacokinetic and first-in-human dosing considerations unique to cell and gene therapies. For in vivo gene therapies, development considerations include vector shedding and biodistribution. Traditional pharmacokinetic principles do not apply to ex vivo gene therapies, given the modification of cells outside the body before re-infusion. Cellular kinetics such as expansion and persistence are relevant in cell therapies like Chimeric Antigen Receptor T cells and Tumor Infiltrating Lymphocytes. A common trend of cell and gene therapy development is the reliance on preclinical models to inform safety, efficacy, and dose selection, with first-in-human dosing further guided by data from related therapies. Rare disease and pediatric drug development present additional challenges due to small patient populations, emphasizing the importance of preclinical evidence and safety considerations. The article outlines the key considerations for cell and gene therapies that are vital for expanding their use. IMPACT: This article provides a synthesis of pediatric rare disease clinical pharmacology considerations for recently approved cell and gene therapies, highlighting how advanced therapeutic products compare with traditional pharmacokinetic and pharmacodynamic frameworks used for small-molecule drugs. The development of advanced therapeutics depends on preclinical modeling, first-in-human dosing strategies, clinical trial design, and regulatory guidance for pediatric use, emphasizing the need for a practical primer on emerging advanced therapeutic products for researchers.

DOI: https://doi.org/10.1038/s41390-026-05138-6
Trends Mol Med. 2026 Jun 04. pii: S1471-4914(26)00115-2. [Epub ahead of print]

Deubiquitinases at organelle quality control bottlenecks in neurodegeneration.

Lisa M Ellerby, Avraham Ashkenazi.

  Neurodegenerative diseases with prominent motor symptoms converge on mitochondrial and lysosomal bottlenecks in selectively vulnerable neurons. Deubiquitinases regulate ubiquitin-dependent organelle fate at these decision points. Emerging evidence suggests that modulating deubiquitinase activity can restore organelle quality control and represents a promising therapeutic strategy.

Keywords:  Parkinson’s disease; polyglutamine expansion diseases; proteostasis; ubiquitin enzymes

DOI:  https://doi.org/10.1016/j.molmed.2026.05.006
FEMS Yeast Res. 2026 Jun 02. pii: foag023. [Epub ahead of print]

Modelling Human Proteostasis and Organelle Homeostasis Disorders in Yeast and Its Application in Drug Discovery.

Anh V Do, Memoona Zahra, Alan L Munn.

Disruptions in cellular homeostasis and proteostasis are central to many human diseases, yet direct mechanistic investigation in human systems remains constrained by biological complexity and ethical limitations. Therefore, researchers have turned to the use of model systems that allow the more efficient dissection of fundamental cellular processes. The unicellular yeast Saccharomyces cerevisiae has emerged as a powerful eukaryotic model for studying disorders driven by defects in homeostasis and proteostasis. The relevant processes are highly conserved in yeast, enabling precise genetic manipulation and real-time analysis of mechanisms that are difficult to study in mammalian systems. Yeast models have been deployed to study prion propagation, lysosomal enzyme trafficking, and mitochondrial dysfunction. Yeast also provides a versatile platform for drug discovery, particularly through the use of the yeast two-hybrid system and high-throughput screens. Despite an inability to recapitulate the full complexity of multicellular organisms, yeast remains an invaluable tool for investigating human diseases and for the development of therapeutics. This review highlights how yeast has uniquely advanced the understanding of human diseases including those associated with prions, lysosomal proteins, and mitochondria and can be combined with the utility of yeast in drug discovery-collectively establishing yeast as a model for studying human disorders.

DOI: https://doi.org/10.1093/femsyr/foag023
Epilepsia. 2026 Jun 05.

Cognitive and behavioral clinical outcome assessments in children with developmental and epileptic encephalopathies: Issues and instruments.

Cinzia Correale, Nicola Specchio, Jenny Downs, J Helen Cross, Simona Cappelletti, Andrea Palacio-Navarro, Sam Geuens, Kette Valente, Andreas Brunklaus, Colin Reilly.

  Children with developmental and epileptic encephalopathies (DEEs) face cognitive and behavioral challenges that may have a greater impact than seizures on their quality of life (QoL). The need to assess these nonseizure outcomes for evaluating treatments is increasingly recognized. Advances in genomic technologies have transformed the diagnostic landscape of rare genetic epilepsies, including DEEs, opening new opportunities for precision medicine. There is also growing interest in drug repurposing, identifying well-tolerated medications for other indications for use in DEEs. Innovative trial designs and the systematic collection of prospective natural history data are essential, given the rarity and heterogeneity of DEEs. The selection of reliable, valid, and meaningful outcome measures of cognition and behavior is crucial for clinical trials and natural history studies. Commonly used tools for assessing cognition and adaptive behavior often exhibit floor effects and may fail to capture subtle, yet clinically significant, changes in functioning that are meaningful for children and their families. There is thus a need to explore a fuller range of clinical outcome assessments (COAs) and scoring methods that could be sensitive to change and suitable for use in rare disease populations. Assessing behavioral and emotional outcomes in children with DEEs is additionally challenging, as many assessment instruments have been developed and validated for use in children without intellectual disability. To fully realize the potential of precision medicine in the DEEs, a robust framework for outcomes assessment is required, one that incorporates sensitive, reliable, and meaningful COAs tailored to this population. Coordinated efforts to identify and adapt existing measures or develop new outcome tools will be crucial for advancing therapeutic strategies that genuinely improve QoL for children with DEEs. This article summarizes the issues faced when selecting outcome measures for DEE trials and reviews commonly used instruments for assessing cognition and behavior in children with DEEs.

Keywords:  clinical outcome assessment; clinical trial readiness; developmental; natural history

DOI:  https://doi.org/10.1002/epi.70308
J Cell Biol. 2026 Aug 03. pii: e202409118. [Epub ahead of print]225(8):

Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.

Julius Winter, Juan C Landoni, Keaton B Holt, Sheda Ben Nejma, Emine Berna Durmus, Tatjana Kleele, Elena F Koslover, Suliana Manley.

In functionally polarized cells, mitochondria can form distinct subpopulations, positioned at sites of varying metabolic and energetic demands. Thus far, the potential presence of such subpopulations and implications of their intracellular trafficking in immobile and proliferative cells remain largely undescribed, despite such cells serving as key models. Here, we use substrate micropatterning to create reproducible morphologies of cultured immortalized cells, enabling us to define mitochondrial subpopulations and follow their trafficking by photoactivation. We discovered that mitochondrial material is dispersed asymmetrically throughout the cell via biased anterograde transport from the perinuclear area. Combining quantitative analysis and in silico modeling, we characterize the causes and consequences of unbalanced mitochondrial trafficking. Our findings indicate that this bias is required to distribute new material resulting from perinuclear mitochondrial biosynthesis to sustain mitochondrial mass distribution across the cell and to maintain normal network connectivity.

DOI: https://doi.org/10.1083/jcb.202409118
Semin Hematol. 2026 May 09. pii: S0037-1963(26)00041-7. [Epub ahead of print]

Evolving insights into mitochondrial presence in RBC in sickle cell disease: Red blood cell and reticulocyte pathophysiology, therapeutic strategies, and future directions.

Yaw Ansong-Ansongton, Daisy Zapet Bamac, Angela Rivers.

  Recent advances in understanding sickle cell disease (SCD) pathophysiology have revealed the critical role of abnormal mitochondrial retention in mature erythrocytes. This comprehensive review examines how disrupted mitochondrial clearance contributes to disease progression through multiple mechanisms, including oxidative stress, metabolic dysfunction, and immune activation. We will review evidence from both human studies and animal models demonstrating that retained mitochondria remain functionally active and contribute to cellular damage. Furthermore, we will highlight emerging findings that active mitochondria in reticulocytes are also detrimental in SCD, exacerbating oxidative stress, and promoting premature cellular damage. This review examines therapeutic approaches targeting mitochondrial dysfunction, including pyruvate kinase activation and mitophagy enhancement strategies. Understanding these mechanisms provides new opportunities for therapeutic intervention in SCD and related disorders.

Keywords:  Erythrocyte mitochondrial retention; Mitochondria; Mitophagy; Reactive oxygen species; Sickle cell disease

DOI:  https://doi.org/10.1053/j.seminhematol.2026.05.003
Intractable Rare Dis Res. 2026 May 31. 15(2): 135-143

Policy lessons regarding medical security for rare diseases inChina: Insights from Zhejiang Province through the multiplestreams framework.

Miao Wang, Chunyu Rong, Pingyang Wang.

  Rare diseases pose a persistent challenge to healthcare systems worldwide due to their low prevalence, high treatment costs, and rapid emergence of novel therapies. In China, while significant progress has been made through national rare disease lists and medical insurance negotiations, substantial medical security gaps remain at the subnational level. This Policy Forum examines the decade-long evolution of rare disease-specific medical security policies in Zhejiang Province (2015-2025) to draw broader lessons for designing sustainable and equitable coverage mechanisms under centralized insurance systems. Using the multiple streams framework (MSF) as an interpretive lens, this article puts forth three policy arguments. First, medical security for rare diseases cannot rely solely on basic medical insurance (BMI); instead, it requires institutional layering that combines insurance-based pooling, fiscal instruments, and social co-assistance. Second, in highly centralized governance contexts, policy entrepreneurship is predominantly state-embedded, with administrative agencies playing a decisive role in coupling problems, solutions, and political mandates. Third, policy innovation in relation to rare diseases is not a one-time event but an iterative process, in which each reform generates new problem definitions and policy windows. The Zhejiang experience demonstrates that under institutional constraints such as standardized benefit lists, local governments can achieve strategic innovation within the available institutional space by shifting their policy focus from reimbursing costs for "drugs on the Nationally Reimbursed Drug List (NRDL)" to targeted compensation for expenditures for drugs not on the NRDL. This pathway improves treatment affordability while maintaining fiscal sustainability, providing actionable insights for China and healthcare systems in other countries facing similar structural constraints.

Keywords:  Zhejiang model; medical security; multiple streams framework; policy change; policy window; rare diseases

DOI:  https://doi.org/10.5582/irdr.2026.01001
Eur J Med Genet. 2026 Jun 02. pii: S1769-7212(26)00020-0. [Epub ahead of print]82 105086

Genotype before phenotype? Reversing the diagnostic odyssey in genomic medicine.

Alain Chebly, Said El Shamieh.

  For decades, the diagnosis of rare genetic disorders has relied on a phenotype-driven approach, often resulting in a prolonged "diagnostic odyssey." The widespread use of whole-exome and whole-genome sequencing has transformed this paradigm, increasingly enabling genotype-first diagnoses before a clear clinical phenotype is recognized. This shift may contribute to a reversal of the diagnostic odyssey, in which genetic findings guide subsequent clinical evaluation through reverse phenotyping. Large-scale biobank studies and newborn genomic screening programs are further accelerating this paradigm shift. Although this approach has improved diagnostic yield, it also introduces interpretative challenges, including the risk of phenotype reinterpretation bias and the persistent burden of variants of uncertain significance (VUS), particularly when genetic variants only partially explain the clinical presentation. This article discusses the emergence of genotype-driven diagnosis and emphasizes the need for balanced integration of genomic and clinical data in modern precision medicine.

Keywords:  Diagnostic odyssey; Genomic medicine; Genomic sequencing; Genotype-first approach; Newborn genomic screening; Precision medicine; Rare diseases; Reverse phenotyping; Variant interpretation

DOI:  https://doi.org/10.1016/j.ejmg.2026.105086
bioRxiv. 2026 May 21. pii: 2026.05.19.726440. [Epub ahead of print]

A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia.

Maltesh Kambali, Sergey Trushin, Muxiao Wang, Rajasekar Nagarajan, Jinrui Lyu, Eugenia Trushina, Uwe Rudolph.

Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimer's and Huntington's diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1α, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

DOI: https://doi.org/10.64898/2026.05.19.726440
Mol Cell. 2026 Jun 04. pii: S1097-2765(26)00287-X. [Epub ahead of print]86(11): 2038-2040

Mitochondria across the globe: Diverse voices, shared energy.

Tim Pflästerer, Andrea Dlasková, Stuart Caldwell, Marijana Croon, Staffan Strömblad, Jae Bum Kim.

Like mitochondria themselves, research on this organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted Mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology and Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.

DOI: https://doi.org/10.1016/j.molcel.2026.04.033
Front Endocrinol (Lausanne). 2026 ;17 1817121

Altered mitochondrial functionality in metabolic disorders: insights from Drosophila studies.

Yunlin Zeng, Yang Yang, Yuao Zhu, Peixin Xu, Chakin Cheong, Yong Juan Zhao, Gyeong Hun Baeg.

  The pathophysiological association between obesity and type 2 diabetes (T2D) increasingly highlights the central role of mitochondrial dysfunction. As critical signaling hubs orchestrating metabolism, mitochondria are pivotal in maintaining metabolic homeostasis. Imbalances in mitochondrial quality control mechanisms lead to an accumulation of damaged mitochondria with abnormal dynamics and functions, exacerbating the progression of obesity, insulin resistance, and T2D. Although therapeutic interventions for obesity and T2D have shown promise, they remain insufficient for achieving sustained remission from obesity and T2D on a global scale. Furthermore, existing rodent models often struggle to fully recapitulate human metabolic disorders due to species-specific metabolic differences and technical limitations. Drosophila melanogaster has emerged as a powerful model organism for deciphering mitochondrial-metabolism interactions due to numerous advantages, including easy genetic manipulation, low gene redundancy, rapid phenotype verification, and the unique opportunity to image live tissues in vivo. Drosophila models effectively recapitulate high-sugar- and high-fat-diet-induced mitochondrial fragmentation, adipose tissue expansion, and insulin resistance-like phenotypes. Furthermore, studies leveraging the genetic tractability of Drosophila have provided critical insights into how mitochondrial impairment contributes to systemic metabolic dysfunction. Here, we introduce recent advances in mitochondrial research regarding metabolic disorders and demonstrate how Drosophila serves as a useful in vivo model to dissect mitochondrial function. Future research should integrate multi-omics approaches and precision medicine strategies targeting mitochondrial metabolic remodeling to break the vicious cycle of obesity and T2D, while developing non-invasive intervention methods to advance translational medicine.

Keywords:  Drosophila melanogaster; mitochondrial dysfunction; mitochondrial quality control; mitophagy; obesity and type 2 diabetes

DOI:  https://doi.org/10.3389/fendo.2026.1817121
Nat Commun. 2026 May 30.

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.

Micol Falabella, Sandra Lopez Calcerrada, Jana Aref, Jiaze Gao, William L Macken, Chiara Pizzamiglio, Renata Kabiljo, Anna Lucia Francavilla, Pauline Gaignard, Antoine Pouzet, Jonathan Levy, Giulia Barcia, Jamie K Leighton, Efstathia Chronopoulou, Germaine Pierre, Riza Köksal Özgül, Ali Dursun, Rebecca Halligan, Helen Mundy, Javeria Raza Alvi, Tipu Sultan, William James Craigen, Lisa Emrick, Jill A Rosenfeld, Gehad Elmakkawy, JiHye Kim, Joseph J Gleeson, Aboulfazl Rad, Gabriela Oprea, Maqbool Hussain, Khalil Ur Rehman, Sadia Riaz, Robert W Taylor, Vincent Procaccio, Maha S Zaki, Erika Fernandez-Vizarra, Ciro Leonardo Pierri, Michael G Hanna, Henry Houlden, Reza Maroofian, Cristina Ugalde, Jan-Willem Taanman, Robert D S Pitceathly.

Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.

DOI: https://doi.org/10.1038/s41467-026-73455-9
Neurosci Bull. 2026 Jun 04.

Gene Editing Technologies for Hereditary Hearing Loss: Prospects and Challenges.

Man Wang, Bei Wang, Minhao Yang, Fangzhi Tan, Jieyu Qi, Renjie Chai.

  Hereditary deafness represents a significant global health challenge with limited therapeutic interventions. Most cases are caused by monogenic mutations inherited in an autosomal dominant or recessive manner, making them suitable targets for gene editing therapies. Recent advances in gene editing technologies have expanded the toolkit for precise genomic modification, including engineered nucleases for gene disruption, base editors (BEs) for point mutations, prime editors (PEs) for substitutions, insertions, and deletions, and mitochondrial editors for modifying mitochondrial DNA (mtDNA). These tools have demonstrated significant efficacy in mouse models of hereditary deafness, highlighting their clinical potential. However, given the high degree of genetic heterogeneity, gene editing technologies in this field remain in an early exploratory stage. In this review, we provide a comprehensive overview of the latest breakthroughs in gene-editing platforms and critically evaluate the potential benefits and existing hurdles to their clinical application for treating congenital hearing impairment.

Keywords:  Gene editing technology; Gene therapy; Hearing restoration; Hereditary hearing loss

DOI:  https://doi.org/10.1007/s12264-026-01651-0
Cell Transplant. 2026 Jan-Dec;35:35 9636897261453307

Mitochondrial transplantation as an immunomodulatory strategy: Modulating polymorphonuclear leukocytes for functional tissue regeneration.

Samantha C Hall, Evan N Main, Gary L Bowlin.

  Following biomaterial implantation, modulation of the acute immune response is essential for tissue regeneration. Polymorphonuclear leukocytes (PMNs) are critical effector cells in wound healing, and PMN dysfunction is mediated by mitochondrial dysfunction and can lead to prolonged inflammation and tissue damage. It was hypothesized that mitochondrial transplantation could be applied to PMNs in pro-inflammatory states as a means of upregulating regenerative proteins. Primary human PMNs were isolated from donor blood. Isolated PMNs and exogenous mitochondria were co-incubated to induce mitochondrial transplantation. Resulting interactions were assessed through microscopy to confirm initial uptake and mitochondria membrane potential retention, intracellular reactive oxygen species (ROS) analyses (n = 5), and PMN secretome quantification (n = 10) using multiplex protein analysis. Human PMNs were able to successfully uptake delivered mitochondria, and regenerative factors essential for tissue repair and immune cell recruitment including fibroblast growth factor-2 (FGF-2), interleukin (IL)-22, monocyte chemoattractant protein-1 (MCP-1), and granulocyte colony-stimulating factor (G-CSF) were significantly upregulated, indicating that exogenous mitochondria represent promising modulators of PMN function with broad clinical potential.

Keywords:  host-biomaterial response; immunoengineering; mitochondrial transplantation; polymorphonuclear leukocyte; tissue regeneration

DOI:  https://doi.org/10.1177/09636897261453307
Brain Dev. 2026 Jun 03. pii: S0387-7604(26)00058-6. [Epub ahead of print]48(4): 104557

Ketogenic diet in children with epilepsy: A bibliometric and science mapping analysis of global research.

Kizbes Meral Kilic, Hilal Aydin.

   OBJECTIVE: The ketogenic diet has become an important therapeutic option for children with drug-resistant epilepsy; however, the structure and evolution of the related literature remain insufficiently clarified. This study aimed to map the global research landscape on ketogenic dietary interventions in pediatric epilepsy using bibliometric and science mapping methods.
METHODS: Publications indexed in the Web of Science database were retrieved in January 2026. After screening and data cleaning, 983 articles published between 1989 and 2026 were included. Bibliometric analyses were performed using the Bibliometrix R package and Biblioshiny interface to assess publication trends, key contributors, collaboration networks, citation patterns, and thematic development.
RESULTS: Scientific output on ketogenic diet interventions in pediatric epilepsy has increased steadily over the past three decades, with a marked acceleration after 2014. A small group of core journals-most prominently Epilepsia, Seizure, and Epilepsy & Behavior-accounts for a large share of publications. The United States, China, and Italy are the leading contributing countries. Keyword and thematic analyses indicate a shift from early mechanistic and pharmacoresistance-focused studies toward broader clinical themes, including efficacy, safety, tolerability, growth outcomes, and alternative dietary approaches such as the modified Atkins diet.
CONCLUSION: The field of ketogenic diet research in childhood epilepsy has evolved into a clinically focused and increasingly multidisciplinary area. While seizure control remains central, emerging themes emphasize individualized treatment, long-term safety, and evidence-based standardization. This study clarifies research dynamics, intellectual frameworks, and knowledge gaps, providing a framework to guide future research and support clinical decision-making.

Keywords:  Bibliometric analysis; Children; Epilepsy; Ketogenic diet; Science mapping

DOI:  https://doi.org/10.1016/j.braindev.2026.104557
bioRxiv. 2026 May 29. pii: 2025.10.08.676630. [Epub ahead of print]

Identifying and targeting abnormal mitochondrial localization associated with psychosis.

Marzieh Haghighi, Donna McPhie, Mohammad Rohban, Erin Weisbart, David J Logan, Kyle W Karhohs, Suzann M Babb, Jessica D Ewald, Johan Fredin Haslum, Caitlin Ravichandran, Beth A Cimini, Shantanu Singh, Bruce M Cohen, Anne E Carpenter.

Therapeutics working by novel mechanisms are needed for patients with psychiatric conditions. Cell-based assays to identify candidates that reverse observed abnormalities could accelerate the process. Here, we imaged peripheral cells (skin fibroblasts) of 168 patients, stained for DNA, actin, and mitochondria. We found mitochondria tend to be farther from the cell border for patients who experience psychosis (including subsets of individuals with bipolar disorder, schizophrenia, and schizoaffective disorder). We observed a reverse trend, albeit not statistically significant, for patients diagnosed with major depression. Because the phenotype could be identified by a single metric, we could query existing databases of cells stained for their mitochondria and treated with various chemical or genetic perturbations. We identified compounds and genes both negatively and positively affecting the psychosis-associated phenotype, including some known to impact psychiatric conditions. Developing therapeutics with novel mechanisms is a complex multi-step challenge. This cell-based assay holds promise for virtual and physical screening to identify candidates for treating psychiatric conditions.

DOI: https://doi.org/10.1101/2025.10.08.676630
medRxiv. 2026 May 24. pii: 2026.05.21.26353759. [Epub ahead of print]

The Biobank Rare Variant consortium powers the discovery of rare genetic associations through global collaboration.

Colorado Center for Personalized Medicine

Rare coding variants can have large effects on disease risk and provide direct routes from human genetics to disease mechanisms and therapeutic targets, but their discovery is constrained by sample size, particularly for low-prevalence diseases. Here we establish the Biobank Rare Variant Analysis (BRaVa) consortium, a global rare variant association resource that integrates sequencing and linked health-record data from ten biobanks and cohorts comprising over 1.2 million individuals across diverse ancestries. We performed gene-based meta-analyses of rare coding variation across 33 clinical endpoints and 11 quantitative traits. Aggregating evidence across biobanks and ancestries identified 514 gene-trait associations, including 31 not previously reported in prior studies or curated association resources following systematic literature review. Notably, 36.1% of gene-level associations were undetectable in any individual biobank, and 91 emerged only through cross-ancestry meta-analysis, demonstrating that federated integration enables discovery beyond the reach of single cohorts. Similar gains were observed at the variant level, where 25.0% of phenotype-locus associations were detectable only through meta-analysis. Effect size estimates were correlated across ancestries with concordant directions of effect, supporting the generalizability of rare variant associations. The identified signals implicate pathways involved in transcriptional and epigenetic regulation, metabolism, vascular and epithelial biology, and immune function, highlighting rare coding variation as an engine for biological discovery across medical record phenotypes. For example, damaging variation in ANKRD12 implicates inflammatory transcriptional dysregulation in asthma and chronic obstructive pulmonary disease, and ultra-rare predicted loss-of-function variants in NAA15 link protein acetylation processes to type 2 diabetes risk. BRaVa establishes a scalable framework and freely available community resource for rare variant meta-analysis across global biobanks. Public release of gene- and variant-level association summary statistics provides a reference map of rare coding variant associations to support disease gene discovery, biological interpretation, and therapeutic target prioritization as sequencing-linked health-record resources continue to expand.

DOI: https://doi.org/10.64898/2026.05.21.26353759
Free Radic Biol Med. 2026 May 29. pii: S0891-5849(26)00822-1. [Epub ahead of print]

Circadian Rhythms, NRF2 Signalling and Redox Homeostasis: A Holy Grail for a Healthy Life Course?

Elizabeth Sutton, Vanja Pekovic-Vaughan.

   SIGNIFICANCE: The circadian ∼24h timing system coordinates physiological and metabolic processes to anticipate daily environmental changes, yet how molecular clock-driven signals interface with redox signalling to shape health across the life course remain incompletely understood. Redox homeostasis encompasses the adaptive maintenance of a biological steady state through the regulation of reduction-oxidation (redox) reactions. Redox reactions are vital in maintaining cellular functions, from regulating cellular proliferation and differentiation to detoxification of harmful substances and metabolic regulation. This adaptive homeostasis allows cells and tissues to transiently adapt to fluctuating levels of internal and external environmental stressors and build stress resilience to potential damaging stimuli. As we age, our baseline stress-protective systems rise, and our cells and tissues lose the ability to transiently and temporally increase their adaptive capacity further, leading to chronic redox shifts in pathophysiological direction and increased susceptibility to disease and frailty.
RECENT ADVANCES: Here we integrate circadian timing, NRF2 signalling and redox balance into a unified circadian-NRF2-redox axis as a life course framework for maintaining health from development through ageing. We propose that circadian clocks regulate NRF2 activity through rhythmic modulation of various redox-sensitive transcriptional and post-translational co-regulators, kinases and miRNAs, thereby shaping the amplitude and timing of antioxidant and metabolic responses. Conversely, NRF2-driven transcriptional programmes modulate mitochondrial function, glutathione synthesis and xenobiotic defence in a time-of-day manner, reinforcing circadian robustness in tissues with high oxidative flux.
CRITICAL ISSUES: The bidirectional interplay between circadian clocks and NRF2-driven redox adaptations generates predictable redox oscillations that gate energy metabolism, cellular repair and immune responses, influencing susceptibility to chronic diseases, from metabolic and cardiorespiratory to neurodegenerative diseases and cancer. We review evidence from in vitro and in vivo experimental models and human studies showing that circadian/NRF/redox misalignments, whether from shiftwork, light pollution, irregular sleep or chronic feeding, amplify oxidative stress and diminish adaptive responses, accelerating health decline with age.
FUTURE DIRECTIONS: We propose that lifestyle interventions that realign circadian timing (consistent sleep/wake or feeding/fasting schedules) and pharmacological strategies that enhance NRF2 activity can restore redox balance and improve disease risk profiles, highlighting a unifying target to predict health trajectories and promote lifelong health. Understanding redox-circadian interactions will help optimise person-centred chronomedicine approaches for advocating preventative health across the life course and for designing smarter therapeutic treatments for redox-based diseases, utilising time-of-day administration of drug treatments and clinical interventions.

Keywords:  Age-related Diseases; Ageing; Chronodisruption; Chronotherapy; Circadian Clock; Circadian Rhythms; NRF2; Oxidative Stress; Redox Homeostasis; Redox-Circadian Interactions

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.318
Mol Syndromol. 2026 Jun;17(3): 288-295

Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.

Merve Setenay Akyüzlüer Güneş, Duygu Duman, Emine Kübra Şen, Miraç Yıldırım, Elif Özsu, Ömer Erdeve, Seda Kaynak Şahap, Fatma Tuba Eminoğlu, Engin Köse.

   Introduction: Mitochondrial diseases caused by mutations in the LRPPRC gene are rare and lead to multisystemic dysfunction. We report two siblings from consanguineous Iraqi parents, both harboring a rare homozygous deletion in LRPPRC (c.2726_2728del; p.Lys909del), previously reported in one other patient. These cases contribute to the expanding phenotypic and geographic spectrum of LRPPRC-related mitochondrial disease.
Case Presentation: The younger sibling, a 9-year-old girl, presented with severe growth retardation, global developmental delay, hypotonia, spastic ataxic gait, and lactic acidosis. Magnetic resonance imaging showed symmetrical hyperintensities in the mesencephalon and thalami, cerebellar atrophy, and an inverted lactate peak on spectroscopy. Hypertrophic cardiomyopathy was also detected. The older sibling, aged 13, exhibited milder manifestations, including axial hypotonia, tremor, ataxia, and persistent hyperlactatemia. Both siblings had elevated lactate levels but otherwise normal metabolic panels. Whole exome sequencing revealed a homozygous mutation in the LRPPRC gene (c.2726_2728del; p.Lys909del) in both patients.
Conclusions: These cases highlight the clinical variability of LRPPRC-related disorders. Our report underscores the importance of considering LRPPRC mutations in the differential diagnosis of early-onset neurodevelopmental delay and multisystemic dysfunction with lactic acidosis, especially in populations with high rates of consanguinity. Early genetic diagnosis via whole exome sequencing is essential for accurate diagnosis, genetic counseling, and family planning.

Keywords:  Ataxia; French-Canadian Leigh syndrome; LRPPRC; Mitochondrial complex IV deficiency

DOI:  https://doi.org/10.1159/000548731