bims-polgdi 2026-05-10 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2026–05–10
forty-one papers selected by
Luca Bolliger, lxBio

Current state of the art in the transmission of mitochondrial DNA pathogenic variants: reviewing preventive-therapeutic alternatives.
Evaluation of PacBio Long-Read and PCR-Based Short-Read Sequencing for Mitochondrial DNA (mtDNA) Variant Detection, with an Emphasis on Detection and Quantification of mtDNA Deletion.
DGUOK-related mitochondrial DNA depletion syndrome presenting with neonatal cholestasis without marked hyperlactatemia: A diagnostic pitfall.
The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
Mitochondrial Function and Dysfunction in Female Fertility: Biological Mechanisms, Genetic Determinants, and Therapeutic Opportunities - A Review.
mGem: More than building blocks? Mitochondrial metabolism, viruses, and the host response to infection.
Supply and Demand in the Mathematics of Rare Disease Drug Development: Why Choosing the Right Model Is Crucial.
An integrated anti-aging framework targeting NAD+ homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT.
Special packaging enables effective mitochondrial delivery.
Exosomes as Advanced Nanocarriers: Overcoming the Blood-Brain Barrier for Targeted Therapeutic Delivery in Neurodegenerative Diseases.
The Dilemma between Data Protection and Data Altruism within the Context of Rare Diseases in the European Health Data Space.
Commentary: Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
Enrichment of Rare Variants in Nuclear-Encoded Mitochondrial Metabolism Genes in Patients with Early-Onset or Familial Parkinson's Disease.
Case Report: A young man with mitochondrial disease: intellectual impairment and myocardial hypertrophy.
Therapeutic Potential of Mitochondrial Transplantation with Focus on DBD.
Regulation of mitochondrial function during spermatogenesis and sperm maturation.
Association of mitochondrial genome variants with Alzheimer's disease in a Chinese population.
Nebulized mitochondrial transplantation attenuates inflammation and improves graft function in a murine donation after cardiac death lung transplant model.
TFAM organizes DNA into compact higher order structures.
Alterations in mitochondrial DNA copy number and oxidative stress markers in blood and muscle tissues of mice following snake envenomation.
Drug-Induced Liver Injury: Mitochondrial Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.
Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.
Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
[Multi-modality strategy for creating innovative drugs].
Global Research Progress of Sepsis and Mitochondria: Bibliometrics and Visualized Analysis.
Optimizing Oligonucleotide Therapeutics: A Model-Informed Drug Development Perspective.
Awareness and knowledge gaps about pediatric rare disease among anesthesia practitioners in China: a survey-based study.
Orientia tsutsugamushi Alters Mitochondrial Function and Selectively Associates with VDAC.
Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
A wait-and-see prognosis: living with a rare progressive disease.
Person-Centered Care in Digital Health Interventions for Chronic Diseases: A Systematic Review.
Genetic Features and Clinical Heterogeneity of Leber Hereditary Optic Neuropathy in Adolescent and Adult Patients: A Case Series on Arab Patients.
Emerging trends and research hot spots in inborn error of immunity: A bibliometric perspective.
A new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury dynamically regulating mitochondrial function to remodel the immune network.
Review of Therapeutic Potential of Coenzyme Q10 in Ophthalmology: Focus on Age-Related Macular Degeneration, Glaucoma, and Retinitis Pigmentosa.
Multiomic Profiling of 85 iPSC Lines from Familial Dementia Reveals Cellular Diversity and Regulators of Organoid Development.
The GA4GH Categorical Variation Representation Specification: A Unified Computational Framework for Reasoning over Genomic Variant Categories.
Energy metabolism dysregulation in idiopathic inflammatory myopathies: mechanisms and therapeutic implications.
Coenzyme Q10 Deficiency and Elevated LEAK Mitochondrial Respiration as Potential Heart Failure Markers in Ebstein Anomaly.
The dual role of heat shock protein 60 in Cardiac diseases: From mitochondrial chaperone to extracellular immunomodulator - A review and future perspectives.

J Assist Reprod Genet. 2026 May 05.

Current state of the art in the transmission of mitochondrial DNA pathogenic variants: reviewing preventive-therapeutic alternatives.

Marta Reguera-Cabezas, Felipe Martínez-Pastor, Cristina Soriano-Úbeda.

  This review analyzes strategies to prevent or reduce the transmission of diseases caused by pathogenic variants in mitochondrial DNA (mtDNA). Among these, we will focus on prenatal screening, preimplantation genetic testing, gene-editing techniques, other molecular tools, and selected heterologous mitochondrial replacement techniques (MRTs), explaining their status and the uncertainties surrounding their clinical application. After this analysis and review, we recognise the limitations of the efficacy of prenatal and preimplantation genetic testing for mitochondrial DNA pathogenic variants, the legal constraints on gene editing, and the status of mitochondrial replacement techniques. MRTs are a safe and possibly more effective alternative for preventing diseases caused by mitochondrial DNA pathogenic variants.

Keywords:  Assisted reproduction; Genetics; Heteroplasmy; Mitochondrial diseases; Mitochondrial replacement

DOI:  https://doi.org/10.1007/s10815-026-03888-0
Int J Mol Sci. 2026 Apr 16. pii: 3562. [Epub ahead of print]27(8):

Evaluation of PacBio Long-Read and PCR-Based Short-Read Sequencing for Mitochondrial DNA (mtDNA) Variant Detection, with an Emphasis on Detection and Quantification of mtDNA Deletion.

Tanaya Jadhav, Matthew Aruta, Maria Alejandra Diaz-Miranda, Avery Zucco, Laura K Conlin, Ramakrishnan Rajagopalan, Jing Wang.

  Accurate detection of all types of mitochondrial DNA (mtDNA) variants, including single large-scale mtDNA deletions (SLSMDs) and multiple mtDNA deletions (MMDs), along with heteroplasmy quantification, is essential for Primary Mitochondrial Disease (PMD) diagnosis. This study compares amplification-free PacBio long-read sequencing (LRS) mtDNA analysis with long-range PCR-based targeted mtDNA sequencing by short-read sequencing (SRS) in terms of detection sensitivity and accuracy. In total, 17 samples, including 4 SLSMD cases (3 blood, 1 muscle), 9 MMD muscle samples, and 4 deletion-negative controls (1 blood, 3 muscle), were sequenced using the PacBio Sequel IIe. Our findings demonstrate LRS's efficacy in detecting single nucleotide variants (SNVs) and large mtDNA deletions with precise breakpoints. LRS can accurately detect and distinguish SLSMD from MMD, providing deletion heteroplasmy without the need for a second methodology. Deletion heteroplasmy computed from LRS was highly correlated with the Droplet Digital PCR (ddPCR) estimates (Pearson's r2 = 0.95). While LRS can detect SNVs with approximately 5% heteroplasmy, only variants exceeding 10% heteroplasmy can attain 100% sensitivity, specificity, and precision when compared to those previously identified through clinical testing. In conclusion, our findings establish PacBio LRS as a robust tool for comprehensive mtDNA analysis capable of accurately detecting and quantifying heteroplasmic mtDNA variants and complex deletions.

Keywords:  heteroplasmy; long-read sequencing; mitochondria DNA; mtDNA deletions; primary mitochondrial diseases

DOI:  https://doi.org/10.3390/ijms27083562
Mol Genet Metab Rep. 2026 Jun;47 101314

DGUOK-related mitochondrial DNA depletion syndrome presenting with neonatal cholestasis without marked hyperlactatemia: A diagnostic pitfall.

Moe Li, Hideo Sasai, Hiroaki Taniguchi, Atsushi Ishida, Yuya Kuwabara, Hideki Matsumoto, Daisuke Terazawa, Tomohiro Kanayama, Tatsuhiko Miyazaki, Akira Hara, Kei Murayama.

  Mitochondrial DNA depletion syndrome (MTDPS) is a group of severe mitochondrial disorders caused by nuclear gene variants that affect mitochondrial DNA (mtDNA) replication and nucleotide synthesis. Deoxyguanosine kinase deficiency is one of the most common subtypes, typically presenting with liver dysfunction in infancy and having a poor prognosis. We report a case of MTDPS presenting with cholestasis and mild hyperlactatemia in the neonatal period, which complicated early diagnosis. Histopathological and genetic analyses established the diagnosis. The patient, a female born at 36 weeks and 1 day of gestation, weighing 2124 g, developed cholestasis, poor feeding, and failure to thrive. Hyperlactatemia was not evident at presentation but gradually increased during the clinical course. Based on suspected mitochondrial disease, mitochondrial cocktail therapy was initiated on day 64. Liver transplantation was not feasible owing to cardiac and neurological complications, and conservative treatment was continued. However, the patient died of multiple organ failure on day 89. Postmortem liver biopsy showed a markedly reduced mtDNA copy number (8.1% of control), and genetic testing revealed a homozygous c.609_610del (p.Tyr204fs) variant in the DGUOK gene (NM_080916.3), confirming the diagnosis of DGUOK-related MTDPS. This case highlights that hyperlactatemia may be absent or only mild in the early stages of MTDPS, making timely diagnosis challenging. Mitochondrial functional analysis and genetic testing should be considered early in infants with unexplained cholestasis and liver failure, regardless of the lactate levels.

Keywords:  Cholestasis; Deoxyguanosine kinase deficiency; Hepatocerebral form; Liver transplantation; Mitochondrial DNA depletion syndrome; Mitochondrial diseases

DOI:  https://doi.org/10.1016/j.ymgmr.2026.101314
J Biol Chem. 2026 May 06. pii: S0021-9258(26)02000-4. [Epub ahead of print] 113128

The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.

Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt.

  Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.

Keywords:  (10): mitochondria; PINK1; Parkin; aging; autophagy; biomarker; mitophagy; neurodegeneration; phospho-ubiquitin; proteasome

DOI:  https://doi.org/10.1016/j.jbc.2026.113128
Reprod Sci. 2026 May 04.

Mitochondrial Function and Dysfunction in Female Fertility: Biological Mechanisms, Genetic Determinants, and Therapeutic Opportunities - A Review.

Sahana Nagaraju, Syed Sagheer Ahmed, Bharathi Doddlu Raghunathnaidu, Mohammad Ali.

  Female fertility relies on tightly regulated mitochondrial bioenergetics to support oocyte maturation, fertilization, and early embryonic development. Beyond ATP generation, mitochondria orchestrate redox signaling, calcium homeostasis, metabolic-epigenetic coupling, and nuclear-mitochondrial communication, thereby shaping oocyte competence and ovarian longevity. Aging, obesity, metabolic stress, and genetic perturbations disrupt these regulatory networks, leading to redox imbalance, impaired oxidative phosphorylation, altered mitochondrial dynamics, and mitochondrial DNA instability. These changes compromise granulosa cell support, impair meiotic progression, and accelerate ovarian aging, contributing to female infertility disorders such as polycystic ovary syndrome. This review integrates therapeutic strategies that actively reprogram ovarian mitochondrial function rather than merely counteracting damage. Mitochondria-targeted antioxidants-including melatonin, resveratrol, N-acetylcysteine, mitochondria-directed scavengers, and coenzyme Q10 restore redox balance, stabilize mitochondrial dynamics, and enhance oocyte bioenergetics. In parallel, metabolic modulators such as metformin, dapagliflozin, and glucagon-like peptide-1 receptor agonists reprogram ovarian bioenergetics by reshaping substrate utilization, suppressing inflammatory and oxidative signaling, and improving mitochondrial efficiency within the ovary. Collectively, these interventions demonstrate that, positioning mitochondria-centered therapies as promising strategies to preserve fertility and extend the female reproductive health span.

Keywords:  Female fertility; Mitochondria-targeted therapeutics; Mitochondrial dysfunction; Ovarian aging; mtDNA instability

DOI:  https://doi.org/10.1007/s43032-026-02113-8
mBio. 2026 May 05. e0250125

mGem: More than building blocks? Mitochondrial metabolism, viruses, and the host response to infection.

Jessica Alvarez, Dustin C Hancks.

  Beyond essential roles as central hubs integrating homeostatic cellular metabolism, mitochondria have emerged as critical determinants of infection outcomes. Mitochondrial activities, like MAVS signaling and the release of cytochrome c and mitochondrial DNA, drive host defenses. Across cell types, mitochondrial metabolism and antiviral responses are also increasingly being connected by evidence such as viral-encoded antagonists. Nonetheless, metabolic rewiring in infected cells is still largely viewed as a means to satisfy biosynthetic demands for both viral replication and the host response. However, perturbation of metabolic states within infected and bystander cells seemingly has consequences for outcomes, implying an incompletely understood metabo-immunoregulatory logic. Here, we consider roles for mitochondrial metabolism reprogramming as an active cue that licenses progressive immune states to adapt host responses. In the coming years, integration of mitochondrial biology and new methodologies, including spatial approaches, will illuminate the interplay of mitochondrial metabolism on primary antiviral responses.

Keywords:  OXPHOS; immune response; immunometabolism; mitochondria; mitochondrial dysfunction; sterile inflammation; viral infection

DOI:  https://doi.org/10.1128/mbio.02501-25
Clin Transl Sci. 2026 May;19(5): e70551

Supply and Demand in the Mathematics of Rare Disease Drug Development: Why Choosing the Right Model Is Crucial.

Marshall L Summar, Janet Woodcock.

  Clinical trials for rare diseases face a fundamental mathematical challenge that conventional randomized controlled trial (RCT) designs cannot overcome. With approximately 95% of the estimated 10,000-16,000 rare diseases lacking approved therapies, and drug development programs failing at rates exceeding 75% in non-oncology indications, the field confronts a stark reality: Traditional trial designs demand patient numbers that simply do not exist. This perspective article examines the critical mismatch between the statistical requirements of different trial designs (the "demand") and the actual patient populations available for study (the "supply"). We demonstrate mathematically that alternative trial designs-particularly patient-as-own-control and natural history comparator models-can reduce required sample sizes by 5- to 20-fold while maintaining statistical rigor. We further point out that a substantial proportion of rare disease trial failures stem not from therapeutic inefficacy but from recruitment and retention challenges inherent to underpowered RCT designs-challenges that are directly addressable through appropriately matched trial design. Given that most rare disease development programs receive only one opportunity to demonstrate efficacy, the continued application of inappropriate statistical models represents both a scientific failure and an ethical and economic challenge to the rare disease community. We propose that regulatory agencies formalize acceptance of alternative trial designs for rare diseases, supported by explicit mathematical frameworks that transparently account for genetic heterogeneity, pediatric populations, and the statistical efficiency gains achieved through within-subject correlation.

Keywords:  clinical trial design; natural history controls; patient‐as‐own‐control; rare diseases; sample size; statistical power

DOI:  https://doi.org/10.1111/cts.70551
Redox Biol. 2026 Apr 24. pii: S2213-2317(26)00189-8. [Epub ahead of print]93 104191

An integrated anti-aging framework targeting NAD+ homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT.

Yidan Sun, June-Chiew Han, Kenneth Tran, Toan Pham, Qiang Zhou, Jun Lu.

  As the global population ages rapidly, delaying and preventing age-related diseases have become urgent priorities in public health and biomedical research. During aging, mitochondrial dysfunction is a core molecular hallmark and a common pathogenic mechanism underlying multiple age-related disorders. Age-related mitochondrial dysfunction typically manifests as diminished metabolic capacity, impaired organelle renewal, and disrupted redox homeostasis. These factors interact to form a feedback loop constraining mitochondrial adaptability. Specifically, the interdependent decline in NAD+ availability, impaired mitochondrial biogenesis, and excessive oxidative stress render single-pathway interventions ineffective in mitigating systemic functional impairments triggered by aging. To address this complex mechanism, this review presents a novel tri-axis anti-aging model encompassing three key compounds: nicotinamide mononucleotide/nicotinamide riboside (NMN/NR), pyrroloquinoline quinone (PQQ), and l-ergothioneine (EGT). Within this framework, NMN/NR serves as a broad NAD+-dependent regulator of mitochondrial homeostasis, with its most immediate effects on metabolic activation, while PQQ and EGT may further strengthen mitochondrial remodeling and redox resilience, respectively. While each compound has distinct functional emphases, they are highly mechanistically coupled, collectively forming a closed-loop network regulating mitochondrial number, function, and homeostasis. This review synthesizes preclinical and emerging clinical evidence supporting the standalone or combined use of NMN/NR, PQQ, and EGT across various diseases. Collectively, by conceptualizing mitochondrial aging as a systemic imbalance rather than isolated molecular defects, this paper highlights a three-axis model of NMN/NR, PQQ, and EGT. This framework offers a theoretical foundation for mitochondrial-targeted anti-aging interventions while laying the groundwork for future clinical research, nutritional interventions, and the development of multi-target combination strategies.

Keywords:  Anti-aging; Ergothioneine; Mitochondria; NMN; NR; PQQ

DOI:  https://doi.org/10.1016/j.redox.2026.104191
Cell Metab. 2026 May 05. pii: S1550-4131(26)00143-9. [Epub ahead of print]38(5): 838-840

Special packaging enables effective mitochondrial delivery.

Caleb Jerred, Judith Hatzfeld, Alessandro Prigione.

Mitochondrial transplantation has emerged as a promising, though still experimental, strategy for treating mitochondria-related diseases. In a recent study in Cell, Du et al. demonstrate that packaging mitochondria within erythrocyte-derived plasma membranes enhances delivery efficiency and integration, thereby advancing the translational potential of this approach toward clinical application.

DOI: https://doi.org/10.1016/j.cmet.2026.04.005
Curr Drug Deliv. 2026 Apr 24.

Exosomes as Advanced Nanocarriers: Overcoming the Blood-Brain Barrier for Targeted Therapeutic Delivery in Neurodegenerative Diseases.

Farhang Aliakbari, Mehregan Rahmani, Kimia Marzookian, Narges Nasrollahi Boroujeni, Alireza Alikhanian, Fahimeh Ghasemi, Daniel E Otzen, Dina Morshedi.

   INTRODUCTION: Exosomes, nanosized extracellular vesicles secreted by diverse cell types, have emerged as promising natural nanocarriers for therapeutic delivery. Their intrinsic ability to cross the Blood-Brain Barrier (BBB) positions them as valuable tools for treating neurodegenerative diseases. This review critically examines exosome biology, transport mechanisms, engineering strategies, and their clinical potential as drug-delivery platforms for the Central Nervous System (CNS).
METHODS: We analyzed recent experimental, translational, and clinical studies on exosomes and engineered derivatives, focusing on BBB penetration, therapeutic cargo delivery, and applications in brain disorders. Key advances and landmark preclinical studies were synthesized to provide a comprehensive perspective.
RESULTS: Exosomes cross the BBB through receptor-mediated transcytosis, lipid raft-associated uptake, and macropinocytosis, enabling bidirectional transport between circulation and brain. Their intrinsic cargo, including proteins, nucleic acids, and lipids, can reflect disease states and serve as predictive biomarkers. Engineered exosomes further enhance delivery potential, as surface functionalization and optimized cargo loading improve brain specificity and therapeutic efficacy in preclinical models. Collectively, both native and engineered exosomes surpass many synthetic carriers in stability, targeting, and BBB penetration.
DISCUSSION: Versus previous reviews, this manuscript integrates exosome composition, engineering, isolation technologies, and administration routes, while also addressing patent and clinical translation challenges. Importantly, it highlights quantitative and mechanistic insights into BBB transport, offering a distinct framework for advancing exosome-based CNS therapies.
CONCLUSION: Exosomes constitute a versatile platform for BBB-crossing drug delivery. By consolidating mechanistic, preclinical, and translational evidence, this review highlights their transformative potential in neurodegenerative disease therapy while outlining limitations and future directions.

Keywords:  Blood-brain barrier; central nervous system; drug delivery; exosomes; extracellular vesicles; nanocarrier; neurodegenerative diseases

DOI:  https://doi.org/10.2174/0115672018430706251211094801
Eur J Health Law. 2026 Apr 17. 33(2): 137-165

The Dilemma between Data Protection and Data Altruism within the Context of Rare Diseases in the European Health Data Space.

Laura Centeno Casado.

This article analyses how the notion of health data under the GDPR has evolved through the legal instruments and provisions on health data sharing in the Data Governance Act (DGA) and the European Health Data Space (EHDS), aiming both legal sources to facilitate data access and governance, including electronic health data for its primary and secondary use, by establishing harmonised rules. These regulations open opportunities to enhance cross-border data access, the promotion of data altruism, and the development of data governance models facilitating biomedical research. In the specific context of rare diseases, however, significant challenges remain emerging from variations between EU Member States implementation of the EHDS. In particular, the EHDS's secondary use framework, the genomic and biobank data exception, and the coexistence with the DGA's consent‑based data altruism model create a complex legal landscape for rare disease research. This contribution intends to clarify the legal bases for secondary use to improve the capacity to protect data subjects' right to data protection, while preserving data value and utility in biomedical research within the context of rare diseases.

DOI: https://doi.org/10.1163/15718093-bja10169
Front Neurol. 2026 ;17 1775667

Commentary: Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.

Josef Finsterer.



Keywords:  L-arginine; MELAS; mitochondrial disorder; seizure; stroke-like episode

DOI:  https://doi.org/10.3389/fneur.2026.1775667
Genes (Basel). 2026 Apr 17. pii: 472. [Epub ahead of print]17(4):

Enrichment of Rare Variants in Nuclear-Encoded Mitochondrial Metabolism Genes in Patients with Early-Onset or Familial Parkinson's Disease.

Gaber Bergant, Vesna M van Midden, Polina Tsygankova, Dorian Laslo, Valentino Rački, Dejan Georgiev, Eliša Papić, Marija Branković, Milena Janković, Marina Svetel, Nataša Teran, Natasa Dragasević Misković, Igor Petrović, Aleš Maver, Ivana Novaković, Zvezdan Pirtošek, Martin Rakuša, Vladimira Vuletić, Borut Peterlin.

  Introduction: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, with several proposed pathogenic mechanisms. Given the established role of mitochondrial dysfunction in PD, this study seeks to investigate the enrichment of rare genetic variants tied to mitochondrial metabolism in cases of early-onset and familial PD. Methods: We performed a retrospective analysis on 248 early-onset and familial PD patients and 1622 control individuals. We assessed both pathway-level and gene-level burden of germline rare variants detected using exome sequencing in 467 nuclear genes related to mitochondrial metabolism. Results: Gene-set mutation burden analysis indicated an increased burden in genes associated with mtDNA maintenance. In addition, gene-level analysis identified a possible association between PD and rare variant burden in 14 mitochondrial metabolism-related genes under dominant or recessive inheritance models. Conclusions: Our findings support a potential contribution of rare germline variants affecting mitochondrial metabolism to the susceptibility in early-onset and familial PD.

Keywords:  Parkinson’s disease; mitochondrial metabolism; mitochondrial variants; mutation burden analysis

DOI:  https://doi.org/10.3390/genes17040472
Front Cardiovasc Med. 2026 ;13 1802202

Case Report: A young man with mitochondrial disease: intellectual impairment and myocardial hypertrophy.

Xiao Luo, Ling Li, Gaofeng Su.

  Mitochondrial diseases are rare multisystem disorders caused by pathogenic variants in mitochondrial or nuclear DNA. We report a 23-year-old male presenting with exercise intolerance, fatigue, sluggish responsiveness, and a history of ptosis and bilateral hearing loss. Echocardiography revealed left ventricular hypertrophy, while brain MRI showed cerebellar atrophy and ventricular enlargement. Laboratory tests demonstrated elevated serum lactate, HbA1c, and high-sensitivity cardiac troponin T. Targeted sequencing identified a pathogenic m.3243A > G variant in the MT-TL1 gene with 55.6% heteroplasmy, confirming mitochondrial encephalomyopathy with cardiac involvement. This case highlights the phenotypic heterogeneity and diagnostic challenges of m.3243A > G-related disorders.

Keywords:  MT-TL1 gene; cardiomyopathy; m.3243A > G variant; mitochondrial cardiomyopathy; mitochondrial diseases

DOI:  https://doi.org/10.3389/fcvm.2026.1802202
Int J Mol Sci. 2026 Apr 09. pii: 3379. [Epub ahead of print]27(8):

Therapeutic Potential of Mitochondrial Transplantation with Focus on DBD.

Chen Guo, Chenwei Gu, Anjie Chen, Sixin Li, Si Shen, Zhonghao Tang, Jiandong Gui, Lijie Zhu, Sheng Wu, Yuanyuan Mi.

  Diabetic Bladder Disease (DBD), a common urological complication of diabetes mellitus, severely compromises the quality of life of affected patients. Mitochondria, the primary energy-producing organelles in cells, are closely correlated with the pathogenesis and progression of DBD. As an emerging therapeutic modality, mitochondrial transplantation exhibits substantial potential for the management of DBD. This paper presents a comprehensive review of mitochondrial transplantation, with a focus on its fundamental theories, application conditions, safety profiles, and mitochondrial sources. Subsequently, we explore the association between mitochondrial dysfunction and the pathological mechanisms underlying DBD, analyze the disparities between mitochondrial transplantation and conventional therapeutic approaches, and discuss the prospects of combined and personalized treatment regimens. Finally, this review summarizes the ethical controversies surrounding this therapeutic strategy and outlines future research trends, aiming to lay a theoretical foundation for the development of novel therapeutic modalities against DBD.

Keywords:  diabetic bladder disease; mitochondrial dysfunction; mitochondrial transplantation; oxidative stress

DOI:  https://doi.org/10.3390/ijms27083379
Cell Mol Biol Lett. 2026 May 07.

Regulation of mitochondrial function during spermatogenesis and sperm maturation.

Kai Meng, Ziming Zhu, Haocheng Jia, Yingying Feng, Jingwen Feng, Yanlin Shen, Wenjia Jiang, Chenyan Liu, Qin Qin, Fei Gao, Jinxiang Yuan.

  With the recent increase in the incidence of male infertility, greater attention is being paid to male reproductive health. The causes of male infertility are complex, and damage occurring during any process from spermatogenesis to fertilization can affect sperm quantity and quality of the sperm. Mitochondria are the power sources of cells and help regulate cellular homeostasis and physiological function. Mitochondria play a crucial role in male reproduction. Mitochondria undergo dynamic changes during spermatogenesis, sperm maturation, and fertilization. Mitochondrial dynamics and mitophagy help regulate the structure and function of mitochondria by meeting the cellular energy requirements of sperm during reproduction and reducing levels of damaged mitochondrial DNA (mtDNA); the elimination of excess mtDNA during fertilization prevents the spread of genetic mutations. Stable mitochondrial function ensures the smooth occurrence and maturation of sperm, maintaining male fertility. Externally induced mitochondrial dysfunction can lead to an inadequate energy supply, oxidative stress, cellular apoptosis, and abnormal sperm structure formation, which can lead to male infertility. In this article, the mechanism through which mitochondrial dysfunction affects the entire process of male reproduction, from spermatogonial stem cell division to final fertilization, and leads to infertility is discussed in chronological order. This article explores potential therapeutic targets for improving male fertility through therapies targeting mitochondrial function to provide a reference for subsequent research and more precise treatment directions.

Keywords:  Energy metabolism; Genomic; Male infertility; Quality control; Spermatogenesis

DOI:  https://doi.org/10.1186/s11658-026-00944-6
J Alzheimers Dis. 2026 May 08. 13872877261442231

Association of mitochondrial genome variants with Alzheimer's disease in a Chinese population.

Xiaoli Hao, Bin Jiao, Yijing Wang, Tianyan Xu, Qijie Yang, Yuan Zhu, Yiliang Liu, Cong Zhang, Xiaoyan Liang, Yafang Zhou, Xinxin Liao, Shilin Luo, Beisha Tang, Jinchen Li, Xuewen Xiao, Lu Shen.

  BackgroundResearch on the mitochondrial genome variants of Alzheimer's disease (AD) in Chinese populations is lacking.ObjectiveThe study aimed to identify mitochondrial DNA (mtDNA) variants associated with AD risk and explore the relationship between mtDNA variants and plasma biomarkers in AD patients.MethodsWhole genome sequencing was performed in 1509 AD patients and 2010 controls from the Chinese population. mtDNA variants were called according to GATK's best practice mitochondrial pipeline. We evaluated the association of AD risk with mtDNA variants and mitochondrial haplogroup. Common variant (MAF≥0.01) based association analysis and gene-based tests of rare variants (MAF<0.01) were carried out with PLINK 1.9 and SKAT-O, respectively. Spearman correlation analysis was performed to assess the association between the burden of mtDNA variants and plasma biomarker levels.ResultsThe frequency of mitochondrial haplogroup G in AD group was nominally higher than control group (p = 0.019, OR = 1.48). Rare variants of MT-CYB gene were significantly enriched in controls compared to AD patients (p = 2.81 × 10-4, OR = 0.886). Besides, the control group exhibited considerably lower mRNA expression of MT-CYB in brain regions compared to AD patients in GEO database. Furthermore, the number of mtDNA indel variants per individual correlated positively with plasma Aβ42 levels.ConclusionsMitochondrial haplogroup G may serve as a risk factor for AD, while rare variants of MT-CYB gene acted as protective factor against AD in mainland China. Moreover, mtDNA variants were related to AD plasma biomarker levels. Our findings highlighted the role of mitochondrial genome variants in the pathogenesis of AD.

Keywords:  Alzheimer's disease; mitochondrial DNA variants; mitochondrial haplogroup; plasma biomarker

DOI:  https://doi.org/10.1177/13872877261442231
Transpl Immunol. 2026 Apr 30. pii: S0966-3274(26)00048-1. [Epub ahead of print]96 102390

Nebulized mitochondrial transplantation attenuates inflammation and improves graft function in a murine donation after cardiac death lung transplant model.

Logan Langerude, Dianna Nord, Alexander McQuiston, Xinsheng Hu, Jennie Kwon, Satish Nadig, Jennifer Mulligan, Carl Atkinson, Zhenxiao Tu.

   BACKGROUND: Mitochondrial transplantation is a promising therapy for ischemia reperfusion injury (IRI), with efficacy demonstrated in preclinical and early clinical cardiac studies. Its application in lung transplantation (LTx), particularly with donation after cardiac death (DCD) donors, remains unexplored. We hypothesized that nebulized delivery of mitochondria at the time of reperfusion would protect against IRI and engage mitochondrial quality-control pathways.
METHODS: A murine allogeneic orthotopic LTx model was used with DCD donor lungs subjected to 18 h of cold ischemia. At reperfusion, recipients received nebulized vehicle, Mitochondria-enriched fractions, or heat inactivated mitochondria-enriched fractions. At 24 h, graft oxygenation, histopathology, edema (wet-to-dry ratio, BAL albumin), and immune infiltration were assessed. BAL cytokines were measured by multiplex assay, mitochondrial uptake by flow cytometry, PINK1 expression, and circulating mitochondrial DNA (mtDNA) by qPCR.
RESULTS: Mitochondria-treated recipients had reduced histologic injury and improved graft function as determined by PaO₂ (p < 0.005). Edema was decreased (wet-to-dry 5.0 ± 0.4 vs 7.6 ± 1.1, p < 0.05), as was neutrophil infiltration (44.7 ± 2.2 vs 91.3 ± 8.0 MPO+ cells/image). BAL proinflammatory cytokines IL-6, KC, and MCP-1 were significantly reduced in recipients receiving mitochondrial therapy (p < 0.05). PINK1 expression was significantly increased in treated lungs, consistent with mitophagy activation. Serum mtDNA levels were unchanged between groups.
CONCLUSIONS: Nebulized mitochondrial transplantation improves oxygenation, reduces IRI, and activates PINK1-dependent quality control without increasing systemic mtDNA. This localized therapy represents a novel strategy to improve outcomes after DCD LTx.

Keywords:  Donation after cardiac death; Ischemia reperfusion injury; Lung transplantation; Mitochondria

DOI:  https://doi.org/10.1016/j.trim.2026.102390
bioRxiv. 2026 Apr 27. pii: 2026.04.24.720727. [Epub ahead of print]

TFAM organizes DNA into compact higher order structures.

Sashi R Weerawarana, Wei Tian, Karolin Luger.

TFAM (Transcription Factor A, Mitochondrial) is an essential human protein that plays two key roles in mitochondrial DNA (mtDNA) homeostasis. TFAM acts as a transcription factor that specifically binds to promoter regions, but it is also solely responsible for organizing mtDNA into nucleoids by nonspecifically covering the entire genome. Many studies have addressed TFAM in transcription regulation, but its role as a genome organizing entity is not well characterized. The current understanding of how TFAM compacts DNA into nucleoids is based on crystal structures of a TFAM monomer bound to short fragments of DNA (22-28 bp). However, this does not adequately reflect the biological role of TFAM in organizing the nucleoid where multiple TFAM molecules oligomerize on the 16.5 kb genome to form the nucleoid. Here, we present a biochemical and structural analysis of TFAM oligomerization on longer DNA. Our results show that TFAM compacts longer segments of DNA into higher order complexes that are homogenous yet exhibit continuous conformational dynamics.
Significance statement: Mutations or damage to mitochondrial DNA (mtDNA) severely impairs cellular respiration and is implicated in many human diseases and aging. 'Transcription Factor A, Mitochondrial' (TFAM) is an essential protein that is solely responsible for packaging mtDNA into nucleoids thereby shielding it from DNA damage. Despite its importance, the mechanism by which this is accomplished is poorly understood. Here, we use biochemistry to show that TFAM oligomerizes on DNA to form compact, homogenous higher order structures in solution. We also examined these complexes at a low resolution using cryo-EM, suggesting an organizational unit of mtDNA. This work reveals there may be a regular organization to mitochondrial nucleoids, providing the basis for further understanding mtDNA compaction by TFAM.

DOI: https://doi.org/10.64898/2026.04.24.720727
Environ Anal Health Toxicol. 2026 Mar;41(1): e2026007

Alterations in mitochondrial DNA copy number and oxidative stress markers in blood and muscle tissues of mice following snake envenomation.

Sunutcha Suntrarachun, Panithi Laoungbua, Suchitra Khunsap, Rattana Suttisee.

  Snake envenomation represents a significant toxicological and public health concern, causing systemic effects mediated by oxidative stress and cellular injury. Mitochondria are especially susceptible to stress generated by venom, however the initial mitochondrial responses after envenomation are not fully understood. This study investigated time- and tissue-dependent changes in relative mitochondrial DNA (mtDNA) abundance and oxidative stress markers in mice exposed to neurotoxic and hematotoxic snake venoms. Neurotoxic venoms included Naja kaouthia (monocled cobra), Ophiophagus hannah (king cobra), Bungarus fasciatus (banded krait), and Bungarus candidus (Malayan krait), while hematotoxic venoms comprised Calloselasma rhodostoma (Malayan pit viper), Daboia siamensis (Siamese Russell's viper), and Trimeresurus albolabris (white-lipped pit viper). Venoms were administered intramuscularly at empirically determined sublethal doses. Whole blood, tibialis anterior muscle tissue, and mononuclear cells (MNCs) were collected at 1, 6, and 24 hours post-exposure. Relative mtDNA copy number was quantified using SYBR-based real-time quantitative PCR targeting mtDNA-encoded genes (16S rRNA and ND1) normalized to a nuclear reference gene, with additional assessment of cytochrome b (Cytb) and cytochrome c oxidase subunit III (COXIII) as indicators of mitochondrial perturbation. Oxidative stress responses were evaluated by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels. Venom exposure induced distinct temporal and tissue-specific patterns of mtDNA-associated changes, accompanied by alterations in lipid peroxidation and antioxidant status. Whole blood consistently exhibited earlier and more robust responses than muscle tissue or MNCs. Although mtDNA-related parameters and oxidative stress markers are not specific to envenomation, their combined temporal profiles reflect venom-induced mitochondrial and redox stress. These findings support the potential utility of blood-based mtDNA and oxidative indicators as sensitive, venom-independent tools for evaluating systemic responses to snake envenomation.

Keywords:  Mitochondrial DNA; Oxidative stress; Snake envenomation

DOI:  https://doi.org/10.5620/eaht.2026007
Chem Res Toxicol. 2026 May 07.

Drug-Induced Liver Injury: Mitochondrial Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.

Brijesh Kumar Verma, Drashti Bhalgama, Pooja Thakur, Debashis Banerjee.

Drug-induced liver injury (DILI) remains a major challenge in drug development and clinical pharmacology, contributing significantly to late-stage attrition and regulatory failure. Growing experimental evidence implicates mitochondrial dysfunction as a central mechanism underlying chemically induced hepatotoxicity. This review provides an integrated analysis of mitochondrial pathways involved in DILI, including disruption of oxidative phosphorylation, inhibition of fatty acid β-oxidation, mitochondrial permeability transition, and mitochondrial DNA damage. We synthesize data from in vitro systems, animal models, and human studies to illustrate how diverse xenobiotics converge on mitochondrial targets to trigger hepatocellular injury. Emerging mitochondrial biomarkers, such as glutamate dehydrogenase, circulating mitochondrial DNA, and microRNAs, are discussed in the context of mechanistic relevance and translational utility. In addition, advances in experimental models including humanized mice and liver organoids are evaluated for their predictive value in drug safety assessment. The review further highlights mitochondria-centered intervention strategies as mechanistic tools to validate injury pathways and inform pharmacological risk mitigation. By integrating mitochondrial biology with applied toxicology, this review provides a mechanistic framework to improve early detection, mechanistic understanding, and prevention of drug-induced liver injury during drug development.

DOI: https://doi.org/10.1021/acs.chemrestox.6c00030
Sci Adv. 2026 May 08. 12(19): eaec0795

Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.

Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.

The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.

DOI: https://doi.org/10.1126/sciadv.aec0795
Cancer Discov. 2026 May 05. OF1

Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2026-043
Nat Commun. 2026 05 07. pii: 4195. [Epub ahead of print]17(1):

Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.

Maria E Gierisch, Enrica Barchi, Mirco Marogna, Moritz H Wallnöfer, Maria Ankarcrona, Luana Naia, Florian A Salomons, Nico P Dantuma.

The accumulation of protein aggregates has been causatively linked to the pathogenesis of neurodegenerative diseases. Here, we conduct a genome-wide CRISPR-Cas9 screen to identify cellular factors that regulate the degradation of an aggregation-prone reporter. Genes encoding proteins involved in mitochondrial homeostasis, including the translation factor eIF5A, are enriched among suppressors of the degradation of the reporter. Genetic or chemical inhibition of eIF5A leads to dissociation of the aggregation-prone substrate from mitochondria, which is accompanied by enhanced ubiquitin-dependent proteasomal degradation. The presence of an aggregation-prone, amphipathic helix that localizes the reporter to mitochondria is crucial for the stimulatory effect of eIF5A inhibition on proteasomal degradation. Additionally, inhibition of eIF5A also enhances degradation of mutant huntingtin and α-synuclein, two disease-associated proteins that contain amphipathic helices and mislocalize to mitochondria. We propose that mitochondria serve as a holdout compartment for aggregation-prone proteins. Therefore, preventing mitochondrial localization of aggregation-prone proteins may offer a viable therapeutic strategy for reducing disease-associated proteins in neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41467-026-72783-0
Nihon Yakurigaku Zasshi. 2026 ;161(3): 140-144

[Multi-modality strategy for creating innovative drugs].

Narihiro Toda.

In recent years, a wide variety of modalities, including small molecules, antibodies, nucleic acids, and gene therapies, have been successfully applied to drug discovery and have demonstrated significant achievements. The diversification and advancement in modalities have expanded the range of targets and diseases we can address, opening new opportunities for drug discovery. At Daiichi Sankyo, we are advancing a multi-modality strategy that shifts the focus from solely small molecules to broader range of modalities. In this strategy, it is critical to select the appropriate modality for each target to transform research concepts into viable drug candidates. Additionally, developing competitive modality technologies and platforms is essential for continuously creating innovative drugs with improved treatment outcomes. Our multi-modality strategy enables us to combine different modality technologies into more advanced modality development.

DOI: https://doi.org/10.1254/fpj.25060
Curr Med Chem. 2026 Apr 30.

Global Research Progress of Sepsis and Mitochondria: Bibliometrics and Visualized Analysis.

Luorui Shang, Yuju Cai, Shuhan Wang, Jinxiao Li, Fangyuan Zhou, Mengqi Zhang, Yuqing Wang, Jianghua Huang, Shenglan Yang.

   OBJECTIVE: Many studies have demonstrated a significant association between mitochondria and sepsis. As research on mitochondria continues to deepen, substantial advancements have been achieved in elucidating the connection between mitochondria and sepsis. Nevertheless, there has been no systematic bibliometric analysis or visualization of the related publications in this field. This study aims to visually present the knowledge system and research focus between mitochondria and sepsis through the method of bibliometrics.
METHODS: An extensive review of existing literature was conducted using the Web of Science Core Collection (WoSCC) database to identify publications investigating the relationship between mitochondria and sepsis. Subsequent bibliometric analysis was conducted using R software (version 4.4.0) with the Bibliometrix package (version 4.2.3), complemented by visualization and network analysis through VOSviewer (version 1.6.20) and CiteSpace (version 6.1.6).
RESULTS: From 1997 to 2025, the Web of Science Core Collection retrieved a total of 1993 relevant publications. The number of publications related to mitochondria and sepsis has continued to increase throughout this period. China, along with the United States and the United Kingdom, plays a central role in advancing research in this field. Leading institutions contributing to this area include the University of Pennsylvania, Harvard University, and the University of London. SINGER M and ZHANG Y are the top authors in this research field. The keyword analysis reveals that the high-frequency terms include sepsis, mitochondrial dysfunction, oxidative stress, and inflammation. We summarized the pathogenesis of sepsis related to mitochondria, as well as the existing and potential therapeutic drugs for sepsis that are associated with these mechanisms.
DISCUSSION: As the comprehensive bibliometric analysis in this field, our study visually presents key research trends and hotspots linking mitochondria to sepsis, emphasizing the significance of mitochondrial dysfunction and other factors in the pathogenesis of sepsis, offering a valuable framework for future scientific and clinical advancements.
CONCLUSION: The field of mitochondrial research in sepsis has experienced steady growth over the past two decades, with substantial contributions from China, the United States, and the United Kingdom. Emerging evidence suggests that future investigations are likely to center on key pathological mechanisms such as mitochondrial dysfunction and oxidative stress.

Keywords:  Sepsis; VOSviewer; bibliometrics; citespace; leukocytes.; mitochondria

DOI:  https://doi.org/10.2174/0109298673433066260127165730
Clin Transl Sci. 2026 May;19(5): e70570

Optimizing Oligonucleotide Therapeutics: A Model-Informed Drug Development Perspective.

Ye Yuan, Vishnu Sharma, Venkatesh Atul Bhattaram, Xiaolei Pan, Justin Earp, Yun Wang, Jiang Liu, Hao Zhu.

  Oligonucleotide therapies have emerged as a powerful therapeutic class, providing novel solutions for diverse diseases through antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and aptamers that specifically target and modulate gene expression or protein function. However, oligonucleotide development faces distinct challenges, particularly the significant disconnect between systemic exposure and tissue activity, as these therapeutics are cleared from circulation relatively rapidly yet persist intracellularly with sustained pharmacological effects. This temporal disconnection, combined with limited clinical trial data due to the predominance of rare disease indications, complicates dose optimization and efficacy prediction using traditional development approaches. Model-informed drug development (MIDD) has emerged as a critical solution to address these unique oligonucleotide challenges by leveraging quantitative models to bridge the PK-PD disconnect, optimize dosing strategies despite limited data, and enhance decision-making throughout development. This manuscript comprehensively reviews how MIDD has been successfully applied across FDA-approved oligonucleotide therapies to inform endpoint selection for accelerated approvals, guide dosing strategies for general and subpopulations, and support efficient clinical development across multiple therapeutic areas. By elucidating MIDD's specific contributions to overcoming oligonucleotide development challenges, this review highlights the essential role of quantitative modeling strategies in advancing oligonucleotide therapeutics and enhancing their clinical and regulatory success.

Keywords:  ASO; MIDD; oligonucleotide therapy; siRNA

DOI:  https://doi.org/10.1111/cts.70570
BMC Pediatr. 2026 May 02.

Awareness and knowledge gaps about pediatric rare disease among anesthesia practitioners in China: a survey-based study.

Yan Ming Kang, Zhen Xia, Xiang Li, Xiao Qin Jiang, Na Hu, Jiang Han, Sai Nan Duan, Dong Xu Chen.

   BACKGROUND: Anesthetic management of pediatric patients with rare diseases presents substantial perioperative challenges and risks. This study evaluated the clinical competency and specific educational needs of anesthesia practitioners in China regarding the perioperative management of this vulnerable patient population.
METHOD: A cross-sectional survey was conducted from May 2024 and March 2025, involving 2127 anesthesia practitioners across China. Data were collected via a validated anonymous questionnaire and analyzed through descriptive statistics and chi-square tests.
RESULT: Among the 2,127 participants, 93.5% were anesthesiologists and 6.5% were nurse anesthetists. Of these, 43.2% (919/2127) reported previous experience in administering anesthesia to children with rare diseases. Despite this exposure, self-assessed competency levels were notably insufficient. Only 9.0% (191/2127) of respondents reported comprehensive knowledge of pediatric rare diseases, and 15.0% (318/2127) expressed adequate confidence in perioperative management protocols. Objective assessment of specific knowledge domains revealed considerable deficiencies: 14.9% (317/2127) of respondents correctly identified contraindications in muscular dystrophy, 6.6% (141/2127) demonstrated adequate understanding of difficult airway indicators, and merely 3.9% (82/2127) accurately recognized depolarizing agent risks. Comparative analysis between self-rated high-familiarity and low-familiarity groups revealed that direct clinical exposure was significantly associated with practitioners' understanding of pediatric rare diseases. Regarding the development of future anesthesia support systems for pediatric rare diseases, practitioners identified two primary requirements: comprehensive diagnostic information (58.6%, 1246/2127) and detailed anesthesia contraindications (57.0%, 1212/2127). Additionally, 50.1% (1065/2127) of respondents emphasized the importance of real-time knowledge base updates to ensure access to current clinical guidelines and safety protocols.
CONCLUSION: This study highlights substantial knowledge gaps and insufficient confidence among anesthesia practitioners in the perioperative management of children with rare diseases, underscoring an urgent need for enhanced training and robust support systems in this specialized area.

Keywords:  Anesthesia; Knowledge gaps; Perioperative support system; Rare diseases

DOI:  https://doi.org/10.1186/s12887-026-06957-6
Pathogens. 2026 Mar 31. pii: 372. [Epub ahead of print]15(4):

Orientia tsutsugamushi Alters Mitochondrial Function and Selectively Associates with VDAC.

Savannah E Sanchez, Travis J Chiarelli, John S Billingsley, Richard T Marconi, Jason A Carlyon.

  Orientia tsutsugamushi is an obligate intracellular alphaproteobacterium and the causative agent of the potentially fatal rickettsiosis, scrub typhus. During infection, O. tsutsugamushi replicates exclusively in the eukaryotic cytosol near mitochondria and alters host metabolic pathways governed by mitochondria. We report that O. tsutsugamushi induces mitochondrial enzymatic impairment and structural abnormalities without altering mitochondrial abundance or the levels of proteins that maintain mitochondrial homeostasis. Confocal and structured illumination microscopy revealed a selective spatial association between O. tsutsugamushi and the mitochondrial membrane protein, voltage-dependent anion channel (VDAC) but not other mitochondrial proteins. Immunosignal for VDAC paralogs 1 and 3 colocalized with cytosolic O. tsutsugamushi organisms whereas VDAC2 did not. Additionally, the antibody specific for VDAC1 and VDAC3 detected proteins of the expected sizes in Orientia membrane fractions. These findings indicate that O. tsutsugamushi negatively impacts mitochondrial function without overt organelle loss and selectively associates with VDAC1/VDAC3.

Keywords:  Orientia tsutsugamushi; host–pathogen interactions; mitochondrial dysfunction; obligate intracellular bacterium; scrub typhus; voltage-dependent anion channel (VDAC)

DOI:  https://doi.org/10.3390/pathogens15040372
bioRxiv. 2026 Apr 24. pii: 2026.04.22.720193. [Epub ahead of print]

Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.

Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.

The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans . Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.

DOI: https://doi.org/10.64898/2026.04.22.720193
Lancet Rheumatol. 2026 May 01. pii: S2665-9913(26)00146-3. [Epub ahead of print]

A wait-and-see prognosis: living with a rare progressive disease.

Jules Morgan.

DOI: https://doi.org/10.1016/S2665-9913(26)00146-3
Healthcare (Basel). 2026 Apr 15. pii: 1048. [Epub ahead of print]14(8):

Person-Centered Care in Digital Health Interventions for Chronic Diseases: A Systematic Review.

Adrijana Svenšek, Lucija Gosak, Tamara Trajbarič, Luka Šajher, Gregor Štiglic, Mateja Lorber.

   BACKGROUND/OBJECTIVES: Digital health interventions are increasingly used to support person-centered care (PCC) in chronic disease management, yet it remains unclear which PCC components are most consistently enabled by digital tools and how these relate to outcomes. This study synthesized evidence on digitally supported PCC for adults with chronic conditions, examining how interventions operationalize PCC and which clinical, patient-reported, and implementation outcomes are reported.
METHODS: A structured literature synthesis was conducted according to PRISMA guidelines across a heterogeneous evidence base, including randomized and pragmatic trials, observational studies, qualitative studies, and systematic reviews. The review protocol was pre-registered in the Open Science Framework (OSF) Registries.
RESULTS: Across 16 included studies, digital solutions most consistently supported PCC through enhanced situational awareness via self-monitoring, strengthened partnership through two-way communication and coaching, and reinforced shared documentation through co-created health plans. Benefits were reported most consistently for process and experience outcomes, such as perceived access to support, engagement, and empowerment. Evidence for sustained long-term clinical improvements, such as glycemic control, was mixed and frequently limited by short follow-up periods and variation in intervention integration.
CONCLUSIONS: Digitalization can strengthen PCC when embedded within relational care models and organizational workflows that translate patient-generated data into meaningful action. Future work should utilize clearer PCC operationalization, longer follow-up, and routine reporting of equity outcomes, alongside targeted training for healthcare professionals delivering PCC in digital encounters.

Keywords:  chronic diseases; digital transformation; person-centered care; sustainable development

DOI:  https://doi.org/10.3390/healthcare14081048
Int Med Case Rep J. 2026 ;19 571657

Genetic Features and Clinical Heterogeneity of Leber Hereditary Optic Neuropathy in Adolescent and Adult Patients: A Case Series on Arab Patients.

Esraa Basalem, Nooran Badeeb.

  Leber hereditary optic neuropathy (LHON) is a rare disorder characterized by painless progressive visual loss. LHON is caused by maternally inherited mitochondrial DNA (mtDNA) point mutations, impairing the electron transport chain and oxidative phosphorylation. Environmental and nuclear factors may further influence disease manifestation. This case series describes the clinical characteristics, mutation profiles, and visual outcomes in patients from Saudi Arabia and Yemen, regions where reported data remain scarce. Patients were diagnosed with LHON based on characteristic clinical features confirmed through genetic testing. The series highlights both adolescent-and adult-disease onset, with most patients carrying the m.11778G>A mutation, consistent with global prevalence patterns. Distinct modifiable risk factors were identified in several cases. Treatment with Idebenone (two out of two patients) was associated with visual improvement and favorable outcomes, while patients treated with coenzyme Q10 reported subjective visual improvement that was not detected through visual assessments. These findings contribute to the limited data on LHON in the Arabian Peninsula underscoring the importance of early genetic testing and treatment initiation. However, the small sample size, non-uniform participant visit schedules, and variable follow-up period limit the generalizability of the findings. Increased regional awareness and reporting, as well as mitigating financial obstacles, are essential to improve diagnostic timing and optimize outcomes in this rare but impactful disorder.

Keywords:  Arabian Peninsula; Idebenone; LHON; m.11778G>A

DOI:  https://doi.org/10.2147/IMCRJ.S571657
J Allergy Clin Immunol Glob. 2026 Jul;5(4): 100704

Emerging trends and research hot spots in inborn error of immunity: A bibliometric perspective.

Hiba Alblooshi, Muhamad Jalal Khan, Farida Almarzooqi.

   Background: Inborn errors of immunity (IEIs) are an expanding group of genetically defined disorders associated with infections, autoimmunity, and malignancy. Advances in high- throughput genomics and updates to international classifications have reformed the field, shifting from phenotype-based descriptions to molecular frameworks. Bibliometric analysis offers a structured approach to mapping research growth, collaboration, and thematic evolution.
Objective: We analyzed global IEI research from 1995 to 2025 using bibliometric methods, focusing on publication trends, collaboration networks, leading contributors, and thematic shifts.
Methods: Publications were retrieved from Web of Science Core Collection and PubMed. After screening, 840 original articles were analyzed with Biblioshiny and VOSviewer to assess citation patterns, coauthorship, thematic clusters, and keyword evolution.
Results: IEI research (n = 840; 333 journals; 7,466 authors) increased at 4.5% annually, with a marked rise after 2018 after next-generation sequencing and International Union of Immunologic Societies classification updates. The United States produced the largest output, while European countries had a higher citation impact per article. Collaboration was strongest between North America and Europe, with other regions remaining more domestically focused. Thematic mapping revealed a transition from clinical phenotypes to genetic, multiomic, and precision frameworks, alongside growing focuses on autoinflammation, immune dysregulation, and rare disease subgroups.
Conclusion: Over 3 decades, IEI research has expanded substantially, reflecting a paradigm shift toward molecular discovery and international collaboration. Persistent regional disparities highlight the need for inclusive genomic studies and equitable partnerships, providing strategic insights to advance clinical immunology and enhance care for patients with rare immune disorders.

Keywords:  Inborn errors of immunity; bibliometrics; genomics; global collaboration; health equity; immunodeficiency; multiomics; precision medicine; rare diseases; translational immunology

DOI:  https://doi.org/10.1016/j.jacig.2026.100704
Cell Death Dis. 2026 May 08.

A new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury dynamically regulating mitochondrial function to remodel the immune network.

Lizheng Huang, Yuqian Wang, Chunyi Li, Xiaojing Wang, Anqi Xiao, Fanglei Han, Jinlan Jiang.

Cerebral Ischemia-Reperfusion Injury (CIRI) is a common pathological process in ischemic stroke. Its core detriment lies in the cascade of subsequent injuries triggered by blood flow restoration after cerebrovascular recanalization, primarily including oxidative stress burst, calcium overload, immune-inflammatory imbalance, and mitochondrial dysfunction, ultimately leading to massive neuronal apoptosis and necrosis. Mitochondria, as central hubs of cellular energy metabolism and apoptosis regulation, exhibit functional disturbances that represent the initiating and core link in CIRI. CIRI triggers complex remodeling of the immune network. This dysregulated immune-inflammatory response forms a vicious cycle with mitochondrial dysfunction, exacerbating brain tissue damage. Mesenchymal Stem Cells (MSCs) and their derivatives have demonstrated significant potential in treating CIRI due to their potent paracrine and immunomodulatory functions. MSCs can repair neuronal functional basis by enhancing mitochondrial biogenesis, improving energy metabolism, inhibiting mitochondrial pathway-mediated apoptosis, restoring dynamic balance, and promoting normal mitophagy. Although existing reviews have explored the role of MSCs or mitochondrial function in CIRI, few studies have systematically integrated the bidirectional regulatory relationship between dynamic mitochondrial function and immune network remodeling. Furthermore, an in-depth analysis of the temporal therapeutic effects of MSCs and their derivatives across different pathological stages of CIRI is lacking. To address this gap, this review proposes a therapeutic strategy: MSCs exert synergistic neuroprotective effects by improving mitochondrial function through multiple targets while systematically reshaping the imbalanced immune network. This review summarizes the latest evidence regarding the temporal therapeutic role of MSCs via the "immune-mitochondrial" axis at different stages of CIRI. It elucidates the pivotal role of mitochondria as a central hub connecting metabolic crisis and immune storm, and untangles novel mechanisms such as MSC-mediated mitochondrial transfer and immune cell metabolic reproprogramming, providing a theoretical foundation for developing novel stroke therapies based on cell therapy.

DOI: https://doi.org/10.1038/s41419-026-08834-7
Antioxidants (Basel). 2026 Apr 19. pii: 506. [Epub ahead of print]15(4):

Review of Therapeutic Potential of Coenzyme Q10 in Ophthalmology: Focus on Age-Related Macular Degeneration, Glaucoma, and Retinitis Pigmentosa.

Michał Wiciński, Anna Fajkiel-Madajczyk, Zuzanna Kurant, Łukasz Rzepiński, Maciej Słupski.

  Coenzyme Q10 (CoQ10), a natural antioxidant produced by the human body, has strong anti-inflammatory properties, reduces oxidative stress, and improves mitochondrial function. It is also known for its strong neuroprotective effects. With age, endogenously produced CoQ10 levels decline, contributing to the development of chronic diseases, including eye disorders. Irreversible ocular diseases that result in blindness present a significant challenge in contemporary medicine, as no fully effective cure exists; current treatments primarily aim to decelerate disease progression, manage symptoms, and preserve residual vision. Our study reviews research on the use of CoQ10 in eye diseases like age-related macular degeneration (AMD), retinitis pigmentosa (RP), and glaucoma, which can cause permanent vision loss and are linked to oxidative stress and mitochondrial dysfunction. This article explores whether CoQ10 can be a safe and effective addition to treatment for these conditions. We also outline directions for future research and explain how CoQ10 functions in the studies discussed in this review.

Keywords:  AMD; CoQ10; RP; coenzyme Q10; glaucoma; ophthalmology

DOI:  https://doi.org/10.3390/antiox15040506
bioRxiv. 2026 Apr 30. pii: 2026.04.29.721747. [Epub ahead of print]

Multiomic Profiling of 85 iPSC Lines from Familial Dementia Reveals Cellular Diversity and Regulators of Organoid Development.

Le Qi, Taylor Bertucci, Susan Borden, Brigitte Arduini, Steven Lotz, Kathryn Bowles, Alison M Goate, Celeste Karch, Sally Temple, Daniel Geschwind.

Patient-derived induced pluripotent stem cells (iPSCs) are used for disease modeling and therapeutic development, yet their systematic molecular and genetic characterization is uncommon. Here, we performed whole genome sequencing (WGS), bulk/single-cell RNA-sequencing (RNA-seq) and DNA methylation analysis on 85 iPSC lines harboring MAPT mutations and corresponding isogenic controls. Single-cell RNA-seq revealed reproducible inter- and intra-line heterogeneity related to quality/pluripotency and nominated surface markers to quantify iPSC subclusters. WGS detected unintended editing events and structural variants, including the 20q21.31 duplication, missed by standard assays. We identified pathways correlated with neural organoid formation efficiency and with genome-editing and clonal-selection effects, underscoring the need to use unedited lines as isogenic controls. This comprehensive dataset improves the utility of the MAPT iPSC collection and provides proof of principle supporting in-depth genomic characterization to improve iPSC utility in biological research.

DOI: https://doi.org/10.64898/2026.04.29.721747
bioRxiv. 2026 Apr 30. pii: 2026.02.10.705161. [Epub ahead of print]

The GA4GH Categorical Variation Representation Specification: A Unified Computational Framework for Reasoning over Genomic Variant Categories.

Daniel Puthawala, Brendan Reardon, Lawrence Babb, Kori Kuzma, James S Stevenson, Wesley A Goar, Robert H Dolin, Robert R Freimuth, Catherine Procknow, Beth Pitel, Parijat Kundu, Akash Rampersad, Eliezer Van Allen, Alex H Wagner.

Categorical variants, or sets of genomic alterations constrained by shared properties, are pervasive across clinical, regulatory, and research domains in the biomedical ecosystem, yet their inconsistent and non-computable representation hinders data interoperability and clinical interpretation. We surveyed genomic knowledgebases spanning regulatory approvals and the biomedical literature and found that categorical variants underpin a substantial proportion of clinical genomics knowledge, but are largely described using incompatible bespoke models. To address this, we developed the GA4GH Categorical Variation Representation Specification (Cat-VRS), a constraint-based framework that provides a unified computable representation for both precise and intentionally broad categories across molecular and systemic variant domains. Cat-VRS enables harmonization of genomic knowledgebases, computable category-based search, and automated matching between assayed variants and categorical entities in clinical and research contexts. By providing a principled, extensible model for categorical variation, Cat-VRS enables computable reasoning over genomic variant categories and establishes a foundation for the standardized representation and exchange of genomic knowledge.

DOI: https://doi.org/10.64898/2026.02.10.705161
Front Immunol. 2026 ;17 1781434

Energy metabolism dysregulation in idiopathic inflammatory myopathies: mechanisms and therapeutic implications.

Yuan Fang, Huihui Chi, Jialin Teng, Chengde Yang, Yue Sun, Yutong Su.

  Idiopathic inflammatory myopathies (IIMs) are being increasingly recognized as disorders driven by profound disturbances in cellular energy metabolism rather than inflammation alone. Recent studies have highlighted mitochondrial dysfunction, oxidative stress, and metabolic reprogramming across glucose, lipid, and amino acid pathways as central mechanisms linking energy metabolism dysregulation to sustained muscle injury. Defective mitophagy, mitochondrial DNA (mtDNA) depletion, and excessive reactive oxygen species (ROS) production create a self-amplifying loop with interferon-driven inflammation, whereas abnormal glycolysis, impaired fatty acid oxidation, and dysregulated tryptophan-kynurenine metabolism further shape the immunometabolic landscape of IIMs. These metabolic shifts not only contribute to muscle weakness and tissue degeneration but are also correlated with disease severity, autoantibody profiles, and treatment resistance. Emerging therapeutic strategies, including antioxidant approaches, mitochondrion-targeted agents, metabolic modulators, and exercise-based interventions, underscore the translational potential of targeting energy homeostasis. This review synthesizes current evidence on energy metabolism abnormalities in IIMs, integrates molecular findings with clinical implications, and highlights future directions for immunometabolic-based precision therapies.

Keywords:  energy metabolism; idiopathic inflammatory myopathies; immunometabolism; metabolic reprogramming; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2026.1781434
Int J Mol Sci. 2026 Apr 08. pii: 3347. [Epub ahead of print]27(8):

Coenzyme Q10 Deficiency and Elevated LEAK Mitochondrial Respiration as Potential Heart Failure Markers in Ebstein Anomaly.

Filip Klaučo, Iveta Šimková, Zuzana Sumbalová, Tereza Hlavatá, Monika Kaldarárová, Guillermo López-Lluch, Anna Gvozdjáková.

  Congenital heart diseases (CHDs) are characterized by profound metabolic remodeling of mitochondrial pathways. However, data regarding mitochondrial respiration, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO) in patients with Ebstein anomaly (EA) are currently unavailable. This study evaluated 14 EA patients and 18 healthy volunteers. In accordance with the 2020 ESC guidelines, patients were stratified into two cohorts: EA-0 (patients currently without an indication for intervention) and EA-1 (patients meeting Class Ia or IIb indications for surgical intervention). Platelet OXPHOS and FAO parameters were determined simultaneously via high-resolution respirometry. CI-linked LEAK respiration (substrates: pyruvate and malate) and FAO-linked LEAK respiration (substrates: octanoylcarnitine and malate) were significantly elevated in EA patients. Furthemore, the EA-1 group showed significantly lower coenzyme Q10 (CoQ10) and γ-tocopherol levels than EA-0. Differences in the measured parameters between groups suggest a state of myocardial adaptation and transient metabolic reprogramming in EA-0 patients, whereas in EA-1 patients, a significant change in mitochondrial metabolism and bioenergetics was found. We hypothesize that increased platelet LEAK mitochondrial respiration and CoQ10 deficiency could be key signals of mitochondrial reprogramming and serve as potential biomarkers for right ventricular dysfunction. The analysis of platelet mitochondrial bioenergetics represents a novel area of translational mitochondrial cardiology, contributing to personalized diagnostics, risk stratification and optimal surgical timing in EA patients.

Keywords:  Ebstein anomaly; FAO; OXPHOS; coenzyme Q10; mitochondrial bioenergetics; personalized treatment; platelets; reprogramming; γ-tocopherol

DOI:  https://doi.org/10.3390/ijms27083347
Biochim Biophys Acta Mol Cell Res. 2026 May 02. pii: S0167-4889(26)00052-2. [Epub ahead of print]1873(5): 120154

The dual role of heat shock protein 60 in Cardiac diseases: From mitochondrial chaperone to extracellular immunomodulator - A review and future perspectives.

Vahid Saqagandomabadi, Adelaide Carista, Stefano Burgio, Francesco Cappello, Valentina Di Felice.

  The abundance of mitochondria in cardiac cells is vital, as they are extremely important for adenosine triphosphate (ATP) synthesis, maintaining redox balance, regulating calcium homeostasis, and facilitating lipid synthesis. One of the most abundant proteins in the mitochondria is the heat shock protein 60 (Hsp60), a chaperone that plays a crucial role in the translocation and folding of mitochondrial proteins. As a stress protein, Hsp60 increases when the heart muscle is under pressure, such as during a heart attack or heart failure. Recently, our research group has demonstrated that Hsp60 can be released under stress conditions in small and large vesicles or freely in the cell culture medium. In this review, we have analysed the published literature to determine whether Hsp60 may function as a damage-associated molecular pattern (DAMP) protein capable of interacting with Toll-like receptors (TLRs) to modulate immune responses, and we hypothesised that Hsp60 released in small extracellular vesicles may act as an immunomodulator.

Keywords:  DAMP; Heart diseases; Hsp60; cardiac cells; immune system; stress

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120154