bims-polgdi 2025-09-21 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–09–21
28 papers selected by
Luca Bolliger, lxBio

Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances.
Molecular Aspects of Mitochondrial Dysfunction in Diabetes, Pearson and Kearns-Sayre Syndromes, and Neurodegenerative Disorders.
Comprehensive basic and clinical studies are needed to improve the treatment and outcome of patients with Kearns-Sayre syndrome.
Manipulating mitochondrial gene expression.
mtDNA base editing: Mind the gap.
Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
[Clinical characteristics analysis of mitochondrial short-chain enoyl-CoA hydratase 1 deficiency with ECHS1 gene c.489G>A compound heterozygous variants].
Reviving mitochondria to restore the mind: stem cell-based bioenergetic rescue in Parkinson's disease.
MitoScribe single-cell molecular recorder logs graded signaling dynamics into mitochondrial DNA.
Mitochondrial Transplantation: A Paradigm Shift in Osteoporosis Therapy.
Advancing Mitochondrial Health in Huntington Disease (HD): Small Molecule Therapies and Neurodegeneration.
Exosome-Based Therapeutics: A Natural Solution to Overcoming the Blood-Brain Barrier in Neurodegenerative Diseases.
Mitochondrial DNA mutations as a potential modifier for the clinical variability of marfan syndrome.
Neuroimaging features of familial MT-TK related mitochondrial disease in a child.
Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants.
A Digital Measure of Eye Movements During Reading Sensitively Captures Oculomotor and Speech Dysfunction, Early Changes, and Disease Progression in Ataxias.
A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.
Mitochondrial RNA in Inflammation.
Neurons and astrocytes have distinct organelle signatures and responses to stress.
Unlocking ferulic acid for neurological diseases and tailoring of nanoformulations to advance its brain delivery.
Evaluating genome sequencing strategies: trio, singleton, and standard testing in rare disease diagnosis.
Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis.
Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
The mechanism and therapeutic potential of SIRT3 in central nervous system diseases: a review.
Deconvolution Methods to Link Multi-Omics Data to Cell Type-Specific Extracellular Vesicle Abundances.
Advances in mRNA-Lipid Nanoparticle Engineering for Immune Cell Targeting and Immune Modulation.
Mesenchymal Stem Cells Senescence: Mechanism and Rejuvenation Interventions.
Danon disease: From genetic origins and molecular defects to therapeutic advances.

MedComm (2020). 2025 Sep;6(9): e70385

Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances.

Jialun Mei, Peng Ding, Chuan Gao, Jian Zhou, Zhiwei Li, Changqing Zhang, Junjie Gao.

  Mitochondrial diseases are a heterogeneous group of inherited disorders caused by pathogenic variants in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins, culminating in defective oxidative phosphorylation and multisystem involvement. Key pathogenic mechanisms include heteroplasmy driven threshold effects, excess reactive oxygen species, disrupted mitochondrial dynamics and mitophagy, abnormal calcium signaling, and compromised mtDNA repair, which together cause tissue-specific energy failure in high demand organs. Recent advances have expanded the therapeutic landscape. Precision mitochondrial genome editing-using mitochondrial zinc finger nucleases, mitochondrial transcription activator-like effector nucleases, DddA-derived cytosine base editor, and other base editing tools-enables targeted correction or rebalancing of mutant genomes, while highlighting challenges of delivery and off-target effects. In parallel, metabolic modulators (e.g., coenzyme Q10, idebenone, EPI-743) aim to restore bioenergetics, and mitochondrial replacement technologies and transplantation are being explored. Despite these promising strategies, major challenges remain, including off-target effects, precise delivery, and ethical considerations. Addressing these issues through multidisciplinary research and clinical translation holds promise for transforming mitochondrial disease management and improving patient outcomes. By bridging the understanding of mitochondrial dysfunction with advanced therapeutic interventions, this review aims to shed light on effective solutions for managing these complex disorders.

Keywords:  base editing; gene therapy; genetic medicine; mitochondrial DNA (mtDNA); mitochondrial diseases; mitochondrial gene editing; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.70385
Int J Gen Med. 2025 ;18 5355-5366

Molecular Aspects of Mitochondrial Dysfunction in Diabetes, Pearson and Kearns-Sayre Syndromes, and Neurodegenerative Disorders.

Amirmohammad Shafiee, Amir Ali Akhlaghi, Abigail Ellstrom, Seyed Omid Mohammadi, Alimohammad Shafiee, Mohanakrishnan Sathyamoorthy.

  Mitochondrial dysfunction results in complex pathophysiological alterations associated with clinical disease states including cancer, cardiovascular diseases, diabetes mellitus, and anxiety disorders. As a key organelle within mammalian cells, the mitochondrion serves as the energetic source of cellular function which are crucial to cellular homeostasis, and cell death. In this report, we review key molecular causes of mitochondrial dysfunction and discuss how it influences insulin resistance, Pearson Syndrome and Kearns-Sayre syndrome, the latter of which occur due to pathogenic variants in mitochondrial DNA that lead to direct cellular pathology. We discuss the molecular and cellular pathophysiological mechanisms, disease interplays, and clinical considerations related to these diseases influenced by mitochondrial dysfunction.

Keywords:  Kearns-Sayre syndrome; Pearson syndrome; insulin resistance; mitochondrial dysfunction

DOI:  https://doi.org/10.2147/IJGM.S539967
Transl Pediatr. 2025 Aug 31. 14(8): 2075-2077

Comprehensive basic and clinical studies are needed to improve the treatment and outcome of patients with Kearns-Sayre syndrome.

Josef Finsterer.



Keywords:  DNA2; Kearns-Sayre syndrome (KSS); deletion; mitochondrial DNA (mtDNA); multisystem involvement

DOI:  https://doi.org/10.21037/tp-2025-425
Biol Chem. 2025 Sep 15.

Manipulating mitochondrial gene expression.

Drishan Dahal, Luis D Cruz-Zargoza, Peter Rehling.

  Mitochondria are essential for cellular metabolism, serving as the primary source of adenosine triphosphate (ATP). This energy is generated by the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Impairments in this machinery are linked to serious human diseases, especially in tissues with high energy demands. Assembly of the OXPHOS system requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. The mitochondrial DNA encodes for 13 protein components, which are synthesized by mitochondrial ribosomes and inserted into the inner membrane during translation. Despite progress, key aspects of how mitochondrial gene expression is regulated remain elusive, largely due to the organelle's limited genetic accessibility. However, emerging technologies now offer new tools to manipulate various stages of this process. In this review, we explore recent strategies that expand our ability to target mitochondria genetically.

Keywords:  RNA; gene expression; genetic tools; mitochondria

DOI:  https://doi.org/10.1515/hsz-2025-0170
Mol Cell. 2025 Sep 18. pii: S1097-2765(25)00713-0. [Epub ahead of print]85(18): 3351-3352

mtDNA base editing: Mind the gap.

Jose Domingo Barrera-Paez, Carlos T Moraes.

In this issue of Molecular Cell, Xiang et al.1 provided insights into the mechanism and structure-guided engineering of DdCBE for mitochondrial DNA base editing. More precise editing was achieved by better defining the editing window.

DOI: https://doi.org/10.1016/j.molcel.2025.08.028
Aging Adv. 2025 Sep;2(3): 108-111

Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.

Kit Neikirk, Suraj Thapliyal, Sepiso K Masenga, Ashton Oliver, Margaret Mungai, Han Le, Heather K Beasley, Andrea G Marshall, Anthonya T Cooper, Taneisha Gillyard Cheairs, Benjamin I Rodriguez, Edgar Garza-Lopez, Prasanna Katti, Antentor Hinton.

  Mitochondrial epigenetics, a burgeoning field bridging mitochondrial biology and epigenetic regulation, has emerged as a critical determinant of aging and age-related diseases. While nuclear epigenetics is well-characterized, the mechanisms governing mitochondrial DNA (mtDNA) regulation, including nucleoid dynamics, non-coding RNAs (ncRNAs), and metabolite-driven modifications, remain underexplored. This review synthesizes evidence that mitochondrial epigenetics influences cardiovascular pathogenesis through altered DNA methylation and histone acetylation patterns, which dysregulate oxidative phosphorylation and nucleoid stability. In neurodegenerative diseases, endoplasmic reticulum-mitochondrial contact points, disrupted by aging, impair calcium homeostasis and promote neuronal apoptosis, while oxidative stress exacerbates mtDNA instability through inefficient repair mechanisms. Cancer cells exploit mitochondrial metabolic reprogramming, where shifts in acetyl-CoA and α-ketoglutarate levels modulate epigenetic enzymes, fostering drug resistance. Potential therapeutic targets include pharmacological modulation of Mitochondrial transcription factor A acetylation/phosphorylation to enhance mtDNA transcription and dietary interventions to boost NAD+ levels, thereby improving mitochondrial function. Transgenerational studies reveal matrilineal inheritance of mtDNA methylation patterns and stress-induced epigenetic memory, though technical limitations in detecting mtDNA methylation persist. Clinically, mitochondrial epigenetic biomarkers like mtDNA hydroxymethylation and lncRNA expression (e.g., Mitoregulin) show promise for early diagnosis and treatment monitoring. Despite advances, challenges include standardizing methods for mtDNA methylation analysis and translating preclinical findings into therapies. This perspective review underscores the need for integrative approaches combining single-cell sequencing and CRISPR-based technologies to dissect mitochondrial-nuclear crosstalk, ultimately paving the way for precision medicine strategies targeting mitoepigenetic pathways to mitigate age-related decline.

Keywords:  aging; epigenetics; methylation; mitochondria; mitochondrial nucleoid; mtDNA

DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00006
Zhonghua Er Ke Za Zhi. 2025 Sep 18. 63(10): 1085-1091

[Clinical characteristics analysis of mitochondrial short-chain enoyl-CoA hydratase 1 deficiency with ECHS1 gene c.489G>A compound heterozygous variants].

Y Liu, T Y Li, J L Wang, C L Xu, M H Song, M T Xu, Z M Liu, F Fang.

Objective: To summarize the clinical characteristics of children with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) caused by c.489G>A (p.Pro163=) compound heterozygous variants in the ECHS1 gene, and to explore genotype-phenotype correlations. Methods: A case series study was performed to analyze clinical, biochemical, metabolic, imaging, genetic, treatment and follow-up outcomes of 24 children with ECHS1 gene c.489G>A(p.Pro163=) variant, who were diagnosed in the Department of Neurology, Beijing Children's Hospital from July 2010 to June 2024. Disease severity was assessed using the Newcastle Paediatric Mitochondrial Disease Scale, and Fisher exact test was applied to compare the improvement rate between valine-restricted and non-restricted groups. Results: These 24 children were all diagnosed after 2022, with a disease duration of 3.35 (1.25, 6.52) years at diagnosis. A total of 8 children initially had negative genetic results, and were finally confirmed by abnormal splicing of ECHS1 gene via skin fibroblast RNA sequencing, with the longest diagnostic time of 14 years. All 24 children presented with Leigh syndrome, including 11 boys and 13 girls, with an onset age of 1.46 (0.96, 2.79) years; 16 children (67%) were mild cases. Common initial symptoms included developmental delay (9 cases) and paroxysmal dystonia (9 cases), followed by developmental regression (3 cases), nystagmus (2 cases), and epilepsy (1 case). Main manifestations were dystonia (18 cases), developmental regression (14 cases), nystagmus (12 cases), developmental delay (11 cases), ataxia (10 cases), vision loss (9 cases), seizures (2 cases), and hearing impairment (1 case). Among 22 children who underwent blood and urine metabolic screening, 21 children (95%) had elevated urinary 2, 3-dihydroxy-2-methylbutyric acid and 19 children (86%) had elevated urinary S-(2-hydroxypropyl) cysteamine. All 24 children had symmetric abnormal signals in bilateral globus pallidus on cranial magnetic resonance imaging, 10 children had isolated globus pallidus involvement, and other common involved sites included caudate nucleus and brainstem (9 cases each), putamen (7 cases), and cerebral white matter (5 cases). At last follow-up, all 24 children survived, with a follow-up duration of 5.40 (2.75, 8.02) years and a maximum age of 17.8 years; 17 children (71%) had varying degrees of clinical improvement. There was no statistical difference in the improvement rate between children with or without valine-restricted diet (12/14 vs. 5/8,P=0309). A total of 18 pathogenic variants in the ECHS1 gene were identified among 24 children, 13 of which were distributed in exons 7 and 8; those carrying c.308T>C, c.523G>A, c.796A>G, and c.832G>A variants were mostly severe cases. Conclusions: Children carrying ECHS1 gene c.489G>A(p.Pro163=) compound heterozygous variants face significant diagnostic delay. Clinical awareness of this synonymous variant needs further improvement for timely diagnosis. All these cases present as Leigh syndrome, mostly mild, with no clear genotype-phenotype correlation identified.

DOI: https://doi.org/10.3760/cma.j.cn112140-20250718-00662
Neurodegener Dis Manag. 2025 Sep 19. 1-11

Reviving mitochondria to restore the mind: stem cell-based bioenergetic rescue in Parkinson's disease.

Supriya Shidhaye, Anis Ahmad Chaudhary, Mayuri Gajghate, Priyanka Singanwad, Milind Umekar, Neha Raut, Hassan Ahmad Rudayni, Rashmi Trivedi.

  Parkinson's disease is a neurodegenerative disorder of aging with dopaminergic neuronal degeneration in the substantia nigra leading to motor dysfunction. Mitochondrial dysfunction is central to its pathophysiology, leading to oxidative stress, derangement of energy metabolism, and induction of neuronal apoptosis. Current therapeutic interventions are symptomatic but fail to stop disease progression. Stem cell-based regenerative strategies have been recognized as potential disease-modifying treatments. Mitochondria-augmented stem cell therapy offers a new mechanism for the correction of cellular bioenergetic deficits. Through genetic manipulations or preconditioning protocols, mesenchymal stem cells and induced pluripotent stem cells are engineered to enhance mitochondrial function and transfer. The engineered cells enable delivery of functional mitochondria into damaged neurons through tunneling nanotubes or extracellular vesicles, promoting ATP production, inhibiting reactive oxygen species, and restoring mitophagy. Preclinical models have demonstrated improved neuronal survival and motor function, and novel technologies like CRISPR gene editing and 3D bioprinting offer improved translational relevance.

Keywords:  Parkinson’s disease; mesenchymal stem cells; mitochondrial dysfunction; mitochondrial transfer; neurorestoration; stem cell therapy

DOI:  https://doi.org/10.1080/17582024.2025.2562741
bioRxiv. 2025 Sep 05. pii: 2025.09.05.674553. [Epub ahead of print]

MitoScribe single-cell molecular recorder logs graded signaling dynamics into mitochondrial DNA.

Linhan Wang, Nikolaos Poulis, Deepak Srivastava, Seth L Shipman.

Genetically encoded DNA recorders convert transient biological events into stable genomic mutations, offering a means to reconstruct past cellular states. However, current approaches to log historical events by modifying genomic DNA have limited capacity to record the magnitude of biological signals within individual cells. Here, we introduce MitoScribe, a mitochondrial DNA (mtDNA)-based recording platform that uses mtDNA base editors (DdCBEs) to write graded biological signals into mtDNA as neutral, single-nucleotide substitutions at a defined site. Taking advantage of the hundreds to thousands of mitochondrial genome copies per cell, we demonstrate MitoScribe enables reproducible, highly sensitive, non-destructive, durable, and high-throughput measurements of molecular signals, including hypoxia, NF-κB activity, BMP and Wnt signaling. We show multiple modes of operation, including multiplexed recordings of two independent signals, and coincidence detection of temporally overlapping signals. Coupling MitoScribe with single-cell RNA sequencing and mitochondrial transcript enrichment, we further reconstruct signaling dynamics at the single-cell transcriptome level. Applying this approach during the directed differentiation of human induced pluripotent stem cells (iPSCs) toward mesoderm, we show that early heterogeneity in response to a differentiation cue predicts the later cell state. Together, MitoScribe provides a scalable platform for high-resolution molecular recording in complex cellular contexts.

DOI: https://doi.org/10.1101/2025.09.05.674553
Int J Nanomedicine. 2025 ;20 11169-11196

Mitochondrial Transplantation: A Paradigm Shift in Osteoporosis Therapy.

Jianlin Shen, Yue Lai, Qingping Peng, Xuan Lin, Shuxuan Chen, Liuqian Guo, Miao Xu, Yanjin Lu, Jiangqi Zhu, Xiaoning Lin, Cheng Zhang, Huan Liu.

  Osteoporosis, a global health crisis marked by compromised bone mineral density and heightened fracture susceptibility, demands innovative therapeutic strategies beyond conventional anti-resorptive approaches. Mitochondrial dysfunction, characterized by impaired bioenergetics, oxidative stress overload, and calcium dysregulation, has emerged as a central driver of osteoblast-osteoclast imbalance. Recent breakthroughs in mitochondrial transplantation (MT)-a revolutionary modality involving the transfer of functional mitochondria to metabolically compromised cells-have demonstrated unprecedented efficacy in preclinical osteoporosis models, restoring bone mass, microarchitecture, and mechanical strength. This review synthesizes cutting-edge insights into mitochondrial dynamics in bone homeostasis, dissects the molecular cascades linking mitochondrial failure to osteoporotic pathogenesis, and critically evaluates MT's potential to redefine osteoporosis management. We also discuss novel mechanisms of intercellular mitochondrial trafficking within the osteocyte dendritic network, explore bioengineered delivery platforms (eg, immunomodulatory hydrogels, nanoparticle-encapsulated mitochondria), and address emerging challenges in clinical translation, including donor source optimization, immune compatibility, and CRISPR-engineered mitochondrial genomes. By integrating single-cell omics data and AI-driven mitochondrial viability predictors, this work charts a roadmap for personalized mitochondrial medicine, positioning MT as a cornerstone of next-generation osteoporosis therapeutics.

Keywords:  mitochondrial disease; mitochondrial transfer; mitochondrial transplantation; osteoporosis

DOI:  https://doi.org/10.2147/IJN.S537166
Curr Aging Sci. 2025 Sep 11.

Advancing Mitochondrial Health in Huntington Disease (HD): Small Molecule Therapies and Neurodegeneration.

Vasanth S, Rakhi Mishra, Subhashree Sahoo, Sadia Parveen, Zuber Khan, Mumtaz, Ruqaiya, Rahul Pal.

  Huntington's disease (HD) is a severe neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, leading to the production of a mutant huntingtin protein. This mutation results in progressive motor, cognitive, and psychiatric impairments, alongside significant neuronal loss. Mitochondrial dysfunction plays a pivotal role in the pathophysiology of HD, contributing to disease progression and neuronal death. This article aims to evaluate small molecule-based therapeutic strategies designed to enhance mitochondrial function as a potential approach to alleviate symptoms and slow the progression of HD and related neurodegenerative disorders. A comprehensive review of recent literature is conducted to identify small molecules targeting mitochondrial dysfunction from Google Scholar, Pub- Med/Medline/PMC, ScienceDirect, Elsevier, Google Patents, and Clinicaltrials.gov.in, among others. The analysis focuses on their mechanisms of action, including reducing oxidative stress, enhancing mitochondrial biogenesis, and improving mitochondrial dynamics and function. The review identifies several promising small molecules capable of targeting mitochondrial dysfunction. These agents demonstrate potential in preclinical studies to alleviate HD symptoms and modify disease progression by addressing key aspects of mitochondrial health. Small molecule therapies targeting mitochondrial dysfunction offer considerable promise for treating HD. However, further research is required to optimize these therapies for clinical use and to evaluate their long-term impact on disease progression to fully establish their therapeutic efficacy.

Keywords:  Huntington’s disease; gene therapy; mitochondrial dysfunction.; mutant huntingtin; neurodegeneration

DOI:  https://doi.org/10.2174/0118746098387655250818072130
MedComm (2020). 2025 Sep;6(9): e70386

Exosome-Based Therapeutics: A Natural Solution to Overcoming the Blood-Brain Barrier in Neurodegenerative Diseases.

Min Sun, Feng Qin, Qian Bu, Yue Zhao, Xiaofeng Yang, Dingwen Zhang, Xiaobo Cen.

  Neurodegenerative diseases present significant therapeutic challenges, primarily due to the restrictive nature of the blood-brain barrier (BBB), which limits drug delivery to the brain. While the BBB is crucial for protecting the brain from harmful substances, it also hinders the effectiveness of treatments for neurodegenerative diseases. Consequently, there is an urgent need for innovative drug delivery systems capable of bypassing the BBB to improve therapeutic outcomes. Exosomes, as endogenous nanoscale carriers, offer substantial promise for brain-targeted drug delivery. Their unique characteristics, including the ability to cross biological barriers, high biocompatibility, intrinsic targeting capacity, natural intracellular transport mechanisms, and robust stability, render them highly promising candidates for drug delivery in the treatment of neurodegenerative disorders. This review delves into various engineering strategies for exosome-mediated targeted drug delivery and provides an in-depth analysis of the structural and functional properties of the BBB under normal and pathological conditions. We emphasize the potential of exosomes as drug delivery vehicles for the central nervous system, particularly in addressing neurodegenerative disorders. Furthermore, we address the key obstacles to the clinical application of exosome-based therapies and propose future research directions aimed at optimizing these methods to develop more effective treatment strategies.

Keywords:  blood–brain barrier; drug delivery systems; exosomes; neurodegeneration therapy; neurodegenerative diseases

DOI:  https://doi.org/10.1002/mco2.70386
QJM. 2025 Sep 18. pii: hcaf188. [Epub ahead of print]

Mitochondrial DNA mutations as a potential modifier for the clinical variability of marfan syndrome.

Yuduo Wu, Xu Zhang, Zhengyang Zhang, Peng An, Yihua He, Hongjia Zhang, Yongting Luo, Junjie Luo.

  Marfan syndrome (MFS) is an autosomal genetic disease caused by FBN1 mutation. Patients with the same FBN1 mutation type exhibit different phenotypes, which indicates additional risk factors. Mitochondrial dysfunction was observed in the aorta of both MFS patients and Marfan murine models. Single nucleotide variants in mitochondrial DNA (mtDNA) may have harmful consequences on a cell. However, the association of mtDNA mutations with MFS has been unclear. Here, we used targeted mtDNA sequencing to detect whole blood mtDNA mutations from 48 healthy controls and 77 MFS patients, including 7 mother-offspring pedigrees. Three rare mtDNA mutations, m.279T > C, m.2361G > A, and m.3316G > A, were identified in a family whose predominant phenotype was eye lesions. The MFS patients with these mutations had more severe symptoms than family members without the mutation. m.9738G > A was identified in a family whose dominant phenotype was aortic manifestation. A sporadic case with this rare mutation site has an aortic aneurysm. We also described the mutation frequency and mutation rate in MFS. The frequency of all solid variants, nonsynonymous variants, pathogenic or likely pathogenic variants and variants of uncertain significance were more abundant in MFS patients compared to the control group. The mutation rate of the coding region, MT-rRNA and MT-tRNA were higher in the MFS group. These data demonstrate frequent mitochondrial mutation in MFS and suggest that the mtDNA mutation might be a potential modifier of MFS phenotypes.

Keywords:  Marfan syndrome; mitochondrial dysfunction; mtDNA sequencing; mtDNA variants

DOI:  https://doi.org/10.1093/qjmed/hcaf188
BMJ Case Rep. 2025 Sep 18. pii: e265230. [Epub ahead of print]18(9):

Neuroimaging features of familial MT-TK related mitochondrial disease in a child.

Leia Salongo, Ben Nguyen, John Ross Crawford.



Keywords:  Neuro genetics; Neuroimaging; Sleep disorders (neurology)

DOI:  https://doi.org/10.1136/bcr-2025-265230
Front Neurol. 2025 ;16 1584748

Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants.

Sundaramurthy Srilekha, Selvakumar Ambika, Nagarajan Hemavathy, Dharani Vidhya, Patrick Yu-Wai-Man.

   Purpose: This study aimed to explore the role of additional mitochondrial DNA (mtDNA) variants in the development of Leber hereditary optic neuropathy (LHON) by screening the entire mitochondrial genome in individuals who had previously tested negative for the three common mtDNA variants: m.3460G > A (MT-ND1), m.11778G > A (MT-ND4), and m.14484 T > C (MT-ND6), by conventional Sanger sequencing.
Methods: Forty-one individuals with a suspected clinical diagnosis of LHON were recruited from the neuro-ophthalmology clinic. Each participant had undergone a comprehensive neuro-ophthalmic examination, including slit lamp examination, indirect ophthalmoscopy, visual field perimetry, optical coherence tomography, and MRI of the brain and orbits. Targeted re-sequencing was conducted using next-generation sequencing (NGS) on the HiSeqX 10 platform (Illumina, San Diego, California) with a 2 × 150 bp paired-end configuration. The sequencing reads were aligned to the human mitochondrial genome sequence (hg19). Variants were filtered with the VariMAT tool (v.2.3.9). Haplogroup analysis was performed using Haplogrep 2 (v2.0). To assess the deleteriousness of nonsynonymous variations, bioinformatics prediction tools such as PolyPhen2, SIFT, CADD, and Mutation Assessor were utilized. In addition, while tools like Consurf, PredictSNP, DynaMut, ENCoM, DUET, SDM, mCSM, were employed to evaluate evolutionary conservation, pathogenicity, structural stability, and functional impact.
Results: Whole mitochondrial genome sequencing of 41 clinically suspected LHON cases identified a total of 1,518 mtDNA variants. Of these, 822 were located in the coding regions, including 555 synonymous and 273 non-synonymous variants. Two heteroplasmic disease-causing variants (m.11778G > A and m.3460G > A) were identified in one individual each (90.0 and 63.6%, respectively). Additionally, rare mtDNA variants listed in Mitomap were found in five individuals (5/41, 12.1%), namely, MT-ND1 (m.3335 T > C, m.3394 T > C, m.3395A > G), MT-ND4L (m.10680G > A), and MT-ND6 (m.14502 T > C), with variants in MT-ND1 being the most prevalent (3/41, 7.3%).
Conclusion: Our study of a well-characterized Indian LHON cohort uncovered rare mtDNA variants that should be considered when assessing undiagnosed optic neuropathy cases. Additionally, it underscores the effectiveness of NGS in identifying heteroplasmic mtDNA variants. This indicates that whole mitochondrial genome sequencing via NGS is a more efficient and preferred approach for routine molecular genetic testing.

Keywords:  bioinformatics analysis; haplogroup analysis; homoplasmy; next generation sequencing; rare variants

DOI:  https://doi.org/10.3389/fneur.2025.1584748
Ann Neurol. 2025 Sep 18.

A Digital Measure of Eye Movements During Reading Sensitively Captures Oculomotor and Speech Dysfunction, Early Changes, and Disease Progression in Ataxias.

Brandon Oubre, Faye Yang, Anna C Luddy, Rohin Manohar, Nancy N Soja, Christopher D Stephen, Jeremy D Schmahmann, Divya Kulkarni, Lawrence White, Siddharth Patel, Anoopum S Gupta.

OBJECTIVE: Sensitive behavioral measures are needed for clinical trials in ataxias and other neurodegenerative diseases. We hypothesized that quantitative analysis of eye movements during a natural multi-component task (passage reading) could produce a measure capable of capturing subclinical signs and disease progression.
METHODS: Binocular gaze sampled at 1000 hertz (Hz) was collected from 102 individuals with ataxia (including 36 spinocerebellar ataxias, 12 Friedreich's ataxia, and 5 multiple system atrophy) and 70 healthy controls. Longitudinal data were available for 26 participants with ataxia in the ongoing Neurobooth natural history study. The Reading Eye Abnormality Digital (READ) score was developed by training a regression model to aggregate saccade and fixation kinematics.
RESULTS: Mean displacement of fixations, the number and frequency of saccades, and the proportion of regressive saccades were related to oculomotor dysfunction, speech dysfunction, and overall ataxia severity. The READ score was reliable (intraclass correlation coefficient [ICC] = 0.96, p < 0.001) and correlated with Brief Ataxia Rating Scale (BARS) total score (r = 0.82, p < 0.001), oculomotor (r = 0.52, p < 0.001), and speech (r = 0.73, p < 0.001) subscores, and patient reports of function including patient-reported outcome measures (PROM)-Ataxia (r = 0.51, p < 0.001) and the Dysarthria Impact Scale (DIS; r = 0.53, p < 0.001). The READ score detected subclinical oculomotor (area under the curve [AUC] = 0.69, p = 0.02) and speech signs (AUC = 0.72, p < 0.001) and disease progression (d = 0.36, p = 0.03). The BARS total did not reach statistical significance in capturing progression between study visits in this cohort (d = 0.27, p = 0.08).
INTERPRETATION: Digital measures of eye movements are a promising approach for sensitively measuring ataxia in clinical trials (including early-stage disease) and may have utility in other neurodegenerative diseases affecting speech or ocular control. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.78039
Neuron. 2025 Sep 12. pii: S0896-6273(25)00624-5. [Epub ahead of print]

A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.

Katherine R Croce, Christopher Ng, Serihy Pankiv, Eddy Albarran, Peter Langfelder, Ana Ramos de Jesus, Glenn M Duncan, Nan Wang, Anna Basile, Caitlin McHugh, Nicole A Litt, Alina Li, Sophia Friedman, Etty P Cortes, Michael C Zody, X William Yang, Jun B Ding, Jean Paul G Vonsattel, Anne Simonsen, David E Housman, Nancy S Wexler, Ai Yamamoto.

  The study of disease modifiers is a powerful way to identify patho-mechanisms associated with disease. Using the strong genetic traits of Huntington's disease (HD), we identified a rare, single-nucleotide polymorphism (SNP) in WDFY3 associated with a delayed age of onset of up to 23 years. Remarkably, the introduction of the orthologous SNP into mice recapitulates this neuroprotection, significantly delaying neuropathological and behavioral dysfunction in two models of HD. The SNP increases expression of the protein autophagy-linked Fab1, YOTB, Vac1, and EEA1 (FYVE) protein (Alfy), an autophagy adaptor protein for the clearance of aggregated proteins, whose ectopic overexpression is sufficient to capture the neuroprotective effects of the variant. Increasing Alfy expression protects not only against HD but also against the toxicity due to phospho-α-synuclein and AT8-positive accumulation. By combining human and mouse genetics, we have uncovered a pathway that protects against multiple proteinopathies, revealing a much-sought-after, shared therapeutic target across a broad range of neurodegenerative diseases.

Keywords:  Huntington’s disease; Parkinson’s disease; WDFY3/Alfy; autophagy; neurodegeneration; proteinopathy; selective autophagy; synuclein; tauopathy

DOI:  https://doi.org/10.1016/j.neuron.2025.08.018
Int J Biol Sci. 2025 ;21(12): 5378-5392

Mitochondrial RNA in Inflammation.

Jian Chen, Chen You, Haibo Xie, Qixing Zhu.

  Mitochondria are dynamic organelles integral to cellular energy metabolism and homeostasis. Beyond their traditional roles, a growing body of evidence underscores the importance of mitochondria as pivotal regulators of innate immune signaling pathways. Recently, mitochondrial RNA (mtRNA) has been identified as a novel modulator of inflammatory responses. mtRNA is detected by intracellular pattern recognition receptors (PRRs), which subsequently activate the mitochondrial antiviral-signaling protein (MAVS) and the interferon regulatory factor 3 (IRF3)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis, as well as inflammasome pathways. This activation leads to the production of type I interferons and pro-inflammatory cytokines. Furthermore, mtRNA facilitates the propagation of inflammatory signals through exosome-mediated intercellular transfer. Among the various forms of mtRNA, mitochondrial double-stranded RNA (mt-dsRNA) is particularly prone to activating inflammatory responses due to its distinctive double-helical structure. The aberrant accumulation of mt-dsRNA is strongly linked autoimmune diseases, degenerative disease, Liver Disease, kidney disease, cancers, cardiovascular diseases, and respiratory ailments. This review proposes innovative therapeutic strategies aimed at degrading pathological mtRNA or interrupting inflammatory pathways by targeting critical regulatory nodes in mtRNA metabolism and its downstream inflammatory processes.

Keywords:  Inflammation; Mitochondrial; mt-dsRNA.; mtRNA

DOI:  https://doi.org/10.7150/ijbs.119841
Cell Rep. 2025 Sep 15. pii: S2211-1247(25)01051-4. [Epub ahead of print]44(9): 116280

Neurons and astrocytes have distinct organelle signatures and responses to stress.

Shannon N Rhoads, Weizhen Dong, Chih-Hsuan Hsu, Ngudiankama R Mfulama, Ridhi Yarlagadda, Joey V Ragusa, Michael Ye, Andy Henrie, Maria Clara Zanellati, Graham H Diering, Todd J Cohen, Sarah Cohen.

  Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cellular function. However, an in-depth characterization of organelles in live neural cells has not been performed. Here, we use multispectral imaging to simultaneously visualize six organelles-endoplasmic reticulum (ER), lysosomes, mitochondria, peroxisomes, Golgi, and lipid droplets-in live primary rodent neurons and astrocytes. We generate a dataset of 173 z stack and 98 time-lapse images, accompanied by quantitative "organelle signature" analysis. Comparative analysis reveals a clear cell-type specificity in organelle morphology and interactions. Neurons are characterized by prominent mitochondrial composition and interactions, while astrocytes contain more lysosomes and lipid droplet interactions. Additionally, neurons display a more robust organelle response than astrocytes to acute oxidative or ER stress. Our data provide a systems-level characterization of neuron and astrocyte organelles that can be a reference for understanding cell-type-specific physiology and disease.

Keywords:  CP: Cell biology; CP: Neuroscience; Golgi; astrocytes; endoplasmic reticulum; lipid droplets; lysosomes; microscopy; mitochondria; neurons; organelles; peroxisomes

DOI:  https://doi.org/10.1016/j.celrep.2025.116280
Int J Pharm. 2025 Sep 16. pii: S0378-5173(25)01010-5. [Epub ahead of print] 126173

Unlocking ferulic acid for neurological diseases and tailoring of nanoformulations to advance its brain delivery.

Paulo Ricardo Alves de Andrade, Raíssa Coelho Motta, Bruno Fonseca-Santos.

  Mental disorders represent a significant global health challenge, with a high prevalence and substantial impact on individual well-being. Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and various mood disorders, contribute significantly to the burden of neurological conditions worldwide. Identifying novel drug targets and exploring natural product-based molecules have become essential priorities in advancing treatment strategies for these complex diseases. Nanoencapsulation technology has emerged as a valuable tool to increase the stability, solubility, and bioavailability of natural products, thus improving their efficacy in treating neurological disorders. By encapsulating natural compounds such as ferulic acid (FA) in nanoscale delivery systems, researchers have aimed to overcome challenges related to poor solubility and bioavailability, ultimately enhancing therapeutic outcomes. In this review, we examine recent advancements focused on the therapeutic potential of FA in AD, PD, MS, brain cancer, depression (DP), anxiety (AX), and epilepsy (EP). Furthermore, we explored the use of nanoscale delivery systems to optimise the delivery of FA for improved treatment efficacy. We aim to inspire discoveries and innovative approaches to address neurological diseases by highlighting current progress and future directions in this field with FA.

Keywords:  Dementia; Hydroxycinnamic acid; Molecular mechanism; Movement disorder; Nanoscale; Neurodegeneration

DOI:  https://doi.org/10.1016/j.ijpharm.2025.126173
Genome Med. 2025 Sep 18. 17(1): 100

Evaluating genome sequencing strategies: trio, singleton, and standard testing in rare disease diagnosis.

Daniel Kaschta, Christina Post, Franziska Gaass, Milad Al-Tawil, Vincent Arriens, Saranya Balachandran, Tobias Bäumer, Valerie Berge, Friederike Birgel, Andreas Dalski, Maike Dittmar, Andre Franke, Sören Franzenburg, Janina Fuß, Bettina Gehring, Rebecca Gembicki, Bianca Greiten, Kristin Grohte, Britta Hanker, Kristian Händler, Lana Harder, Yorck Hellenbroich, Theresia Herget, Gloria Herrmann, Olaf Hiort, Kirstin Hoff, Birga Hoffmann, Nadine Hornig, Irina Hüning, Monika Kautza-Lucht, Juliane Köhler, Anna-Sophie Liegmann, Jasmin Lisfeld, Britt-Sabina Löscher, Nils G Margraf, Michelle Meyenborg, Anna Möllring, Hiltrud Muhle, Eva Maria Murga Penas, Henning Nommels, Dzhoy Papingi, Imke Poggenburg, Jelena Pozojevic, Philip Rosenstiel, Andreas Recke, Kimberly Roberts, Laelia Rösler, Franka Rust, Maj-Britt Salewski, Katharina Schau-Römer, Christian Schlein, Varun K A Sreenivasan, Louiza Toutouna, Caroline Utermann-Thüsing, Amelie T van der Ven, Alexander E Volk, Janne Wehnert, Sandra Wilson, Rixa Woitschach, Veronica Yumiceba, Christine Zühlke, Alexander Münchau, Norbert Brüggemann, Inga Vater, Almuth Caliebe, Inga Nagel, Malte Spielmann.

   BACKGROUND: Short-read genome sequencing (GS) is among the most comprehensive genetic testing methods available, capable of detecting single-nucleotide variants, copy-number variants, mitochondrial variants, repeat expansions, and structural variants in a single assay. Despite its technical advantages, the full clinical utility of GS in real-world diagnostic settings remains to be fully established.
METHODS: This study systematically compared singleton GS (sGS), trio GS (tGS), and exome sequencing-based standard-of-care (SoC) genetic testing in 416 patients with rare diseases in a blinded, prospective study. Three independent teams with divergent baseline expertise evaluated the diagnostic yield of GS as a unifying first-tier test and directly compared its variant detection capabilities, learning curve, and clinical feasibility. The SoC team had extensive prior experience in exome-based diagnostics, while the sGS and tGS teams were newly trained in GS interpretation. Diagnostic yield was assessed through both prospective and retrospective analyses.
RESULTS: In our prospective analysis, tGS achieved the highest diagnostic yield for likely pathogenic/pathogenic variants at 36.1% in the newly trained team, surpassing the experienced SoC team at 35.1% and the newly trained sGS team at 28.8%. To evaluate which variants could technically be identified and account for differences in team experience, we conducted a retrospective analysis, achieving diagnostic yields of 36.7% for SoC, 39.1% for sGS, and 40.0% for tGS. The superior yield of GS was attributed to its ability to detect deep intronic, non-coding, and small copy-number variants missed by SoC. Notably, tGS identified three de novo variants classified as likely pathogenic based on recent GeneMatcher collaborations and newly published gene-disease association studies.
CONCLUSIONS: Our findings demonstrate that GS, particularly tGS, outperforms SoC in diagnosing rare diseases, with sGS providing a more cost-effective alternative. These results suggest that GS should be considered a first-tier genetic test, offering an efficient, single-step approach to reduce the diagnostic odyssey for patients with rare diseases. The trio approach proved especially valuable for less experienced teams, as inheritance data facilitated variant interpretation and maintained high diagnostic yield, while experienced teams achieved comparable results with singleton analysis alone.

Keywords:  Diagnostic yield; Exome sequencing; Genome sequencing; Rare disease; Standard of care

DOI:  https://doi.org/10.1186/s13073-025-01516-7
Neurobiol Dis. 2025 Sep 15. pii: S0969-9961(25)00320-1. [Epub ahead of print] 107103

Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis.

Xie Yipeng, Wang Guiqian, Zhu Qiaochu, He Tengjie, Zhao Yan, Huang Hai, Zhou Jing.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive degeneration of motor neurons and early deterioration of neuromuscular junctions (NMJs). Increasing evidence indicates that mitochondrial dysfunction plays a pivotal role in driving NMJ degeneration in ALS.
OBJECTIVE: This review aims to comprehensively summarize the molecular mechanisms by which mitochondrial defects contribute to NMJ instability, with a particular focus on bioenergetics, calcium homeostasis, oxidative stress, and impaired mitochondrial biogenesis.
CONCLUSION: Mitochondrial dysfunction is a core driver of NMJ degeneration in ALS. Targeting mitochondrial biogenesis and metabolism-particularly through the PGC-1α pathway-represents a promising strategy to preserve NMJ integrity and slow disease progression.

Keywords:  Amyotrophic lateral sclerosis; Calcium homeostasis; Mitochondria; Mitochondrial biogenesis; Neuromuscular junction; PGC-1α; ROS

DOI:  https://doi.org/10.1016/j.nbd.2025.107103
Trends Immunol. 2025 Sep 16. pii: S1471-4906(25)00215-7. [Epub ahead of print]

Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.

Ana Belén Plata-Gómez, Weixin Chen, Ping-Chih Ho, Guang Sheng Ling.

  Mitochondrial lipid metabolism plays a pivotal role in tumor immunosurveillance and immune evasion. This review explores how mitochondrial regulation shapes immune cell metabolism within the tumor microenvironment (TME), focusing on the antitumor effects of the mitochondrial-fueled immune response and the detrimental impact of impaired mitochondrial function on immune cell cytotoxicity. Although current studies support this dual role, critical gaps remain, including how immune cells adapt differently to the lipid-rich TME, and how therapies can target lipid metabolism without harming immune memory. By synthesizing current findings and highlighting these uncertainties, this review highlights mitochondrial lipid metabolism as a promising therapeutic axis in cancer immunotherapy.

Keywords:  immunometabolism; lipid metabolism; mitochondria; tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.it.2025.08.005
Front Pharmacol. 2025 ;16 1652296

The mechanism and therapeutic potential of SIRT3 in central nervous system diseases: a review.

Chuanbin Hong, Yupeng Wei, Yuchen Wang, Guangfu Lv, Xinglu Dong, Xiaowei Huang.

  Sirtuin-3 (SIRT3) is a mitochondrial deacetylase highly expressed in the nervous system, known to regulate mitochondrial homeostasis, energy metabolism, neuroinflammation, apoptosis, and oxidative stress, suggesting its potential neuroprotective role in central nervous system (CNS) disorders. Recent studies indicated that SIRT3 improves neuronal survival by reducing oxidative damage, alleviating neuroinflammation, and modulating autophagy. Therefore, it is imperative to conduct more in-depth and extensive investigations into the mechanisms underlying SIRT3 in central nervous system disorders. This review summarized current research advances on SIRT3, including its fundamental molecular structure, key downstream targets, and mechanisms of action in certain CNS diseases. It further analyzed the potential pharmacological mechanisms of several SIRT3 agonists and explored their therapeutic value in improving CNS disorders. Based on existing evidence, SIRT3 emerges as a promising therapeutic target, offering novel strategies for treating neurological diseases.

Keywords:  central nervous system diseases; mitochondrial function; silent information regulator 3; sirt3; sirtuin-3; therapeutic potential

DOI:  https://doi.org/10.3389/fphar.2025.1652296
Proteomics. 2025 Sep 15. e70043

Deconvolution Methods to Link Multi-Omics Data to Cell Type-Specific Extracellular Vesicle Abundances.

Iben Skov Jensen, Jannik Hjortshøj Larsen, Per Svenningsen.

  Extracellular vesicles (EVs) provide non-invasive information on cellular health and disease. Yet, with the small size of EVs and more than 200 cell types contributing EVs to the extracellular fluids, it is challenging to determine whether changes in EV-associated lipids, RNAs, and proteins occur because of differences in expression or cell type-specific EV abundances. This limits our use of EV-based biomarkers and our understanding of how EVs contribute to health and diseases. In recent decades, next-generation RNA sequencing methods have fueled the development of transcriptome deconvolution methods to determine cell type proportions in tissue RNA samples. These methods can also estimate cell type-specific EV abundances using the EV's RNA "fingerprint"; however, differences between cell and EV RNA composition can significantly bias the estimates. Based on a recent benchmarking study of transcriptome deconvolution methods, we will review technical and biological factors that drive the most accurate deconvolution, focusing on mRNA sequencing data from EVs. Moreover, we will describe biological factors that can affect the interpretation of the deconvolution methods of cell type-specific EV abundance estimates in acute and chronic conditions and give a perspective on how deconvolution can be used to monitor physiological and disease processes in the human body.

Keywords:  RNA; biomarker; exosome; metabolomics; proteomics; transcriptomics

DOI:  https://doi.org/10.1002/pmic.70043
Small Methods. 2025 Sep 16. e01401

Advances in mRNA-Lipid Nanoparticle Engineering for Immune Cell Targeting and Immune Modulation.

Cheesue Kim, Yeji Lee, Hyukjin Lee, Byung-Soo Kim.

  Immunotherapy has transformed therapeutic paradigms, especially in oncology, by leveraging antibodies, cytokines, and cell-based strategies. In recent years, immunotherapy has expanded its impact to combat a broad spectrum of diseases, including fibrotic, autoimmune, and infectious disorders. Messenger RNA (mRNA)-based platforms offer distinct advantages for immunotherapy by enabling in vivo synthesis of proteins with native post-translational modifications to enhance bioactivity and reduce immunogenicity. mRNA also allows non-viral, transient reprogramming of immune cells in vivo, supporting scalable manufacturing and eliminating the risk of insertional mutagenesis. However, naked mRNA faces clinical limitations including inherent instability, poor cellular uptake, and non-targeted delivery. Lipid nanoparticles (LNPs) can overcome these challenges by encapsulating mRNA for protected and efficient delivery to target cells. Importantly, recent advances have demonstrated the potential of mRNA-LNPs to modulate immune cell function with cell-type specificity, enhancing therapeutic precision. This review highlights progress in engineering mRNA-LNPs for targeted immune cell delivery, strategies for immune cell-specific modulation, and applications across immune-related pathologies. Design considerations to improve delivery efficiency and immunological outcomes are also discussed, supporting the clinical translation of mRNA-LNP immunotherapies.

Keywords:  cancer immunotherapy; immune modulation; inflammation; lipid nanoparticles; mRNA

DOI:  https://doi.org/10.1002/smtd.202501401
Int J Med Sci. 2025 ;22(14): 3692-3708

Mesenchymal Stem Cells Senescence: Mechanism and Rejuvenation Interventions.

Qinghong Meng, Yan Zheng, Xiaobo Chen, Jiawei Mu, Changlin Li, Yiwen Gao, Wei Liu, Yuliang Wang.

  Aging has become one of the most significant challenges and burdens on public health and healthcare systems worldwide. However, it is possible to slow down the aging process through various interventions. Mesenchymal stromal/stem cells (MSCs) have emerged as one of the most promising therapeutic agents for combating aging and treating various age-related chronic medical conditions. This is primarily due to their well-known cellular plasticity and potent multipotency, which enable them to promote tissue repair and regeneration, as well as address inflammatory conditions. Remarkably, the high quality and functional activity of MSCs are negatively affected by cellular senescence, particularly in both healthy-aging MSCs and replicative senescent MSCs. This is a critical issue when considering the provision of "personalized" or "universal" clinical-grade products. Therefore, this review aims to summarize the biological properties, immunomodulatory dysfunction, and underlying mechanisms of senescent MSCs. Additionally, it discusses the current promising techniques published for rejuvenating senescent MSCs and optimizing their therapeutic potential.

Keywords:  ageing; cellular senescence; mesenchymal stromal/stem cells; priming interventions

DOI:  https://doi.org/10.7150/ijms.115650
Dis Mon. 2025 Sep 16. pii: S0011-5029(25)00169-5. [Epub ahead of print] 102015

Danon disease: From genetic origins and molecular defects to therapeutic advances.

Rishabh Chaudhary, Alpana Singh.

  Danon disease (DD) represents a rare and complex X-linked disorder, characterized by hypertrophic cardiomyopathy, skeletal muscle deterioration, and cognitive deficits. At its core, the disease stems from mutations in the LAMP2 (lysosome-associated membrane protein 2) gene, which result in a critical deficiency of LAMP-2, particularly the LAMP-2B isoform. This loss destabilizes normal autophagic clearance, leading to the buildup of dysfunctional autophagic vacuoles that ultimately disrupt cellular homeostasis. Although accurately modeling the full range of DD symptoms remains challenging, patient-specific induced pluripotent stem cells and innovative LAMP-2-deficient animal models have provided valuable insights into the disease's molecular and cellular basis. Recent research points decisively to mitochondrial dysfunction and fragmentation as pivotal contributors to disease progression, shifting our understanding of DD beyond lysosomal defects alone. These mechanistic revelations have inspired new therapeutic directions, with gene therapy emerging as a particularly promising candidate based on encouraging preclinical results and ongoing clinical studies. Moving forward, a deeper integration of molecular insights with therapeutic innovation will be essential to developing effective strategies that address the multifaceted pathology of DD and improve outcomes for affected individuals. In this review, we provide a comprehensive analysis of DD, focusing on its genetic and molecular underpinnings, particularly the role of LAMP-2 deficiency in disrupting autophagy and mitochondrial integrity. We critically evaluate experimental models that have advanced our understanding of DD pathogenesis. Additionally, we discuss emerging therapeutic strategies, with an emphasis on gene therapy and other innovative approaches aimed at restoring cellular homeostasis and mitigating cardiomyopathy and neuromuscular symptoms.

Keywords:  Autophagy arrest; Danon disease; LAMP-2; LAMP-2B isoform; X-linked lysosomal storage disorder

DOI:  https://doi.org/10.1016/j.disamonth.2025.102015