bims-polgdi 2025-11-30 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–11–30
forty papers selected by
Luca Bolliger, lxBio

Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.
Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.
Mitochondrial Quality Control and Cell Death.
Electron microscopy visualization of cell-free mitochondrial DNA-containing extracellular vesicles in human plasma, serum, and saliva.
Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.
Mitochondrial Base Editing of the m.8993T>G Mutation Restores Bioenergetics and Neural Differentiation in Patient iPSCs.
Intrinsic errors in mitochondrial translation trigger a decline in cell fitness.
New insights from mendelian randomization and mediation analysis: causal relationships between mitochondrial DNA copy number and telomere length in pulmonary fibrosis.
Analysis of Bush Cricket Oogenesis Provides an Insight into the Function and Anagenesis of an Enigmatic Organelle Assemblage: The Balbiani Body.
Mitochondrial NAD+ drives liver regeneration.
Extracellular vesicles for delivery of functional telomerase.
Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration.
Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications.
Advances in Intranasal Delivery of Exosomes for Central Nervous System Disorders.
Social Media Use Among Parents and Caregivers of Children With Rare Genetic Diseases: Scoping Review.
Exploring Mitochondrial DNA Copy Number in Italian Children with ADHD: Implications for Neurobiological Mechanisms.
Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.
Importance and Potential of Rare Disease Research in Pediatric Rheumatology and Beyond: Pushing Frontiers.
Topical Treatments for Rare Genetic Dermatological Diseases: A Narrative Review.
Mechanistic Interplay of Gut Microbiota and Blood-Brain Barrier Integrity in Neurodegenerative Diseases.
Cytosolic mtDNA and associated EYA-mediated pro-inflammatory signaling modulate healthspan in Drosophila.
Audio long read: Faulty mitochondria cause deadly diseases - fixing them is about to get a lot easier.
The Role of Mitochondrial Complexes in Liver Diseases.
Data Augmentation and Synthetic Data Generation in Rare Disease Research: A Scoping Review.
Special Issue: "New Insights of Biomarkers in Neurodegenerative Diseases".
Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.
Metabolic toxicity and neurological dysfunction in methylmalonic acidemia: from mechanisms to therapeutics.
Age-related hearing loss involves mitochondrial DNA instability and copy number depletion in the cochlea: Insights from in vivo and in vitro models.
Mitochondrial crosstalk between bone marrow stromal cells and chondrocytes: implication for cartilage repair in osteoarthritis.
Mitochondrial capacities and quality control following short- and long-term weight restoration after simulated anorexia nervosa.
Drivers of Diagnostic Delay in Mitochondrial Disease: Missed Recognition of Canonical Features.
"I don't grieve as much as I used to": A qualitative study on parents of children with rare and undiagnosed conditions navigating grief in the context of uncertainty.
Neurodegenerative Disease and Autophagy in iPSC models.
Current Achievements in Gene Therapy Strategies and Delivery Systems in Preclinical and Clinical Models of Heart Failure.
Constellation illuminates rare disease genetics.
Molecular crosstalk for longevity: exercise and the AMPK/SIRT1/PGC-1α/Irisin/BDNF axis.
Preventive and Protective Effects of Nicotinamide Adenine Dinucleotide Boosters in Aging and Retinal Diseases.
MitoLandscape, a semi-automated pipeline for subcellular localization and quantification of mitochondria.
Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.
Mesenchymal stem cell therapy for end-stage liver disease: adversity and opportunity.

Int J Mol Sci. 2025 Nov 15. pii: 11052. [Epub ahead of print]26(22):

Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.

Dhienda C Shahannaz, Tadahisa Sugiura, Taizo Yoshida.

  Mitochondrial dysfunction is a pivotal contributor to cardiac disease progression, making it a critical target in regenerative interventions. Extracellular vesicles (EVs) have recently emerged as powerful mediators of mitochondrial transfer and cardiomyocyte repair. This review highlights recent advancements in EV bioengineering and their applications in cardiac mitochondrial rescue, with a particular focus on EVs derived from induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Drawing upon a growing body of preclinical evidence, we examine the mechanisms of mitochondrial content delivery, EV uptake dynamics, and comparative bioenergetic restoration outcomes across EV sources. Special emphasis is placed on therapeutic outcomes such as adenosine triphosphate (ATP) restoration, reactive oxygen species (ROS) modulation, and improvements in contractility and infarct size. The convergence of mitochondrial biology, stem cell-derived EV platforms, and engineering innovations positions mitochondria-enriched EVs as a promising non-cellular regenerative modality for cardiovascular disease.

Keywords:  cardiac regenerative therapy; cardiomyocyte repair; extracellular vesicles (EVs); heart failure; induced pluripotent stem cell (iPSCs); mitochondrial dysfunction; mitochondrial transfer; regenerative medicine; stem cell-derived exosomes; targeted organelle delivery

DOI:  https://doi.org/10.3390/ijms262211052
bioRxiv. 2025 Nov 11. pii: 2025.11.10.687605. [Epub ahead of print]

Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.

Jiaqi Xie, Phyo W Win, Charles Newcomb, Shaopeng Zeng, Christina A Castellani, Dan E Arking.

Mitochondrial DNA copy number (mtDNA-CN) is a metric of mitochondrial function that has been associated with a variety of diseases including cardiovascular disease and all-cause mortality. To investigate genes and pathways affected by mtDNA-CN variation, we perturbed HEK 293T cells with ethidium bromide to deplete mtDNA. Using RNASeq and methylation microarrays, we evaluated transcriptomic and methylomic changes in treated cell lines. We observed an 8-fold decrease in mtDNA-CN and compensatory shifts in mitochondrial transcription to support mtDNA replication. Nuclear transcriptomic and methylomic analysis highlighted changes in metabolic pathways, including oxidative phosphorylation and canonical glycolysis. Longitudinal analyses revealed that the identified genes and pathways have different response timing, with nuclear response lagging behind mitochondrial response. These findings further elucidate the mechanisms behind mtDNA maintenance and responses to cellular energetics as well as mitochondrial-nuclear crosstalk dynamics.

DOI: https://doi.org/10.1101/2025.11.10.687605
Int J Mol Sci. 2025 Nov 16. pii: 11084. [Epub ahead of print]26(22):

Mitochondrial Quality Control and Cell Death.

Zurui Zhang, Mengyuan Zhang, Hongchi Jin, Shuang Lv, Yilei Li, Yanru Li.

  Mitochondrial quality control includes mitochondrial biogenesis, fusion, fission (to maintain mitochondrial function), and mitochondrial autophagy (for removing damaged mitochondria). This is a highly delicate and complex process involving many molecules. Mitochondrial quality control is crucial for maintaining mitochondrial homeostasis and function, preserving energy supply, eliminating damaged mitochondria to prevent cytotoxicity, promoting mitochondrial regeneration and repair, protecting cells from oxidative stress and senescence, and facilitating cellular communication and material exchange. In this review, we introduce the structure and function of mitochondria, the mechanisms of quality control, and the relationship between mitochondrial quality control and cellular processes such as pyroptosis, apoptosis, and ferroptosis. We also summarize the proteins, enzymes, and their molecular mechanisms involved in these processes and propose a "spatiotemporal-threshold" model for the mitochondrial quality control-cell death axis.

Keywords:  apoptosis; ferroptosis; mitochondrial autophagy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; pyroptosis

DOI:  https://doi.org/10.3390/ijms262211084
medRxiv. 2025 Oct 17. pii: 2025.10.15.25338094. [Epub ahead of print]

Electron microscopy visualization of cell-free mitochondrial DNA-containing extracellular vesicles in human plasma, serum, and saliva.

Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, Jonathan R Brestoff, Martin Picard.

Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and purposes. To expand our understanding of cf-mtDNA biology, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy people (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles- consistent with mitochondrial ultrastructure-are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary results challenge the notion that, under normal conditions, the majority of cf-mtDNA exists as naked and potentially pro-inflammatory forms. Instead, these results are consistent with the concept of mitochondria transfer or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.

DOI: https://doi.org/10.1101/2025.10.15.25338094
Int J Mol Sci. 2025 Nov 19. pii: 11180. [Epub ahead of print]26(22):

Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.

Samantha Su Ping Low, Laura Greaves, Ryan Silk, Colin A Semple, Charlie Gourley.

  Mitochondrial DNA (mtDNA) mutations are prevalent across cancer genomes, and growing evidence implicates their multifaceted role in energy metabolism with tumorigenesis. Ovarian cancer, in particular, demonstrates high mtDNA copy numbers and increased incidences of truncating and missense mtDNA mutations, with heteroplasmy levels predictive of prognosis. This review provides a comprehensive description of published mtDNA sequencing data in ovarian cancer, the majority being high-grade serous samples, encompassing both coding and non-coding regions. MtDNA mutations within non-coding regions, such as the D-loop control region, can affect mtDNA replication and transcription, hence affecting overall mtDNA copy numbers, while mtDNA mutations within coding regions can directly impact respiratory complex function and downstream metabolic pathways. MtDNA mutations may serve as clinically valuable diagnostic biomarkers for ovarian cancer and predictors for chemoresistance. We also explore ongoing efforts to deepen our understanding of mitochondrial oncogenetics through the creation of novel cancer models enabled by mitochondrial gene editing techniques. Developing robust human ovarian cancer cell models will be critical to elucidate mechanistic and phenotypic consequences of mtDNA mutations, assess drug response and resistance and identify new therapeutic targets to advance precision oncology in this emerging field.

Keywords:  gene editing; heteroplasmy; mitochondrial DNA; ovarian cancer; somatic mutations

DOI:  https://doi.org/10.3390/ijms262211180
Genes (Basel). 2025 Nov 01. pii: 1298. [Epub ahead of print]16(11):

Mitochondrial Base Editing of the m.8993T>G Mutation Restores Bioenergetics and Neural Differentiation in Patient iPSCs.

Luke Yin, Angel Yin, Marjorie Jones.

   BACKGROUND: Point mutations in mitochondrial DNA (mtDNA) cause a range of neurometabolic disorders that currently have no curative treatments. The m.8993T>G mutation in the Homo sapiens MT-ATP6 gene leads to neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) when heteroplasmy exceeds approximately 70%.
METHODS: We engineered a split DddA-derived cytosine base editor (DdCBE), each half fused to programmable TALE DNA-binding domains and a mitochondrial targeting sequence, to correct the m.8993T>G mutation in patient-derived induced pluripotent stem cells (iPSCs). Seven days after plasmid delivery, deep amplicon sequencing showed 35 ± 3% on-target C•G→T•A conversion at position 8993, reducing mutant heteroplasmy from 80 ± 2% to 45 ± 3% with less than 0.5% editing at ten predicted off-target loci.
RESULTS: Edited cells exhibited a 25% increase in basal oxygen consumption rate, a 50% improvement in ATP-linked respiration, and a 2.3-fold restoration of ATP synthase activity. Directed neural differentiation yielded 85 ± 2% Nestin-positive progenitors compared to 60 ± 2% in unedited controls.
CONCLUSIONS: Edits remained stable over 30 days in culture. These results establish mitochondrial base editing as a precise and durable strategy to ameliorate biochemical and cellular defects in NARP patient cells.

Keywords:  DdCBE; MT-ATP6; NARP; base editing; heteroplasmy; iPSCs; m.8993T>G; mitochondrial DNA

DOI:  https://doi.org/10.3390/genes16111298
bioRxiv. 2025 Oct 15. pii: 2025.10.13.682189. [Epub ahead of print]

Intrinsic errors in mitochondrial translation trigger a decline in cell fitness.

Güleycan Lutfullahoglu Bal, Kah Ying Ng, Eli Berzell, Ani Akpinar, Alex E Ekvik, Lidiia Koludarova, Seyedehshima Naddafi, Clemens Raths, Tania Vane-Tempest, Jordyn J VanPortfliet, Sarah O'Keefe, Arafath K Najumudeen, Tuula A Nyman, James B Stewart, A Phillip West, Brendan J Battersby.

Defects in the faithful expression of the human mitochondrial genome underlies disease states, from rare inherited disorders to common pathologies and the aging process itself. The ensuing decrease in the capacity for oxidative phosphorylation alone cannot account for the phenotype complexity associated with disease. Here, we address how aberrations in mitochondrial nascent chain synthesis per se exert a decline in cell fitness using a classic model of mitochondrial induced premature aging. We identify how intrinsic errors during mitochondrial nascent chain synthesis destabilize organelle gene expression, triggering intracellular stress responses that rewire cellular metabolism and cytokine secretion. Further, we show how these mechanisms extend to pathogenic variants associated with inherited human disorders. Together, our findings reveal how aberrations in mitochondrial protein synthesis can sensitize a cell to metabolic challenges associated with disease and pathogen infection independent of oxidative phosphorylation.
Teaser/One-Sentence Summary: Aberrations in mitochondrial translation elongation trigger activation of intracellular stress responses associated with disease and aging.

DOI: https://doi.org/10.1101/2025.10.13.682189
QJM. 2025 Nov 23. pii: hcaf290. [Epub ahead of print]

New insights from mendelian randomization and mediation analysis: causal relationships between mitochondrial DNA copy number and telomere length in pulmonary fibrosis.

Yan Li, Yunfeng Xia, Zhenzong Han, Jixiang Liu, Lin Hou.

   BACKGROUND: Variations in mitochondrial DNA copy number can lead to mitochondrial dysfunction, subsequently accelerating cellular senescence, a process implicated in the pathogenesis of multiple respiratory diseases. However, the causal relationship between mitochondrial DNA copy number and respiratory diseases, as well as the potential mediating factors involved, remains to be fully elucidated.
OBJECTIVE: This study aimed to establish the causal link between mitochondrial DNA copy number and pulmonary diseases and to explore the potential mediating role of telomere length in this association.
METHODS: Univariate Mendelian randomization (UVMR) analyses were conducted to assess the relationships among mitochondrial DNA copy number, respiratory diseases, and telomere length in immune cells. To refine the causal inference, multivariable Mendelian randomization (MVMR) was employed. The mediating effect of telomere length on the causal pathway between mitochondrial DNA copy number and pulmonary diseases was specifically investigated.
RESULTS: UVMR analysis revealed a significant causal association between mitochondrial DNA copy number (n = 395,718) and pulmonary fibrosis (n = 469,126). In the MVMR model, the genetic associations among mitochondrial DNA copy number, naïve T-cell telomere length, and pulmonary fibrosis remained robust. Importantly, naïve T-cell telomere length was identified as a critical mediator in the causal pathway linking mtDNA copy number to pulmonary fibrosis.
CONCLUSIONS: This study provides genetic evidence supporting a causal relationship between reduced mitochondrial DNA copy number and increased risk of pulmonary fibrosis. It also highlights naïve T-cell telomere length as a key intermediary factor in this process. Nonetheless, further in vivo and in vitro investigations are needed to validate these findings and to elucidate the underlying molecular mechanisms.

Keywords:  Mendelian randomization analysis; Mitochondrial DNA copy number; Pulmonary fibrosis; naïve T-cell telomere length

DOI:  https://doi.org/10.1093/qjmed/hcaf290
Results Probl Cell Differ. 2026 ;76 167-182

Analysis of Bush Cricket Oogenesis Provides an Insight into the Function and Anagenesis of an Enigmatic Organelle Assemblage: The Balbiani Body.

Szczepan M Bilinski, Malgorzata Sekula, Magda Sochaczewska, Waclaw Tworzydlo.

Balbiani body (Bb) is an intricate, oocyte-specific organelle complex described in the ooplasm of nearly all examined vertebrates and invertebrates. The Bb is devoid of a limiting membrane and consists of such organelles as elements of endoplasmic reticulum (ER), Golgi complexes (GCs), mitochondria, and characteristic accumulations of fibrillo-granular material, termed the "nuage." Despite numerous studies, the functioning of the Bb remains not completely understood. Until now at least four disparate functions have been attributed to the Bb: (1) delivery of germinal granules and localized mRNAs to the oocyte vegetal cortex; (2) transfer of mitochondria to the polar (germ) plasm; (3) selective elimination of dysfunctional (damaged, containing mutated mitochondrial DNA (mtDNA)) mitochondrial units in female germline cells; and (4) formation of oocyte reserve materials, e.g., lipid droplets. Such functional variability obviously raises several intriguing questions for students of developmental and cellular biology. Here we present the results of our studies on oogenesis of bush crickets that advance our understanding of the Bb function and anagenesis of this organelle complex during the evolution of bilateral animals.

DOI: https://doi.org/10.1007/978-3-032-06766-1_9
Nat Metab. 2025 Nov 24.

Mitochondrial NAD+ drives liver regeneration.

DOI: https://doi.org/10.1038/s42255-025-01414-7
Cell Commun Signal. 2025 Nov 26. 23(1): 509

Extracellular vesicles for delivery of functional telomerase.

Yingying He, Yumeng Cui, Lijuan Wang, Wen Yang, Ruping Wang, Yanghua Li, Yue Ma, Yanli Lin, Xiaojie Wu, Long Cheng, Chengjiang Zhou, Youliang Wang.

   BACKGROUND: Telomerase, essential for maintaining chromosomal telomere integrity and preventing cellular senescence, represents a promising therapeutic target. However, the inherent risks associated with existing treatments for telomerase deficiency-related diseases necessitate the development of safe and precise targeted delivery systems capable of reaching specific cell populations. Extracellular vesicles (EVs), nanoscale membrane-bound particles naturally secreted by cells, mediate intercellular communication by transporting bioactive molecules, including proteins and nucleic acids. We hypothesized that EVs could function as intrinsic vehicles for telomerase delivery.
METHODS: To investigate this, we demonstrated the effective encapsulation of functional telomerase components, specifically TERT and TERC, within EVs. Furthermore, we observed that enhanced TERT expression led to increased telomerase activity within the EVs, as confirmed by TRAP assay results.
RESULTS: These telomerase-loaded EVs, leveraging their inherent targeting capabilities and unique vesicular structure, efficiently delivered the active enzyme to recipient cells. In aged mice, delivery of telomerase via EVs restored endogenous telomerase activity, preserved telomere integrity, and attenuated senescence across multiple tissues. We observed that the internalized telomerase modulated the expression of senescence-associated markers, thereby delaying cellular aging and promoting cellular proliferation.
CONCLUSIONS: These findings support the feasibility of EV-mediated intercellular telomerase delivery, suggesting a potential avenue for developing therapeutic interventions for pathologies associated with telomerase deficiency.

Keywords:  Cellular senescence; Extracellular vesicles; TERT; Telomerase

DOI:  https://doi.org/10.1186/s12964-025-02524-1
Pharmacol Res. 2025 Nov 21. pii: S1043-6618(25)00468-2. [Epub ahead of print]222 108043

Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration.

Chenrong Jin, Juhui Qiao, Huilin Gong, Xiaorui Yu, Xinran Wang, Jiao Xi, Runying Mi, Shiting Yu, Daian Pan, Siming Wang, Xiaolin Tong, Daqing Zhao, Meichen Liu.

  Aging profoundly impacts the brain, serving as a primary driver of neurodegenerative diseases through mechanisms closely linked to mitochondrial dysfunction. Despite its clinical significance, the molecular mechanisms remain unclear, and safe, effective therapies are urgently needed. Here, leveraging ginseng's neuroprotective potential, we screened for blood-brain barrier-permeable saponins with optimal neuroprotective efficacy and identified ginsenoside Re (Re) as the predominant mitochondrially targeted neuroprotective saponin. Midlife Reintervention, temporally aligned with the natural window of mitochondrial hyperfusion, rescued age-related degenerative pathology in Drosophila. Re administration ameliorated dopaminergic neuron loss, mitigated muscles pathology, improved cognitive-motor deficits, and extended healthspan. Mechanistic studies revealed that Re directly binds to the Drp1 across multiple species via the highly conserved L94 residue, triggering robust S616 phosphorylation that drives Drp1 translocation to mitochondria, thereby restoring fission-fusion equilibrium. Re further spatiotemporally coupled fission-mitophagy through the Drp1-Atg1/ULK1 axis, enabling autophagosome initiation and ensuring efficient clearance of damaged organelles. This dual regulation enhanced bioenergetic capacity and delayed functional decline. Genetic ablation of Drp1 L94 completely abolished Re's benefits, while translational studies in mice confirmed that healthspan extension required intact Drp1-L94 functionality. Notably, Re demonstrated conserved neuroprotective efficacy in both human induced pluripotent stem cells-derived dopaminergic neurons and Drosophila Parkinson's model, indicating preservation of the Drp1-mitophagy pathway across species. Our findings establish Re as a geroprotector that targets the conserved Drp1-L94 residue to restore mitochondrial homeostasis. By spatiotemporally coupling fission to Atg1-mediated mitophagy during the critical midlife hyperfusion window, Re delays neurodegeneration, thereby establishing a molecular basis for developing therapies against age-related decline.

Keywords:  Brain aging; Drp1 mutants; Ginsenoside Re; Mitochondrial dynamics; Mitophagy axis

DOI:  https://doi.org/10.1016/j.phrs.2025.108043
Transl Neurodegener. 2025 Nov 27. 14(1): 60

Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications.

Zhichun Chen, Zixu Mao, Weiting Tang, Yuxuan Shi, Jun Liu, Yong You.

  Aging is a multifaceted biological process affecting various organ systems. Immunosenescence, a key feature of aging, markedly increases susceptibility to infections, cancers, autoimmune diseases, and also neurodegenerative disorders. Immunosenescence not only accelerates normal aging but also drives the progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the lack of a consensus on the mechanistic hallmarks of immunosenescence presents a major barrier to the development and validation of anti-aging therapies. In this review, we propose 11 hallmarks of immunosenescence: genomic instability, telomere attrition, epigenetic dysregulation, stem cell exhaustion, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, altered intercellular communication, and microbiome dysbiosis. We also elucidate the intricate interplay between immunosenescence and both normal brain aging and neurodegenerative pathologies, highlighting the pivotal involvement of age-related immune dysregulation in the pathogenesis of neurodegenerative disorders. This mechanistic connection is particularly evident in prototypical neurodegenerative conditions such as AD and PD, where immunosenescence appears to significantly contribute to disease progression and phenotypic manifestations. Given that the ultimate goal of immune aging research is to prevent or alleviate age-related diseases, we also discuss potential hallmark-targeting anti-immunosenescence strategies to delay or even reverse normal aging and neurodegeneration.

Keywords:  Anti-aging therapy; Brain aging; Hallmarks; Immunosenescence; Neurodegenerative disease

DOI:  https://doi.org/10.1186/s40035-025-00517-1
Mol Neurobiol. 2025 Nov 27. 63(1): 193

Advances in Intranasal Delivery of Exosomes for Central Nervous System Disorders.

Babak Arjmand, Ali Reza Mojavezi, Amirhossein Kamroo, Rosa Kalami Yazdi, Mostafa Rezaei-Tavirani, Mohamad-Sadegh Vahedi.

  Central nervous system disorders are major global health challenges that contribute to significant morbidity and mortality. Traditional therapeutic strategies often face substantial limitations, primarily due to the blood-brain barrier, which restricts the delivery of pharmacological agents to the brain and consequently affects treatment effectiveness. In recent years, in order to enhance the efficacy of the central nervous system treatments, exosome-based approaches have gained interest. Exosomes, small extracellular vesicles (30-150 nm) secreted by cells, present a feasible therapeutic strategy due to their ability to cross the blood-brain barrier and transport bioactive molecules. Reflecting the traits of their parent cells (e.g., glioma stem cells and glioblastoma multiforme), exosomes can be isolated from body fluids, which enhances their clinical applicability. Additionally, intranasal delivery provides a non-invasive method to administer exosomes, using the olfactory and trigeminal nerve pathways to bypass the blood-brain barrier and directly target the brain. This method shows great promise in enhancing therapeutic efficacy for CNS disorders. However, challenges such as rapid mucociliary clearance, enzymatic degradation, and limited bioavailability reduce efficacy. Advances in exosome engineering, nanocarrier systems, and novel delivery devices are under investigation to mitigate these constraints. However, clinical translation requires further research to guarantee safety, consistency, and scalability. In this context, intranasal exosome delivery holds considerable promise as a non-invasive strategy for central nervous system disorder treatment, contingent on overcoming the current biological and technical barriers.

Keywords:  Blood-brain barrier; Central nervous system disorders; Exosomes; Intranasal delivery; Nanocarrier engineering; Therapeutic loading

DOI:  https://doi.org/10.1007/s12035-025-05563-4
J Med Internet Res. 2025 Nov 28. 27 e77087

Social Media Use Among Parents and Caregivers of Children With Rare Genetic Diseases: Scoping Review.

Charlotte Davis, Laura Bogaert, John Powell, Karen Low.

   BACKGROUND: Caring for children with rare genetic disorders is challenging due to complex medical needs and limited information. Often, information is scarce due to geographical dispersion and lack of access to expertise. Social media groups are increasingly used in parenting and in healthcare as tools for data sharing and acquisition, and online peer support. Online groups relating to specific rare diseases are increasingly used by parents navigating the difficulties of understanding their child's diagnosis and providing them with support. Parents expect professionals to interact with them about information reported from online groups, but little is known regarding the content within these groups and the impact on families.
OBJECTIVE: We aimed to synthesize current knowledge of social media use among parents and caregivers of children with a rare genetic syndrome to inform how these data might be used in parent-doctor interactions and in the research setting.
METHODS: We completed a comprehensive literature review across Web of Science, PubMed, and PsycINFO using a search strategy with themes of caregivers, rare genetic disease, and social media. Studies published in English from 2005 onwards, with parents and caregivers as a cohort and a focus on rare genetic diseases, were included. In total, 159 articles were identified, which underwent a title sift followed by an abstract sift based on inclusion and exclusion criteria. Reference lists of included articles were also reviewed. A total of 12 studies were included, and a critical synthesis methodology was used to extract relevant points.
RESULTS: Most parents and caregivers use social media platforms, especially Facebook (Meta Platforms, Inc), particularly the group function. They are using social media groups as a tool for finding information related to their child's rare genetic disease. A majority also engaged in online groups by sharing information and contributions of their own. This review highlights that caregivers are seeking three main types of support from social media: (1) medical information around diagnosis and treatments, (2) practical tips on care needs and equipment, and (3) social support, involving connection with other families who shared similar experiences. The use of social media improved accessibility to information regardless of time or geography and reduced feelings of isolation. Caregivers felt empowered in decision-making, and their interactions with health care professionals improved. Challenges include misinformation, concerns around privacy, emotional impacts of comparison, and a lack of online spaces for the rarest conditions.
CONCLUSIONS: Social media is a key tool for caregivers of children with rare genetic diseases. Addressing the associated challenges and harnessing the potential of these platforms can positively impact these families. Health care providers should consider discussing social media engagement in conversations with caregivers, and future research should focus on larger, longitudinal studies to explore the impacts of social media engagement.

Keywords:  genetic disease; online support group; parent; rare disease; social media

DOI:  https://doi.org/10.2196/77087
Diseases. 2025 Nov 19. pii: 378. [Epub ahead of print]13(11):

Exploring Mitochondrial DNA Copy Number in Italian Children with ADHD: Implications for Neurobiological Mechanisms.

Luigi Citrigno, Annamaria Cerantonio, Ludovico Neri, Pierluigi Sebastiani, Alessia Colanardi, Gabriele Turacchio, Tiziana Del Beato, Beatrice Marziani, Anna Aureli.

   BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition frequently accompanied by behavioral dysregulation. While genetic factors involving monoaminergic systems have been implicated, emerging evidence suggests a role for mitochondrial dysfunction in ADHD pathophysiology. Mitochondrial DNA copy number (mtDNA-cn), a surrogate marker of mitochondrial biogenesis and cellular energy demand, may reflect underlying neurobiological alterations and oxidative stress-related mechanisms relevant to ADHD.
METHODS: We assessed mtDNA-cn in the peripheral blood of 56 Italian children and adolescents with ADHD and 27 age- and sex-matched healthy controls. ADHD symptoms and aggressive behavior were evaluated using DSM-5 criteria and the Conners' 3 Rating Scales. Genotyping was performed for MAOA (rs6323, rs1137070) and 5-HTT (rs4795541) polymorphisms.
RESULTS: ADHD patients showed significantly higher mtDNA-cn than controls (p = 0.002), supporting mitochondrial dysregulation. Comparing the ADHD patient subgroups with aggressive behavior and those without, a non-significant reduction in mtDNA-cn was observed in the first subgroup. Notably, individuals with the TT genotype (rs6323) or CC genotype (rs1137070) had significantly higher mtDNA-cn compared to controls with the same genotypes (p = 0.031). Similar increases were seen across all 5-HTT rs4795541 genotypes in ADHD patients.
CONCLUSIONS: Our findings suggest that mitochondrial alterations may contribute to ADHD pathophysiology. The association between mtDNA-cn and monoaminergic gene variants highlights a potential link between neurotransmitter metabolism, oxidative stress, and mitochondrial function. Thus, mtDNA-cn may serve as a peripheral biomarker and therapeutic target in ADHD.

Keywords:  5-HTT; ADHD; MAOA; aggressive behavior; mtDNA-cn; polymorphisms

DOI:  https://doi.org/10.3390/diseases13110378
FEBS Open Bio. 2025 Nov 23.

Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.

Chatnapa Panusatid, Rapasviranda Soiyangsuk, Maneeluck Tanadjindarat, Chayanon Peerapittayamongkol.

  Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder caused by mitochondrial DNA mutations in complex I of the respiratory chain, leading to impaired ATP production, mitochondrial fragmentation, and oxidative stress that contribute to vision loss. This study investigated the potential repurposing of metformin, a widely used antidiabetic drug, in fibroblasts from LHON patients carrying the m.11778G>A mutation. Fibroblasts from LHON patients and healthy individuals were treated with metformin, and mitochondrial function was assessed using high-content imaging, biochemical assays, immunoblotting, immunofluorescence, and Seahorse analysis. Metformin reduced mitochondrial fragmentation, increased network length, stabilized mitochondrial membrane potential, enhanced ATP production, and lowered ROS accumulation under oxidative stress. Metformin significantly increased mitophagy and autophagic flux, as shown by LC3B puncta quantification with and without chloroquine, and activated AMPK signaling through increased AMPKα1/2 phosphorylation and AMPKβ1 Ser182 phosphorylation. In addition, metformin promoted PGC-1α nuclear translocation, indicating stimulation of mitochondrial biogenesis, while maintaining mtDNA copy number and supporting oxidative phosphorylation. These findings suggest that metformin, at clinically relevant concentrations, enhances mitochondrial health and function in LHON fibroblasts, supporting its potential as an affordable and safe therapeutic option to mitigate vision loss in LHON.

Keywords:  AMPK activation; Leber's hereditary optic neuropathy; Metformin; Mitochondrial dynamics; Mitophagy; Primary fibroblasts

DOI:  https://doi.org/10.1002/2211-5463.70165
ACR Open Rheumatol. 2025 Dec;7(12): e70138

Importance and Potential of Rare Disease Research in Pediatric Rheumatology and Beyond: Pushing Frontiers.

Christian M Hedrich.

Although individually occurring in less than 1 in 2,000 people, cumulatively, more than 7,000 rare diseases affect approximately 6% of the population worldwide. Children and young people are disproportionally challenged in number and severity, which may be explained by the large proportion of genetic conditions among rare diseases (70%-80%). Indeed, an estimated 30% of children with rare diseases do not survive past their fifth birthday. Because rare diseases are frequently missed or diagnosed with a delay of several years and <5% of rare diseases have a licensed treatment, the impact of rare diseases on the indivual affected (independent of age) and wider society is significant. To address these challenges sufficiently, rare disease expert centers combining research activity with patient care are needed to develop diagnostic tests, prognostic tools, and new treatments. This expert-driven approach promises expedited diagnosis and efficacious treatment and care. Although restricted by chronic underfunding, rare disease research keeps delivering new exciting treatment options and technologies, some of which have revolutionized care not only in niche areas of medicine but also common diseases (the use of interleukin-1 blockers in gout or COVID-19-associated hyperinflammation, etc). However, rare disease research and care will only be successful in collaborative, mutidisciplinary and multiprofessional teams that involve patients and families as equal partners and span across institutional and national borders. Lastly, the use of state-of-the-art computational approaches to share knowledge and associate molecular with clinical phenotypes, treatment responses, and disease outcomes will amplify our ability to serve patients and the society.

DOI: https://doi.org/10.1002/acr2.70138
Pharmaceuticals (Basel). 2025 Nov 19. pii: 1762. [Epub ahead of print]18(11):

Topical Treatments for Rare Genetic Dermatological Diseases: A Narrative Review.

Beatriz de Araujo Oliveira, Ana Torres, Eduardo Ricci-Júnior, Isabel F Almeida, Mariana Sato S B Monteiro.

  Rare diseases are conditions that affect up to 65 people per 100,000 individuals. They are also known as "orphan diseases", because they attract limited interest from researchers and pharmaceutical industries. Epidermolysis bullosa (EB), ichthyosis, Hailey-Hailey disease (HHD), Darier disease (DD), erythrokeratoderma, porokeratosis, inflammatory linear verrucous epidermal nevus (ILVEN) and piebaldism are examples of rare genetic skin diseases with few approved treatments. Topical treatments are the principal approach for rare dermatological diseases, and it can be useful to manage the symptoms or the patophysiology of these diseases. This study aimed to conduct a comprehensive review of the topical treatments of EB, ichthyosis, HHD, DD, erythrokeratodermias, porokeratosis, ILVEN, and piebaldism. The search was performed across the SciELO, MEDLINE®/PubMed®, Embase and Cochrane databases. This review identified porokeratosis, EB, and congenital ichthyosis as the rare genodermatoses with the highest number of reported studies and topical treatment options. In contrast, conditions such as piebaldism, erythrokeratodermia, and HHD have fewer reported topical interventions. For most rare genetic dermatological diseases, treatment aims to improve quality of life and control clinical signals and symptoms. Creams, gels, and ointments are frequently used as the main pharmaceutical approaches, and several pharmacological classes are employed, including keratolytics, retinoids, vitamin D analogs, topical corticosteroids, calcineurin inhibitors, and cytotoxic or antiproliferative agents. This review highlights the potential of off-label use of topical therapies as cost-effective alternatives in the treatment of rare genetic skin disorders. It also reinforces the critical role of compounded medicines in allowing for dose optimization, drug repurposing, and formulation adjustments, personalizing treatment to achieve improved therapeutic outcomes.

Keywords:  compounding medicines; dermatological diseases; orphan diseases; rare genetic diseases; topical treatments

DOI:  https://doi.org/10.3390/ph18111762
Mol Neurobiol. 2025 Nov 22. 63(1): 137

Mechanistic Interplay of Gut Microbiota and Blood-Brain Barrier Integrity in Neurodegenerative Diseases.

Suleiman Ibrahim Mohammad, Yasir Mohammed Hammood, Asokan Vasudevan, Subasini Uthirapathy, Suhas Ballal, A Sabarivani, Swati Mishra, Deepak Nathiya, Zahraa Haleem Al-Qaim, Abed J Kadhim.

  The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a vital role in maintaining overall health through digestion, nutrient production, and immune modulation. Factors such as diet, lifestyle, and medication use significantly influence its composition. Concurrently, the blood-brain barrier (BBB) serves as a crucial protective barrier, regulating the passage of substances between the bloodstream and the brain. Disruption of the BBB is linked to various neurological disorders and cognitive decline. Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's, can be exacerbated by compromised BBB integrity, allowing harmful substances to penetrate the brain and accelerate neuronal degeneration. This review examines the complicated relationship between gut microbiota and BBB integrity, focusing on their collective impact on neurodegenerative diseases. Despite advancements in understanding these systems independently, there remains a critical gap in comprehending their interconnected roles in neurodegeneration. Addressing this gap is paramount for developing innovative therapeutic strategies. Specifically, this review suggests that modulating the gut microbiota offers a promising and actionable approach to preserve BBB integrity, thereby presenting a novel avenue for mitigating neurodegeneration and improving the prognosis and quality of life for affected individuals.

Keywords:  Blood–brain barrier; Gut microbiota; Neurodegenerative disease; Neuroinflammation; Short-chain fatty acids; Tight junctions

DOI:  https://doi.org/10.1007/s12035-025-05447-7
Res Sq. 2025 Oct 13. pii: rs.3.rs-7634140. [Epub ahead of print]

Cytosolic mtDNA and associated EYA-mediated pro-inflammatory signaling modulate healthspan in Drosophila.

David Walker, Ricardo Aparicio, Roberta Alessi, Agathe Solans, Matin Mojdeh, Vartika Sharma, Paul Oh, Matea Zelich, Toby Frank, Jae Hur.

Mitochondrial dysfunction and pro-inflammatory signaling are each key drivers of aging. However, a clear understanding of the connections between mitochondrial homeostasis, inflammation and lifespan determination remains elusive. Upon mitochondrial stress or damage, mtDNA can be released into the cytosol thus encountering cytosolic DNA sensors and activating pro-inflammatory responses. Here, we report a striking age-related increase in cytosolic mtDNA, which can be counteracted by mitophagy, in Drosophila brain and muscle tissue. We find that upregulation of DNase II, an acid DNase which digests DNA in the autophagy-lysosome system, reduces cytosolic mtDNA levels in aged flies and prolongs healthspan. Reducing the abundance of cytosolic DNA in aged flies also dampens Rel/NF-κB pro-inflammatory signaling. Furthermore, we show that inhibition of EYA, a Rel/NF-κB-binding protein involved in immune sensing of DNA, in aging neurons counteracts brain aging and prolongs healthspan. Our findings identify DNase II and EYA as therapeutic targets to prolong healthspan.

DOI: https://doi.org/10.21203/rs.3.rs-7634140/v1
Nature. 2025 Nov 28.

Audio long read: Faulty mitochondria cause deadly diseases - fixing them is about to get a lot easier.

Gemma Conroy, Benjamin Thompson.

DOI: https://doi.org/10.1038/d41586-025-03797-9
J Clin Transl Hepatol. 2025 Nov 28. 13(11): 976-985

The Role of Mitochondrial Complexes in Liver Diseases.

Hai An.

  Mitochondrial respiratory complexes (Complexes I-V) and their assembly into respiratory supercomplexes (SCs) are fundamental to liver bioenergetics, redox homeostasis, and metabolic adaptability. Disruption of these systems contributes to major liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, drug-induced liver injury, viral hepatitis, and hepatocellular carcinoma, by impairing adenosine triphosphate synthesis, increasing oxidative stress, and altering metabolic pathways. Recent advances have clarified the structural-functional interdependence of individual complexes within SCs, revealing their dynamic remodeling in response to physiological stress and pathological injury. These insights open opportunities for clinical translation, such as targeting SC stability with pharmacological agents, nutritional strategies, or gene therapy, and employing mitochondrial transplantation in cases of severe mitochondrial failure. Precision medicine approaches, incorporating multi-omics profiling and patient-derived models, may enable individualized interventions and early detection using SC integrity as a biomarker. By linking molecular mechanisms to therapeutic strategies, this review underscores the potential of mitochondrial-targeted interventions to improve outcomes in patients with liver disease.

Keywords:  ATP; ATP production; Adenosine triphosphate; Electron transfer chain; Energy metabolism; Liver disease; Mitochondrial complex

DOI:  https://doi.org/10.14218/JCTH.2025.00194
Med Sci (Basel). 2025 Nov 06. pii: 260. [Epub ahead of print]13(4):

Data Augmentation and Synthetic Data Generation in Rare Disease Research: A Scoping Review.

Rebecca Finetti, Bianca Roncaglia, Anna Visibelli, Ottavia Spiga, Annalisa Santucci.

   BACKGROUND: Rare diseases represent a significant research challenge due to the limited availability of data, small patient cohorts, and heterogeneous phenotypes. Data augmentation and synthetic data generation are increasingly adopted to mitigate these limitations.
METHODS: This scoping review maps the application of data augmentation and synthetic data generation methods as strategies to address these limitations. A total of 118 studies published between 2018 and 2025 were identified through PubMed, Scopus, and Electronics Engineers (IEEE) Xplore.
RESULTS: Imaging data headed the field, followed by clinical and omics datasets. Classical augmentation, mainly geometric and photometric transformations, emerged as the most frequent approach, while deep generative models have rapidly expanded since 2021. Rule- and model-based methods were less common but demonstrated high interpretability in small datasets.
CONCLUSIONS: Overall, these techniques enabled dataset expansion and improved model robustness. However, both approaches require rigorous validation to confirm biological plausibility. Together, these methods can transform data scarcity from a barrier into a driver of methodological innovation, enabling more inclusive rare disease research.

Keywords:  data augmentation; machine learning; rare diseases; synthetic data

DOI:  https://doi.org/10.3390/medsci13040260
Int J Mol Sci. 2025 Nov 09. pii: 10869. [Epub ahead of print]26(22):

Special Issue: "New Insights of Biomarkers in Neurodegenerative Diseases".

Ioannis Liampas.

The early and accurate detection and monitoring of neurodegenerative disorders remain among the most pressing challenges in modern neuroscience [...].

DOI: https://doi.org/10.3390/ijms262210869
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00071-9. [Epub ahead of print]148 299-353

Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.

Tripti Nair, Ditsa Sarkar, Sumit Murmu, Rahul Singh Rawat, Biplab Singha.

  Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.

Keywords:  Molecular chaperones; Neurodegenerative diseases; Oxidative stress; Post-translational modifications; Protein aggregation; Protein misfolding; Proteostasis; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.013
Mol Med. 2025 Nov 26. 31(1): 333

Metabolic toxicity and neurological dysfunction in methylmalonic acidemia: from mechanisms to therapeutics.

Mengmeng Du, Miaomiao Li, Shengnan Wu, Xue Wu, Yongxing Chen, Changlian Zhu.

  Methylmalonic acidemia (MMAemia) is an inborn error of organic acid metabolism characterized by the accumulation of toxic metabolites-including methylmalonic acid (MMA), 2-methylcitric acid (2-MCA), propionic acid (PA), homocysteine (Hcy), ammonia, and lactate-due to defects in methylmalonyl-CoA mutase or impaired cobalamin metabolism. These metabolites exert profound effects on the central nervous system, contributing to neurological injury through tightly interconnected mechanisms, including mitochondrial dysfunction, neuroinflammation, and excitotoxicity. This review synthesizes current evidence on how these metabolites trigger neurological dysfunction, integrating findings from clinical studies, animal models, and cellular systems. We also highlight the increasingly recognized role of aberrant post-translational modifications (e.g., methylmalonylation, propionylation, lactylation) in disrupting metabolic network architecture and reprogramming cellular metabolism. Despite advances in supportive therapies, intracerebral metabolite accumulation remains a therapeutic challenge. We discuss emerging strategies targeting mitochondrial protection, redox homeostasis, and inflammation-including enzyme replacement, gene therapy, antioxidant regimens, and exosome-based delivery. A deeper mechanistic understanding of metabolite-driven neurotoxicity is critical to the development of targeted interventions that can improve neurological outcomes in MMAemia.

Keywords:  Excitotoxicity; Methylmalonic academia; Mitochondrial dysfunction; Neuroinflammation; Post-translational modification; Therapeutic strategies; Toxic metabolites

DOI:  https://doi.org/10.1186/s10020-025-01395-z
Hear Res. 2025 Nov 12. pii: S0378-5955(25)00289-8. [Epub ahead of print]469 109471

Age-related hearing loss involves mitochondrial DNA instability and copy number depletion in the cochlea: Insights from in vivo and in vitro models.

Akil Turner, Bo Ding, Xiaoxia Zhu, Tam Nguyen, Parveen Bazard, Robert D Frisina.

  Age-related hearing loss (ARHL) is a highly prevalent sensory neurodegenerative disorder that involves various molecular mechanisms. The present study investigated if age-related oxidative stress (OS) induces alterations in mitochondrial DNA (mtDNA) copy number and heteroplasmy, using complementary in vivo and in vitro models. Aged (30-month) CBA/CaJ mice have elevated auditory brainstem response (ABR) thresholds amplitudes vs. young (3-month) CBA/CaJ mice, a key physiological characteristic of ARHL The in vitro experiments employed the strial SV-K1 cochlear cell line treated with hydrogen peroxide (H2O2). Both the aged cochleae and H2O2-treated cells exhibited a significant (∼50 %) reduction in mtDNA copy number compared to their respective controls with enhanced levels of malondialdehyde (MDA). Therefore, in both the in vivo and in vitro models, OS drove mtDNA depletion. High-depth sequencing employing nuclear mtDNA pseudogene (NUMT)-avoidant methodologies revealed non-random distribution of heteroplasmic variants. Mutation hotspots were identified within the mitochondrial genome, particularly in regions encoding cytochrome c oxidase subunit 1 (COX1) and cytochrome b (CYTB) in both models. While H2O2 treatment induced a more widespread expansion of low-frequency variants, aging mice primarily showed shifts in the allele frequency distribution of existing variants rather than an accumulation of novel mutations. These findings demonstrate that OS is also a key factor of mtDNA regional mutational burden in the aging cochlea. The parallel mtDNA alterations observed in aged tissues and OS cells underscore mitochondrial genomic instability as a central mechanism in ARHL, highlighting potential targets for interventions aimed at preserving mitochondrial integrity and therefore auditory function.

Keywords:  Age-related hearing loss; Aging; Cochlea; Gene; Mitochondrion; Mutation; Oxidative stress

DOI:  https://doi.org/10.1016/j.heares.2025.109471
Connect Tissue Res. 2025 Nov 25. 1-17

Mitochondrial crosstalk between bone marrow stromal cells and chondrocytes: implication for cartilage repair in osteoarthritis.

Baihui Zhang, Jiasi Zhang, Danyang Yue, Xiao Huang, Jun Pan.

   PURPOSE/AIM: Mitochondria are vital dynamic organelles released by cells into extracellular space, endocytosed in or transferred between cells in contact. Mitochondria from healthy bone marrow stem cells (MSCs) show rescue effects on chondrocytes, accordingly a concept of using healthy MSC mitochondria for cartilage regeneration is put forward. Therefore, whether mitochondria from healthy MSCs help to save chondrocytes in damaged cartilage microenvironment is intriguing. We answered this question by considering coexistent MSCs and chondrocytes, and their released mitochondria in damaged joint.
MATERIALS AND METHODS: Mitochondria were extracted from primarily cultured MSCs and chondrocytes of osteoarthritis (OA) human patients to represent mitochondria released endogenously by MSCs and chondrocytes in damaged joint. While mitochondria were extracted from healthy rats to represent mitochondria exogenously added during MSC mitochondrial repair for the inaccessibility of healthy human. The mitochondria were co-cultured with another type of cells. Endocytosing and afterward positioning of exogenous mitochondria, as well as induced alterations in mitochondria and cellular behaviors of recipient cells were assayed.
RESULT: Our results suggested that although mitochondria from healthy MSCs advantaged remedy for inflammatory chondrocytes, mitochondria from healthy and OA chondrocytes, as well as from OA MSCs disadvantaged chondrocytes remedy, no matter the mitochondria were from the same or different species. However, reactive oxygen species (ROS) modulation alleviated the disadvantage.
CONCLUSIONS: Our results provide a reminder for careful consideration of mitochondrial therapy, and explanation for unsuccessful repair of damaged cartilage by MSCs from aspect of mitochondria, as well as potential remedy through ROS modulation.

Keywords:  Mitochondrial therapy; ROS; cartilage regeneration; differentiation; stem cells

DOI:  https://doi.org/10.1080/03008207.2025.2590044
Exp Physiol. 2025 Nov 29.

Mitochondrial capacities and quality control following short- and long-term weight restoration after simulated anorexia nervosa.

Megan E Rosa-Caldwell, Toby L Chambers, Lauren Breithaupt, Ruqaiza Muhyudin, Patience Salvalina Okoto, Sadie R Thompson, Emily E Rothacker, Claire Greenhill, Katie A Wood, Kevin A Murach, Sarah H White-Springer, Ursula B Kaiser, Seward B Rutkove.

  Anorexia nervosa (AN) is a psychiatric disorder characterized by prolonged caloric restriction and skeletal muscle atrophy. Mitochondrial health is a key mediator of muscle function, yet the role of mitochondria during AN and following weight regain has not been investigated. The objective of this study was to evaluate mitochondrial capacities and quality control mechanisms in a rodent model of AN, spanning the acute underweight phase and multiple recovery periods. Through a series of experiments, 8-week-old female Sprague-Dawley rats underwent a 30-day simulated AN protocol, followed by different durations of weight recovery via ad libitum feeding. Following designated interventions, muscle performance on a submaximal fatiguing protocol and components of mitochondrial function were evaluated. AN resulted in 23%-25% lower muscle performance compared to healthy controls, and these alterations remained even after short-term weight gain. AN rats had 23% lower contribution of complex I to maximal mitochondrial electron transfer as well as alterations to genes important for mitochondrial translation and dynamics, many of which were not resolved with short-term recovery. With long-term recovery, muscle performance and mRNA content of genes related to mitochondrial translation were similar to healthy controls. However, genes related to mitochondrial fission were greater than healthy controls. AN results in reduced muscle performance during a fatiguing protocol, reliance on mitochondrial complex I and genes related to mitochondrial quality control. Many alterations persist with short-term weight recovery; however, given sufficient time, many facets of mitochondrial health appear to normalize following AN, though there still may be long-term consequences to mitochondrial dynamics.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial translation; mitophagy; muscle fatigability; starvation

DOI:  https://doi.org/10.1113/EP093325
medRxiv. 2025 Oct 14. pii: 2025.10.09.25337582. [Epub ahead of print]

Drivers of Diagnostic Delay in Mitochondrial Disease: Missed Recognition of Canonical Features.

Rory J Tinker, Neil Jacob, Mohammad Ghouse Syed, Janhawi Kelkar, Colleen Donnelly, Ibrahim Elsharkawi, Jaya Ganesh, Bruce Gelb, Vikas Pejaver, Tamas Kozicz, Eva Morava.

Background: Diagnostic delay is common in mitochondrial disease, and its drivers remain unclear despite advances in molecular diagnostics.
Methods: We retospectively analyzed 58 individuals with molecularly confirmed mitochondrial disease at the Mount Sinai Mitochondrial Disease Clinic, diagnosed after 2016. Diagnostic delay was partitioned into intervals from symptom onset to clinical suspicion, and from suspicion to molecular diagnosis. Demographic, phenotypic, and genetic data were abstracted from health records, and Human Phenotype Ontology terms were compared before and after diagnosis using ClinPhen.
Results: Most delays occurred between symptom onset and clinical suspicion (mean 8.17 years) rather than after suspicion (mean 0.63 years), yielding a mean total delay of 8.8 years (median 3.0). Delay decreased sharply by year of birth (r = -0.99, p < 1.5 × 10^-48) and symptom onset (r = -0.98, p < 1.4 × 10^-36), but showed no meaningful trend with year of diagnosis. Developmental delay predicted shorter diagnostic intervals. Canonical features such as seizures, hypotonia, and stroke were frequently documented years before suspicion, underscoring missed opportunities.
Conclusions: Diagnostic delay reflects missed recognition rather than testing limitations. Systematic capture of early phenotypes and AI/NLP-based mining of electronic health records could proactively flag patients for reflexive sequencing, shortening diagnostic delay.

DOI: https://doi.org/10.1101/2025.10.09.25337582
J Genet Couns. 2025 Dec;34(6): e70149

"I don't grieve as much as I used to": A qualitative study on parents of children with rare and undiagnosed conditions navigating grief in the context of uncertainty.

Tara Maria Hoffmann, Bettina Friedrich, Celine Lewis.

  The aim of this qualitative interview study was to explore the lived experiences of parents, experiencing high anxiety and poorer quality-of-life/family functioning, caring for a child with a rare and undiagnosed condition. Data analysis led to the generation of a substantial corpus of insights focusing on how parents cope with grief amidst the uncertainty surrounding their child's condition. Whereas much is known about grief related to death in pediatric cancer patients, research focusing on grief in the area of rare and undiagnosed conditions is sparse. We conducted semi-structured interviews with 24 parents of children affected by a rare and undiagnosed condition undergoing whole genome sequencing (WGS) through the Genomic Medicine Service (GMS) in England and Wales. Participants were purposively sampled based on scores to validated psychological measures. We used reflexive thematic analysis, situated within an interpretivist and post-positivist research paradigm, to explore the data. The central organizing concept was named "Navigating Grief In The Context Of Uncertainty." This overarching theme describes how these parents grieve the loss of the envisioned future they held while navigating an unpredictable reality shaped by their child's undiagnosed condition. Our findings also highlight the "potential ongoingness" of grief, although it may change over time. Parents adapt through constructive reframing, seeking meaning and acceptance, and fostering resilience all of which we found to aid in coping. Understanding the grieving process, particularly the role of uncertainty, is essential for improving the clinical support provided to families affected by rare and undiagnosed conditions and for designing future psychological intervention strategies that address parents who grieve the loss of their anticipated family life.

Keywords:  ambiguous loss; chronic sorrow; coping with grief; family grief; genomic sequencing; grief; mental health; parent caregivers; psychosocial support; rare diseases; uncertainty; undiagnosed conditions

DOI:  https://doi.org/10.1002/jgc4.70149
Neurosci Res. 2025 Nov 26. pii: S0168-0102(25)00174-9. [Epub ahead of print] 104991

Neurodegenerative Disease and Autophagy in iPSC models.

Sodbileg Odonchimed, Keiko Imamura, Haruhisa Inoue.

  Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates, which impair normal cellular function. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-derived models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.

Keywords:  autophagy; disease model; iPSCs; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.neures.2025.104991
Curr Heart Fail Rep. 2025 Nov 29. 22(1): 43

Current Achievements in Gene Therapy Strategies and Delivery Systems in Preclinical and Clinical Models of Heart Failure.

Sarah Khan, Carol Wittlieb-Weber, Joseph W Rossano.

   PURPOSE OF REVIEW: Current treatment strategies for heart failure primarily aim to slow disease progression. In the case of rare genetic disorders with associated cardiomyopathies, management is largely supportive. Gene therapy offers a promising alternative that is potentially curative. This review explores gene therapy strategies, vector selection and relevant molecular targets. We also examine pre-clinical and clinical trials investigating gene therapy in cardiomyopathies.
RECENT FINDINGS: Clinical trials for several genetic disorders-including Danon disease, Fabry disease and Duchenne muscular dystrophy-have demonstrated encouraging results. However, with the use of viral vectors and associated immunogenicity eliciting a strong inflammatory response in some patients, there remains a substantial risk of morbidity and mortality. For rare diseases, gene therapy represents a potentially curative, one-time treatment strategy. As the field advances, further work is required to improve vector technology, reduce immunogenicity, decrease off-target effects and address the associated ethical considerations.

Keywords:  AAV vectors; Cardiomyopathy; Clinical trials; Danon disease; Gene therapy; Heart failure

DOI:  https://doi.org/10.1007/s11897-025-00734-9
medRxiv. 2025 Nov 10. pii: 2025.10.15.25337675. [Epub ahead of print]

Constellation illuminates rare disease genetics.

Siyuan Cheng, Qing Zhang, Xinchang Zheng, Shalini Jhangiani, Jacqueline C Weir, Jesse R Farek, Heer H Mehta, Ziad M Khan, Yi Han, Huyen H Dinh, Kerstin P Blankenburg, Jennifer E Posey, Richard A Gibbs, Donna M Muzny, Claudia M B Carvalho, Mitchell A Bekritsky, Ali Crawford, Daniel Calame, James Han, Fritz J Sedlazeck.

Despite significant advances in genomic sequencing, the resolution of many rare disease cases is still hindered by variant detection limitations. Short reads struggle in homologous regions, and long reads remain costly and difficult to scale. Here, we present the first systematic evaluation of Illumina's Constellation sequencing technology for rare disease research. By fragmenting long DNA molecules directly on the flow cell surface, Constellation unlocks proximity information that enables long-range phasing and structural variant detection. Across 21 families, Constellation independently identified all known causative variants and resolved previously unsolved trios. It reliably resolved complex structural and copy number variants (e.g. impacting MECP2 ) and recovered haplotype phasing information across key disease impacting variants, all from low DNA input using existing Illumina infrastructure. These findings establish Constellation as a scalable, cost-efficient advance, closing critical diagnostic gaps and broadening access to long-range variant analysis in rare disease genomics.

DOI: https://doi.org/10.1101/2025.10.15.25337675
Mol Biol Rep. 2025 Nov 29. 53(1): 142

Molecular crosstalk for longevity: exercise and the AMPK/SIRT1/PGC-1α/Irisin/BDNF axis.

Ral De Sousa.



Keywords:  Elderly; Neurodegenerative diseases; Neuroinflammation; Physical activity

DOI:  https://doi.org/10.1007/s11033-025-11315-3
Int J Mol Sci. 2025 Nov 11. pii: 10923. [Epub ahead of print]26(22):

Preventive and Protective Effects of Nicotinamide Adenine Dinucleotide Boosters in Aging and Retinal Diseases.

Saba Noreen, Soon Sung Lim, Deokho Lee.

  Nicotinamide adenine dinucleotide (NAD+) boosting can sustain energy metabolism and neurovascular stability in the retinal tissue. Depletion of NAD+ is linked to the development of pathological retinal conditions, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction, oxidative stress, and inflammation occur in these diseases. This review summarizes substantial evidence of therapeutic NAD+ boosters, including nicotinamide, nicotinamide mononucleotide, or nicotinamide riboside. They help improve mitochondrial function and lessen neurovascular injury. We also emphasize the importance of natural products and sirtuins in facilitating cytoprotective effects through the regulation of mitochondrial balance and inflammation. Developments in drug delivery methods, such as nanoparticle encapsulation and targeted eye treatments, are promising for enhancing the bioavailability and effectiveness of NAD+ boosters. The novelty of this work is its combination of mechanistic insights regarding NAD+ metabolism with efficacy data from preclinical studies. Furthermore, natural products may work together to boost their therapeutic effects against retinal damage. Together, our review article highlights NAD+ metabolism as a potential therapeutic target for addressing retinal degeneration and maintaining vision in aging, neurologic disorders, and various metabolic diseases, including diabetes.

Keywords:  B vitamins; inflammation; mitochondrial function; neuroprotection; nicotinamide; nicotinamide mononucleotide; oxidative stress; retinopathy; sirtuins

DOI:  https://doi.org/10.3390/ijms262210923
Front Cell Dev Biol. 2025 ;13 1668779

MitoLandscape, a semi-automated pipeline for subcellular localization and quantification of mitochondria.

Enrico Negri, Virginia Fernández, Víctor Borrell.

  The precise characterization of mitochondrial morphology and subcellular localization provides crucial insights into cellular metabolic states and developmental fates. However, accurately analyzing mitochondria in cells with complex morphologies remains challenging, particularly within intact tissues where current methodologies lack sufficient resolution and specificity. Here we introduce MitoLandscape, an innovative pipeline tailored for comprehensive mitochondrial analysis at single-cell resolution in the developing nervous system. MitoLandscape integrates Airyscan super-resolution microscopy, semi-automated segmentation (leveraging ImageJ and 3DSlicer), machine-learning-driven pixel classification (ilastik), and a modular custom Python script for robust and versatile analysis. Using graph-based representations derived from manual annotations and binary mitochondrial images, MitoLandscape efficiently extracts detailed morphological parameters from distinct subcellular compartments, applicable from cells with simple morphologies to complex neuronal architectures. Additionally, the pipeline quantifies mitochondrial distribution relative to specific cellular landmarks, such as nucleus or soma. We validated MitoLandscape in vitro and in neural tissue, demonstrating its capability to precisely and reliably map mitochondrial features in diverse biological contexts. MitoLandscape represents a powerful, user-friendly, and highly adaptable solution for investigating mitochondrial biology in cell and developmental research.

Keywords:  computational biology; machine learning; morphology; neurodevelopment; organelle; super-resolution

DOI:  https://doi.org/10.3389/fcell.2025.1668779
Pediatr Res. 2025 Nov 22.

Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.

Anahid A Assadourian, Julian A Martinez-Agosto.

Neurodevelopmental disorders (NDDs) include a broad spectrum of phenotypes spanning from intellectual disability (ID) to developmental delay (DD) and autism spectrum disorder (ASD). As neurodevelopmental phenotypes are a common presenting feature of an underlying genetic condition, professional medical organizations recommend genetic testing for all individuals with a NDD. When testing is pursued, identified genetic differences can lead to personalized clinical management with early diagnosis supporting the development of surveillance and intervention for co-occurring adverse health outcomes. Despite this, barriers to testing have prevented individuals from receiving a genetics referral and testing. Current therapeutic modalities including small molecule drugs, gene therapies, and antisense oligonucleotide therapies have emerged and shown promise in preclinical trials with therapeutic drugs gaining FDA approval. However, translational challenges are extensive, especially for identifying biomarkers of drug effects in the CNS. In this review, we discuss diagnostic approaches and clinical utility of genetic testing for rare genetic neurodevelopmental disorders, emerging development of individualized therapies, and progress for current therapeutics in addition to challenges with clinical translation and delivery. We will highlight opportunities for early diagnosis and treatment that are steadily gaining ground in favor of optimizing long-term health outcomes and improving quality of life for neurodiverse individuals. IMPACT: The path from genomics to therapeutics for neurodevelopmental disorders continues to present multiple opportunities and challenges. While emerging genome-wide sequencing and gene editing technologies deliver increased diagnostic yields and alternatives to life-long small molecule therapies, clinical translation has been challenging due to inherent cost and genetic heterogeneity. Limited access to genetic testing despite practice guidelines remains a barrier towards precision therapeutics for rare neurodevelopmental disorders, while pre-clinical investigations face obstacles when translating to human subjects. This review will summarize the impact of existing successes in diagnosis and therapeutics for neurodevelopmental disorders while highlighting ongoing challenges and areas of future opportunities.

DOI: https://doi.org/10.1038/s41390-025-04611-y
Stem Cell Res Ther. 2025 Nov 28. 16(1): 666

Mesenchymal stem cell therapy for end-stage liver disease: adversity and opportunity.

Shiqi Li, Yichen Wang, Su-Meng Li, Yaxin Zhu, Yan-Qin Du, Xin Zheng, Jun Wu.

  End-stage liver disease (ESLD) is one of the predominant diseases contributing to high morbidity and mortality worldwide, with etiologies including alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease, and metabolic-associated liver disease. Currently, liver transplantation remains the only effective treatment, however, its clinical application is significantly limited by donor shortages, immune rejection, and high medical costs. Among the five types of stem cells that have been experimentally applied to liver diseases, mesenchymal stem cells (MSCs) have emerged as the most extensively studied, with the largest number of experimental and clinical research platforms worldwide. This review compiles findings from 25 preclinical and clinical studies on MSCs in the treatment of ESLD, aiming to elucidate the core mechanisms of action and then outline both the challenges in MSC clinical translation and the novel opportunities arising from cutting-edge research.

Keywords:  Clinical translation; End-stage liver disease (ESLD); Mechanisms of action; Mesenchymal stem cells (MSCs); Preclinical and clinical studies; Stem cell therapy

DOI:  https://doi.org/10.1186/s13287-025-04788-3