bims-polgdi 2025-10-19 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–10–19
thirty papers selected by
Luca Bolliger, lxBio

From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation.
Nanoengineered mitochondria for mitochondrial dysfunction and anti-aging interventions.
Ethical challenges in extending mitochondrial replacement therapy (MRT) for overcoming poor egg quality in older women without mitochondrial diseases.
POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
Breathing new life into male fertility: the potential of mitochondrial transplantation.
Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
Pearls and Oy-sters: Chronic Progressive External Ophthalmoplegia With Electrical Myotonia and Negative Initial Genetic Testing.
OPTIMIZATION OF ILLUMINA® NEXTERA™ XT LIBRARY PREPARATION FOR THE MITOCHONDRIAL GENOME SEQUENCING AND CONFIRMATORY SANGER SEQUENCING.
Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives.
Cerium-based nanoparticles for neurodegeneration: emerging redox therapeutics beyond pharmaceuticals.
Exosomes in epilepsy: bridging neuroinflammation, diagnosis, and therapeutic delivery.
Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer.
Genetic convergence in brain aging and neurodegeneration: from cellular mechanisms to therapeutic targets.
Extracellular vesicles for the delivery of gene therapy.
Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.
Interfacing extracellular vesicles with bioengineered materials for regenerative medicine.
Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex.
Application of Induced Pluripotent Stem Cells (iPSCs) in Hereditary and Viral Diseases of the Liver: Modeling and Treatment.
Crosstalk Between Allergic Inflammation and Autophagy.
Out of Sync? Rare Genetic Disease and the Chronopolitics of Care.
The mitochondrial side of frailty.
Targeting Genome Stability to Mitigate Human Aging and Disease.
Gene and RNA Editing: Revolutionary Approaches to Treating Diseases.
Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.
Beyond energy: Mitochondrial control of platelet lifecycle through redox, calcium, and dynamics.
POLR3A mutations cause nucleolus abnormalities and aberrant telomerase RNA metabolism in induced pluripotent stem cells from Wiedemann-Rautenstrauch premature aging syndrome patient.

Mol Cell Biol. 2025 Oct 17. 1-27

From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.

Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.

  Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.

Keywords:  Mitochondria; mitochondrial disease; protein import; protein quality control

DOI:  https://doi.org/10.1080/10985549.2025.2566671
Front Immunol. 2025 ;16 1640748

Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation.

Yangyang Zhao, Chunlei Wu, Xiaoxue Liang, Mengjiao Yang.

  Circulating cf-mtDNA has emerged as a dual-functional entity in human pathophysiology, serving not only as a disease biomarker but also as a potent innate immune activator through its molecular pattern recognition. Extracellular mtDNA engages PRRs, triggering dysregulated pro-inflammatory signaling in multiple cell lineages. Elevated mtDNA in circulation correlates with pathogenesis of autoimmune disorders, infectious diseases, critical illnesses, neurological disorders, and hematological abnormalities. Therapeutic strategies combining mtDNA monitoring with inhibitors targeting its release mechanisms and downstream pathways offer novel immunomodulatory strategies. This review systematically examines the therapeutic nexus of blood-derived mtDNA in immune activation and disease progression. Here we aim to elucidate the function of mtDNA in disease pathobiology while highlighting mitochondria's central position in human systemic homeostasis.

Keywords:  blood circulation; cell-free DNA; extracellular vesicles; immunity; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.3389/fimmu.2025.1640748
Front Aging. 2025 ;6 1688482

Nanoengineered mitochondria for mitochondrial dysfunction and anti-aging interventions.

Siqi Deng, Yingying Ren, Qian Zhang, Qinling Liu, Jiaxin Long, Kelsey Picard, Miguel Martin, Thomas Miller, Chaofan Yuan, Yunxiang He, Junling Guo.

  Aging is a multifactorial process and a major risk factor for chronic disease. Among its hallmarks, mitochondrial dysfunction plays a central role, driven by impaired respiration and accumulated mitochondrial DNA mutations that disrupt energy metabolism and redox balance. Conventional mitochondrial transplantation has been explored as a therapeutic strategy, but its emphasis on increasing mitochondrial quantity without restoring function has limited success. Recent advances in nanoengineered mitochondria that integrate isolated mitochondria with functional nanomaterials, offer new opportunities to enhance organelle quality, boost metabolic activity, and achieve targeted delivery. Preclinical studies highlight their promise in cardiovascular, neurodegenerative, and other age-related disorders. In this mini-review, mitochondrial dysfunction in aging is first introduced, followed by the summary of rational designed strategies for engineering mitochondrial biohybrids and their emerging applications, and finally translational challenges are further discussed. By bridging materials science and mitochondrial therapy, nanoengineered mitochondria may represent a next-generation approach to anti-aging interventions.

Keywords:  age-related diseases; anti-aging; mitochondrial function restoration; nanoengineered mitochondrial biohybrids; surface functionalization

DOI:  https://doi.org/10.3389/fragi.2025.1688482
J Assist Reprod Genet. 2025 Oct 18.

Ethical challenges in extending mitochondrial replacement therapy (MRT) for overcoming poor egg quality in older women without mitochondrial diseases.

Alexis Heng Boon Chin, Adrian Villalba, Ido Alon, Ningyu Sun, Jiao Yang.

  Recently, eight healthy human offspring were born through mitochondrial replacement therapy (MRT) with pronuclear transfer (PNT), aimed at preventing the transmission of pathological mitochondrial DNA (mtDNA) mutations. These encouraging preliminary results on the safety of MRT, accompanied by some early neonatal findings and ongoing follow-ups, open up the possibility for its broader application in addressing age-related female infertility by enhancing oocyte quality in older women, commonly referred to as ooplasmic donation or ooplasmic transfer. Because female fertility declines sharply with age, and not all women choose to undergo elective egg freezing (oocyte cryopreservation), there will always be a substantial number of older female IVF patients who are unable to conceive with their own oocytes. For such patients, enabling them to conceive genetically related offspring via MRT would be a far more preferable alternative to conventional egg donation, which disrupts the continuity of maternal genetic lineage. However, extending the use of MRT from the prevention of mitochondrial diseases to the treatment of age-related infertility raises numerous ethical issues. A significant challenge lies in balancing the aspirations of infertile older women to have genetically related offspring with the medical risks and ethical concerns associated with the MRT procedure. To navigate these ethical challenges, some policy recommendations are proposed, including (i) MRT should be conducted in clinical trials until its long-term safety is validated, (ii) rigorous patient counseling to ensure informed consent, (iii) stringent regulations to govern egg donation for MRT, and (iv) implementation of an internationally recognized ethical and regulatory framework for MRT.

Keywords:  Advanced reproductive age; Female infertility; Genome; Mitochondrial donation; Mitochondrial replacement techniques; Ooplasm

DOI:  https://doi.org/10.1007/s10815-025-03713-0
Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):

POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.

Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.

POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.

DOI: https://doi.org/10.26508/lsa.202302563
Mol Biol Rep. 2025 Oct 17. 52(1): 1043

Breathing new life into male fertility: the potential of mitochondrial transplantation.

Bunty Sharma, Akshat Ashutosh Jha, Shafiul Haque, Hardeep Singh Tuli, Kawaljit Singh Kaura, Ujjawal Sharma.

  Male infertility affects about 7% of men worldwide. Along with this disease also comes stigma and taboo that overshadow its emotional and psychological impacts. Despite its widespread prevalence, many cases of male infertility remain idiopathic. This review illustrates the use of mitochondrial transfer in addressing male fertility issues, particularly in situations where sperm movement is hindered and there are problems with mitochondrial function. Various factors can trigger male infertility, such as problems with sperm quality or quantity, genetic disorders, hormonal imbalances, testicular injuries, infections, or lifestyle habits. Stress, anxiety, and depression are parameters that can make matters worse by disrupting hormone levels and sperm production. Currently, there's no reliable treatment for mitochondrial dysfunction, which plays a role in oxidative stress and lower ATP production. Mitochondrial transfer works by injecting healthy mitochondria into deficient cells; this, in turn, improves ATP production and reduces oxidative stress. This leads to improvements in sperm motility and viability. The technique has already been used and found effective in improving embryo quality in human oocytes, which shows its potential application in male infertility treatments. Therefore, in the present review, we discussed the mechanisms used for mitochondrial transfer, intercellular communication pathways, purification, and delivery techniques that can enhance therapeutic outcomes. By consolidating recent advances in this domain, we aim to present a comprehensive overview of mitochondrial transfer as an innovative intervention in the management of male infertility. The ultimate goal is to transform male infertility from a challenging condition into a manageable one. This will offer new hope to affected individuals and couples through advanced reproductive technologies and targeted therapeutic interventions.

Keywords:  Infertility; Male fertility; Mitochondrial transplantation; Sperm motility; Therapeutic application

DOI:  https://doi.org/10.1007/s11033-025-11158-y
Adv Ophthalmol Pract Res. 2025 Nov-Dec;5(4):5(4): 278-284

Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.

Shanshan Cao, Yong Liu, Mingming Sun, Yuan Zhang, Yonghua Sun, Quangang Xu, Shihui Wei, Huanfen Zhou.

   Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder primarily caused by mutations in MT-ND1, MT-ND4, and MT-ND6, leading to retinal ganglion cell degeneration and severe vision loss. While 90%-95% of cases involve three common mutations (m.11778G > A, m.3460G > A, m.14484T > C), the genetic and clinical profiles of rare mutations remain poorly characterized, contributing to diagnostic challenges.
Methods: This cohort study analyzed 26 genetically confirmed LHON patients harboring rare mitochondrial DNA (mtDNA) mutations. Patients underwent best-corrected visual acuity (BCVA), optical coherence tomography (OCT) measurements (peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer [GCL] thickness), and neuroimaging findings. Prognostic outcomes were compared between pediatric (≤16 years) and adult (>16 years) subgroups.
Results: The cohort (male:female = 4.2:1) exhibited a median onset age of 17 years (range:4-42), with 30.77% unilateral involvement. Rare mutations were distributed in MT-ND4(34.62%,m.11696G > A), MT-ND1(34.62%,including m.3733G > A/m.3866T > C), and MT-ND6 (23.08%, m.14502T>C), with 26.92% harboring dual mutations. Younger patients showed significantly better visual recovery (59.09% vs. 22.73% achieving BCVA ≥ 0.3, P = 0.014), despite comparable baseline vision and structural OCT parameters (pRNFL/GCL thickness, all P > 0.05). T2 hyperintensity in the optic nerve magnetic resonance imaging (MRI) was present in 38.46% of cases.
Conclusions: Our study probes into the clinical and genetic diversity of LHON with rare mtDNA mutations, revealing varied clinical presentations, such as more frequent unilateral involvement and enhanced optic nerve T2 MRI signals. Visual recovery was significantly better in the younger cohort. These results suggest the need for broader genetic testing in atypical LHON cases and offer insights into better prognostic strategies for new therapies.

Keywords:  Leber's hereditary optic neuropathy; Maternal inheritance; Mitochondrial DNA; Rare mutation

DOI:  https://doi.org/10.1016/j.aopr.2025.08.001
Neurology. 2025 Nov 11. 105(9): e214313

Pearls and Oy-sters: Chronic Progressive External Ophthalmoplegia With Electrical Myotonia and Negative Initial Genetic Testing.

Brian Y Li, Julia H Greenberg, Connolly Steigerwald, Renkui Bai, Kurenai Tanji, Elina Zakin, Nicolas J Abreu.

Chronic progressive external ophthalmoplegia (CPEO), a genetic syndrome characterized by slowly progressive paresis of extraocular muscles, is often due to single large-scale deletions of the mitochondrial genome (mtDNA). Owing to heteroplasmy, mtDNA variants are often not uniformly expressed across tissues. This genetic variability affects clinical presentation and diagnostic testing. We report a case of a 34-year-old woman who presented with symptoms suspicious for a genetic myopathy: chronic asymmetric ptosis, slowly progressive asymmetric weakness, and external ophthalmoplegia. After initial nondiagnostic peripheral genetic testing, whole-exome and mitochondrial genome sequencing of muscle revealed a single large-scale mtDNA deletion, consistent with a diagnosis of mtDNA deletion-associated CPEO. Of interest, electrophysiologic studies showed myotonia in select muscles, a rarely reported finding. We discuss the clinical presentation and diagnostic approach in suspected CPEO, with an emphasis on common pitfalls in genetic testing for mitochondrial myopathies and the need for appropriate tissue and genetic testing modality selection.

DOI: https://doi.org/10.1212/WNL.0000000000214313
Med Glas (Zenica). 2025 Aug 25. 22(2): 191-194

OPTIMIZATION OF ILLUMINA® NEXTERA™ XT LIBRARY PREPARATION FOR THE MITOCHONDRIAL GENOME SEQUENCING AND CONFIRMATORY SANGER SEQUENCING.

Nejira Handžić, Dino Pećar, Selma Durgut, Naida Mulahuseinović, Ivana Čeko, Adna Ašić, Mirza Izmirlija, Sabina Šegalo, Lana Salihefendić, Rijad Konjhodžić.

   AIM: Due to increasing use of mitochondrial DNA (mtDNA) sequencing in both forensic practice and clinical disease research, this study explores the optimization of the next-generation sequencing (NGS) method for whole mitochondrial genome analysis on the Illumina MiSeq platform.
METHODS: Initial attempts using pre-made commercial primers were unsuccessful, leading to the design of novel custom-designed primers in our laboratory and optimization of sequencing chemistry and protocols. A comprehensive protocol was developed, involving long-range amplification, enzymatic fragmentation, and the use of IDT® for Illumina DNA/RNA UD Indexes and MiSeq Reagent Nano Kit v2 (300 cycles), whereby DNA extraction, quantification, and library preparation were all performed according to optimized protocols.
RESULTS: Successful amplification was confirmed using gel electrophoresis and Agilent Bioanalyzer, with optimized conditions yielding clear, specific amplicons 9.8 and 8.5 kb in length. Sequencing results demonstrated high-quality reads with an average coverage depth of 742x and a GC content of 43-45%. The study highlights the efficiency of custom primers and individual library normalization for reliable mtDNA sequencing.
CONCLUSION: These findings advance the application of NGS in forensic and clinical settings by enhancing the detection of rare mutations and mitochondrial heteroplasmy, paving the way for routine mtDNA analysis using NGS technology.

Keywords:  mitochondrial genome; mutations; next-generation sequencing

DOI:  https://doi.org/10.17392/1950-22-02
Mol Genet Metab. 2025 Oct 08. pii: S1096-7192(25)00252-5. [Epub ahead of print]146(3): 109260

Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).

Xueyang Pan, Yue Wang, Ning Liu, Xi Luo, V Reid Sutton, William J Craigen, Qin Sun.

  Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging. To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions. These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.

Keywords:  Chronic progressive external ophthalmoplegia (CPEO); ETC complex enzymatic assay; Heteroplasmy; Kearns-Sayre syndrome (KSS); Mitochondrial electron transport chain (ETC); Single large-scale mtDNA deletion syndrome (SLSMDS); mtDNA deletion; mtDNA next-generation sequencing (NGS)

DOI:  https://doi.org/10.1016/j.ymgme.2025.109260
J Neuroinflammation. 2025 Oct 15. 22(1): 235

cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives.

Huayu Li, Ruixin Cai, Yu Zhou, Yichen Jiang, Sijie Tan.

  Aging is a major risk factor for neurodegenerative diseases, yet the underlying mechanisms linking aging to neurodegeneration remain incompletely understood. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in sensing mislocalized cytoplasmic DNA, triggering innate immune responses such as type I interferon (IFN-I) and NF-κB signaling, and promoting senescence-associated secretory phenotypes (SASP). In the aging central nervous system (CNS), cellular senescence is accompanied by mitochondrial DNA (mtDNA) leakage, nuclear DNA damage, and other changes that may aberrantly activate the cGAS-STING pathway. This activation drives neuroinflammation, potentially increasing susceptibility to neurodegenerative diseases or exacerbating pre-existing pathology. Conversely, neurodegenerative disease-related processes-such as pathological protein aggregation-can further stimulate cGAS-STING signaling, amplifying inflammatory cascades and accelerating cellular senescence. This review explores the molecular mechanisms linking cGAS-STING activation to neurodegeneration and discusses potential therapeutic strategies targeting this pathway.

Keywords:  Aging; Microglia; Neurodegenerative diseases; Neuroinflammation; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12974-025-03563-8
RSC Adv. 2025 Oct 08. 15(45): 37540-37569

Cerium-based nanoparticles for neurodegeneration: emerging redox therapeutics beyond pharmaceuticals.

Keerti Mishra, Shourya Tripathi, Amrendra K Tiwari, Rafquat Rana, Pooja Yadav, Manish K Chourasia.

Delivering therapeutic agents across the blood-brain barrier (BBB) remains a formidable hurdle in the treatment of neurodegenerative diseases, which are primarily driven by mitochondrial dysfunction, oxidative stress, and neuroinflammation. Although our understanding of these disease mechanisms has advanced, effective treatments are still limited due to the restrictive nature of the BBB. In this context, nanotechnology has emerged as a promising approach, offering engineered nanocarriers capable of traversing the BBB and enabling targeted drug delivery to the brain. Amongst the various nanomaterials explored, cerium-based nanoparticles have gained particular attention as promising candidates for neurodegenerative disease therapy. Their multifunctionality stemming from reversible redox behaviour, enzyme-mimicking activity, sustained antioxidant effects, and anti-inflammatory properties, combined with their ability to penetrate the BBB and provide neuroprotection, positions them as a powerful platform for future therapeutic strategies. This review begins with a concise overview of the shared pathological mechanisms underlying neurodegenerative diseases, highlights BBB-related drug delivery challenges, and discusses nanocarrier strategies for brain targeting, focusing on cerium-based nanoparticles. We then delved into the structural features, synthesis techniques, and distinctive redox properties of cerium-based nanomaterials, with emphasis on cerium oxide and cerium vanadate. Their therapeutic potential is explored across Alzheimer's and Parkinson's diseases, as well as in stroke, multiple sclerosis, and glioblastoma. Key insights into their physicochemical properties, BBB permeability, and neuroprotective mechanisms are provided. We also address current limitations, including nanoparticle stability, toxicity, and translational barriers, and conclude with future directions for optimizing cerium-based nanozymes in neurotherapeutics.

DOI: https://doi.org/10.1039/d5ra03599f
Front Immunol. 2025 ;16 1667122

Exosomes in epilepsy: bridging neuroinflammation, diagnosis, and therapeutic delivery.

Bin Li, Yanping Zhu, Lixia Chen, Jiajia Cui, Zhenchang Zhang.

  Epilepsy, as a chronic neurological disorder marked by recurrent seizures, is closely linked to neuroinflammation and immune dysregulation. Exosomes, extracellular vesicles with potent immunomodulatory properties, have emerged as key players in mitigating epilepsy-associated inflammation by targeting glial activation and balancing pro- and anti-inflammatory cytokine release. Their ability to cross the blood-brain barrier (BBB) enables targeted delivery of anti-inflammatory cargo, such as miRNAs and proteins, offering promise for diagnosing and treating drug-resistant epilepsy. This review highlights exosomes' dual role as biomarkers of inflammatory pathways and therapeutic vehicles for immune modulation. By suppressing neuroinflammation and restoring neuronal homeostasis, exosome-based strategies may revolutionize epilepsy management, though clinical translation requires further optimization of isolation and engineering techniques.

Keywords:  blood-brain barrier; drug delivery; drug-resistance; epilepsy; exosomes; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2025.1667122
Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070

Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.

Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.

  Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.

Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA

DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
Nature. 2025 Oct;646(8085): 530-532

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

Gemma Conroy.



Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Diseases; Gene therapy; Genomics

DOI:  https://doi.org/10.1038/d41586-025-03307-x
Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00214-8. [Epub ahead of print] 189472

Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer.

Tianguang Cheng, Min Pan, Yi Qiao, Jing Tu.

  Mitochondrial DNA (mtDNA) is crucial for cellular metabolism, oxidative stress responses, and genomic stability, with mutations linked to cancer progression and therapeutic resistance. Mitochondrial heteroplasmy, the coexistence of wild-type and mutant mtDNA within a cell or across populations, plays a key role in mitochondrial dysfunction, tumor heterogeneity, and disease pathogenesis. Advances in single-cell technologies like quantitative PCR (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and long-read sequencing (TGS) have enabled precise mapping of heteroplasmic variants, providing insights into their role in cancer. This review evaluates current detection methods, discussing their strengths, limitations, and relevance to cancer research. We also explore the biological implications of heteroplasmy in cellular dynamics, nuclear mitochondrial DNA segments (NUMTs), and cancer pathogenesis, highlighting emerging technologies and future directions for studying mtDNA mutations at single-cell resolution in cancer. Ultimately, this review provides a critical synthesis of how single-cell mtDNA heteroplasmy analysis is reshaping our understanding of tumorigenesis and identifies key methodological and challenges that must be addressed to realize its full potential in precision oncology.

Keywords:  Cancer metabolism; Heteroplasmy; Mitochondrial DNA; Sequencing; Single cell

DOI:  https://doi.org/10.1016/j.bbcan.2025.189472
J Neurogenet. 2025 Oct 16. 1-20

Genetic convergence in brain aging and neurodegeneration: from cellular mechanisms to therapeutic targets.

Picheswara Rao Polu, Shubham Mishra.

  The distinction between normal brain aging and neurodegeneration has traditionally been viewed as a binary classification, yet emerging evidence reveals a complex continuum of shared genetic mechanisms underlying both processes. This review synthesises current understanding of conserved molecular pathways that contribute to age-related neural decline across the spectrum from healthy aging to pathological neurodegeneration. We examine how fundamental cellular processes including protein quality control, mitochondrial dysfunction, inflammation, and synaptic maintenance are genetically regulated and become progressively dysregulated during aging. Key genetic pathways, such as insulin/IGF signalling, autophagy-lysosomal networks, and stress response mechanisms demonstrate remarkable conservation from model organisms to humans, suggesting evolutionary constraints on neural aging processes. The review highlights how genetic variants in these pathways can determine individual trajectories along the aging-neurodegeneration continuum, influencing susceptibility to diseases like Alzheimer's, Parkinson's, and ALS. We discuss evidence from comparative studies in C. elegans, Drosophila, rodents, and human populations that illuminate shared vulnerability genes and protective factors. Understanding these convergent mechanisms offers unprecedented opportunities for therapeutic intervention, as strategies targeting fundamental aging processes may simultaneously address multiple neurodegenerative conditions. This integrated perspective challenges traditional disease-centric approaches and supports the development of unified therapeutic strategies for promoting healthy brain aging while preventing neurodegeneration.

Keywords:  Neurodegeneration; brain aging; genetic pathways; mitochondrial dysfunction

DOI:  https://doi.org/10.1080/01677063.2025.2571127
Nat Rev Bioeng. 2025 May;3(5): 360-373

Extracellular vesicles for the delivery of gene therapy.

Emilio Di Ianni, Wataru Obuchi, Koen Breyne, Xandra O Breakefield.

Gene therapy has brought hope for the treatment of previously incurable diseases, such as genetic disorders, cancers and autoimmune diseases. However, gene therapy requires efficient delivery with cell and tissue specificity, which remains challenging owing to the limited targeting and cargo-loading capacity of viral delivery vehicles, as well as immunogenicity and toxicity concerns. Extracellular vesicles can be designed as non-viral carriers for gene therapy owing to their ability to deliver multiple cargo types, including transgenes, small encoding or non-coding RNA, DNA and functional proteins. Importantly, extracellular vesicles are immunologically neutral and can cross biological barriers. In this Review, we discuss the application of extracellular vesicles in gene therapy. We outline how the inherent content of extracellular vesicles can facilitate different gene-therapy approaches and examine the design of extracellular vesicles for the loading of gene-therapy tools, targeted delivery and cargo release. Finally, we survey clinical applications of extracellular vesicles and highlight important engineering and translational challenges.

DOI: https://doi.org/10.1038/s44222-025-00277-7
Nucleic Acids Res. 2025 Oct 14. pii: gkaf1000. [Epub ahead of print]53(19):

Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.

Genevieve Trombly, Afaf Milad Said, Alexei P Kudin, Kerstin Hallmann, Anano Kakabadze, Viktoriya Peeva, Kerstin Becker, Karl Köhrer, Gábor Zsurka, Wolfram S Kunz.

The mitochondrial isoform of LIG3 is proposed to catalyze both circularization of newly replicated mitochondrial DNA (mtDNA) and rejoining of free mtDNA strands in base excision and single-strand break repair. Inactivation of LIG3 has been reported to cause embryonic lethality in mice due to loss of mtDNA. Here, we applied genome editing to inactivate LIG3 in HEK 293 cells and observed only a moderate decrease of mtDNA copy numbers. BrdU incorporation experiments confirmed ongoing synthesis of intact supercoiled mtDNA. Using ultra-deep long-read sequencing of isolated mtDNA, we detected increased frequencies of single-strand and double-strand breaks clustering at sites with high GC-content, as well as hallmarks of accelerated degradation of linear mtDNA. This is likely due to the missing repair of intrinsic oxidative single-strand breaks, since the frequency of detected single-strand breaks was dependent on oxygen tension and on expression levels of enzymes involved in ROS (reactive oxygen species) defense. Exogenous oxidative challenge, that resulted in transient mtDNA damage in wild-type cells, caused dramatic mtDNA loss in LIG3-/- cell lines. Thus, our data provide evidence for the pivotal role of LIG3 in preventing mtDNA loss after oxidative damage and corroborate the hypothesis that oxidative strand break-induced mtDNA degradation is highly relevant for mtDNA turnover in vivo.

DOI: https://doi.org/10.1093/nar/gkaf1000
Acta Biomater. 2025 Oct 14. pii: S1742-7061(25)00766-4. [Epub ahead of print]

Interfacing extracellular vesicles with bioengineered materials for regenerative medicine.

Kristiyan Stiliyanov-Atanasov, Sara Bagur-Cardona, Silvia Chiera, Héctor Capella-Monsonís, Manuel Gomez-Florit.

  Extracellular vesicles (EVs) are promising tools for cell-free regenerative medicine due to their ability to modulate biological processes. However, rapid clearance and poor targeting limit their efficacy and clinical translation. Recent bioengineering advances have enabled EVs integration with biomaterials to enhance their stability, bioavailability, and controlled release, maximizing their therapeutic potential. This review analyzes the strategies used to interface EVs with biomaterials, including hydrogels, scaffolds, and implantable materials, and discusses their application in tissue engineering and regenerative medicine field. The advantages and limitations of different EVs sources, from tissue-resident cells to stem cells, and EVs immobilization techniques, from physical entrapment to covalent binding, are examined. Challenges in clinical translation are addressed, while proposing potential solutions to accelerate the development of EV-biomaterial hybrids for therapeutic use. The integration of EVs with bioengineered materials represents a paradigm shift, offering innovative solutions for enhancing the innate ability of EVs to promote tissue repair and functional recovery. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) have emerged as powerful tools for regenerative medicine, yet challenges such as rapid clearance and limited targeting hinder their clinical application. This review explores the integration of EVs with bioengineered materials to enhance their stability, control their release, and maximize therapeutic potential. We provide a comprehensive analysis of state-of-the-art strategies to bridge biomaterials science and EV therapeutics, highlighting their advantages and translational challenges. Furthermore, this review offers a roadmap of the challenges required to overcome for advancing EV-based therapies toward clinical translation.

Keywords:  Biomaterials; Extracellular Vesicles; Hydrogels; Polymers; Regenerative Medicine; Tissue Engineering

DOI:  https://doi.org/10.1016/j.actbio.2025.10.022
Int J Mol Sci. 2025 Sep 23. pii: 9270. [Epub ahead of print]26(19):

Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex.

Ruxana T Sadikot, Prabagaran Narayanasamy, Zhihong Yuan, Deandra Smith, Daren L Knoell.

  Mitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn supplementation in PGC-1α-mediated macrophage mitochondrial biogenesis and immune function following infection with Mycobacterium avium complex (MAC). Our novel findings show that Zn is an important regulator of PGC-1α, TFAM and mitochondrial biogenesis, leading to enhanced bacterial phagocytosis and bacterial killing in macrophages. Mechanistically, we show that the Zn importer ZIP8 (Zrt/Irt-like protein) orchestrates Zn-mediated effects on PGC-1α and mitochondrial function. Taken together, defective Zn biodistribution may increase susceptibility to infection, whereas Zn supplementation may provide a tractable host-directed therapy to enhance the innate immune response in patients vulnerable to MAC infection.

Keywords:  Mycobacterium avium; biogenesis; macrophages; mitochondria dysfunction; zinc

DOI:  https://doi.org/10.3390/ijms26199270
Int J Mol Sci. 2025 Sep 26. pii: 9432. [Epub ahead of print]26(19):

Application of Induced Pluripotent Stem Cells (iPSCs) in Hereditary and Viral Diseases of the Liver: Modeling and Treatment.

Vladimir Andriianov, Alina Malyutina, Egor Panferov, Alexander Karabelsky, Roman Ivanov, Ekaterina Minskaia, Vasiliy Reshetnikov.

  The high prevalence and diversity of liver diseases present a significant problem for modern healthcare. Despite FDA approval of gene therapy drugs to treat hemophilia A and B, available treatment methods for other hereditary liver diseases are mainly limited to the frequently ineffective traditional therapies and surgical intervention. In recent years, significant progress has been made in the treatment of hepatitis C, but hepatitis B is still considered an incurable disease. In this regard, the treatment of hereditary and viral liver diseases using gene or cell therapy remains relevant. This review is focused on the current state of the induced pluripotent stem cells (iPSCs) field in the context of modeling and treatment of hereditary, viral, and some other liver diseases, both ex vivo and in vivo. Here we present a detailed discussion of the possible ways of modeling liver diseases ex vivo using iPSCs (reprogramming of patient somatic cells and genetic engineering (GE) of healthy iPSCs), summarize gene editing (GE) and non-GE approaches for the treatment of liver diseases, and demonstrate that iPSCs and their derivatives are widely used to treat liver diseases in vivo. Taken together, we are presenting a comprehensive analysis of 2D and 3D iPSC-based products in the context of liver diseases, discussing the advantages and disadvantages of this platform, including the comparison with other types of stem cells and animal models. This analysis may help understand not only the potential but also the limitations associated with the use of iPSCs in the context of various types of liver diseases.

Keywords:  disease modeling; iPSCs; induced pluripotent stem cells; liver disease; liver disease modeling; liver disease treatment

DOI:  https://doi.org/10.3390/ijms26199432
Int J Mol Sci. 2025 Oct 07. pii: 9765. [Epub ahead of print]26(19):

Crosstalk Between Allergic Inflammation and Autophagy.

Jaewhoon Jeoung, Wonho Kim, Dooil Jeoung.

  Autophagy is a conserved process that involves the degradation of damaged proteins and organelles to restore cellular homeostasis. Autophagy plays a critical role in cell differentiation, immune responses, and protection against pathogens, as well as the development and progression of allergic inflammation. Crosstalk between autophagy and signaling pathways modulates immune responses to inflammatory signals. Here, we discuss the regulatory roles of autophagy in allergic inflammation. Autophagy can promote allergic inflammation by enhancing the secretion of inflammatory mediators. Impaired autophagy resulting from the accumulation of autophagosomes can exacerbate allergic inflammation. Mast cell degranulation and activation require energy provided by mitochondrial respiration. Mast cell activation is accompanied by morphological changes and mitochondrial fragmentation. Mitochondrial fragmentation (mitophagy) induced by oxidative stress involves the degradation of defective mitochondria. Therefore, we discuss the relationship between mitophagy and allergic inflammation. Targeting autophagy and oxidative stress can be a strategy for developing anti-allergy therapeutics. In this review, we also discuss future research directions to better understand allergic diseases with respect to autophagy and develop effective anti-allergy drugs.

Keywords:  allergy; autophagy; crosstalk; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/ijms26199765
Sociol Health Illn. 2025 Nov;47(8): e70106

Out of Sync? Rare Genetic Disease and the Chronopolitics of Care.

Catherine Coveney.

  Drawing on the experiences of parents of children diagnosed with Noonan Syndrome, I examine how living in and between multiple temporalities of care impacts parents' sense of temporal autonomy and social inclusion. Employing the concept of 'crip time', I connect everyday choreographies of care with their temporal politics to analyse the chronopolitics of care in the context of rare genetic disease, crafting theoretical synergies between the sociology of health and illness, critical disabilities studies and the sociology of temporality. I argue that care time is crip time, requiring parents to juggle competing temporal rhythms that deviate from the chrononormative time order. Parents describe good care as making time and giving time to be with their child to meet their embodied care needs. Meanwhile, the inflexible and unpredictable nature of medical time can be experienced as oppressive and disruptive to the family's care rhythms. Temporal conflicts can create a sense of disconnection, leaving family's feeling out of sync, socially and emotionally. I suggest the need for a new focus on the chronopolitics of care within formal and informal care relations, to support parent carers to regain their temporal autonomy and a regain a shared sense of time and community.

Keywords:  care; caregiving; chronopolitics; crip time; disability; lived experience; noonan syndrome; rare genetic disease; temporalities

DOI:  https://doi.org/10.1111/1467-9566.70106
Curr Opin Clin Nutr Metab Care. 2025 Oct 06.

The mitochondrial side of frailty.

Emanuele Marzetti, Rosa Di Lorenzo, Anna Picca.

   PURPOSE OF REVIEW: Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential.
RECENT FINDINGS: Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression.
SUMMARY: Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations.

Keywords:  inflammaging; metabolic dysregulation; mitochondrial quality control; oxidative capacity; physical frailty

DOI:  https://doi.org/10.1097/MCO.0000000000001175
Annu Rev Pathol. 2025 Oct 14.

Targeting Genome Stability to Mitigate Human Aging and Disease.

Debra Toiber, Björn Schumacher.

The maintenance of a stable genome requires constant repair. Congenital DNA repair defects lead to cancer susceptibility and progeroid (premature aging-like) syndromes. Even with intact repair, DNA lesions accumulate in aging organisms, leading to replication and transcription stress and age-dependent somatic mutations. These, in turn, can compromise cellular function and elevate cancer risk. DNA damage response (DDR) mechanisms can lead to cellular death and senescence, and targeting the DDR has emerged as therapeutic strategy not only in cancer but also to protect from age-associated phenotypes. Inhibiting DNA repair can promote cancer cell death. Eliminating senescent cells may alleviate proinflammatory consequences on their tissue environment. Moreover, strategies to limit DNA damage and augment repair in normal cells are in active development. Here, we review emerging concepts for targeting genome maintenance mechanisms to lower cancer risk and lengthen healthy lifespan by extending the integrity and functionality of somatic genomes.

DOI: https://doi.org/10.1146/annurev-pathmechdis-042624-105942
MedComm (2020). 2025 Oct;6(10): e70389

Gene and RNA Editing: Revolutionary Approaches to Treating Diseases.

Jia-Mei Li, Jie Huang, Yan Liao, Ting Hu, Chang-Li Wang, Wang-Zheqi Zhang, Chen-Wei Huang.

  Gene editing and RNA editing technologies are advancing modern medicine by enabling precise manipulation of genetic information at the DNA and RNA levels, respectively. The third-generation gene editing tools, particularly Clustered regularly interspaced shortpalindromic repeats (CRISPR)/CRISPR-associated (Cas) system, have transformed genetic disease treatment with high efficiency, precision, and cost effectiveness, while RNA editing, via adenosine deaminase acting on RNA (ADAR) enzymes and CRISPR-Cas13, offers reversible regulation to avoid genomic integration risks. Despite advancements, challenges persist in delivery efficiency, tissue specificity, and long-term safety, limiting their clinical translation. This review systematically discusses the molecular mechanisms and technological evolution of these tools, focusing on their promising applications in treating nervous system disorders (e.g., Alzheimer's, Parkinson's), immune diseases (e.g., severe combined immunodeficiency, lupus), and cancers. It compares their technical attributes, analyzes ethical and regulatory issues, and highlights synergies between the two technologies. By bridging basic research and clinical translation, this review provides critical insights for advancing precision medicine, reshaping disease diagnosis, prevention, and treatment paradigms.

Keywords:  CRISPR–Cas; RNA editing; gene editing; precision medicine

DOI:  https://doi.org/10.1002/mco2.70389
Biochem J. 2025 Oct 10. pii: BCJ20243016. [Epub ahead of print]

Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.

Yerranna Boggula, Arpan Chatterjee, Gaurav Simaiya, Amita Pal, Akash Srinivasan, Naresh Babu Sepuri.

  Mitochondrial protein homeostasis depends mainly on the efficient import and folding of nuclear-encoded proteins, and defects in this process can lead to proteotoxicity, which is harmful to the cell. Mitochondrial chaperones and proteases are essential defense mechanisms that ensure dysfunctional proteins' proper concentration, folding, and degradation. Lon protease 1 (Pim1 in yeast) is the mitochondrial matrix protease known to prevent protein aggregation by degrading unfolded proteins. Here, we show that two essential components of ATP-dependent presequence translocase and associated motor (PAM complex)- Pam18 and Pam16 are specifically targeted for degradation by the proteolytically active Lon/Pim1, both in vitro and in vivo. Further, overexpression of Pam18 and Pam16 exacerbates the growth defect of the delta pim1 strain. Hence, our study reveals, for the first time, that components involved in protein import are substrates of Pim1, which could have potential implications for regulating mitochondrial protein import and proteostasis.

Keywords:  Lon/Pim1 protease; Mitochondria; Protein turnover; Proteolysis; Proteostasis; Saccharomyces cerevisiae; mitochondrial protein import; presequence translocase-associated motor

DOI:  https://doi.org/10.1042/BCJ20243016
Redox Biol. 2025 Oct 11. pii: S2213-2317(25)00405-7. [Epub ahead of print]87 103892

Beyond energy: Mitochondrial control of platelet lifecycle through redox, calcium, and dynamics.

Xinle Wang, Rui Liao, Qihang Huang, Jingyan Li, Xiang Li, Xiaolin Gan, Yiwei Wang, Chunling Zhao, Qibing Mei, Jianping Chen, Anguo Wu, Xiaogang Zhou, Jianming Wu.

  Platelet disorders, caused by quantitative deficiencies or functional impairments, significantly contribute to cardiovascular, neurological, and iatrogenic pathologies. Although platelets are indispensable for hemostasis, thrombosis, and immune responses, the molecular mechanisms governing their biogenesis from megakaryocytes (MKs) and subsequent functional regulation remain incompletely understood. Mitochondria, inherited from MK progenitors, are now recognized as central regulators of platelet physiology and pathology. Emerging evidence demonstrates that mitochondrial processes critically regulate MK differentiation and thrombopoiesis, unveiling novel pathways in platelet formation. Mitochondria regulate metabolism, calcium (Ca2+) regulation, reactive oxygen species (ROS) signaling, autophagy, and dynamics, directly modulate essential platelet activities, such as activation dynamics, lifespan, and coagulation efficiency, in physiological and pathological contexts. This review synthesizes emerging evidence on the multi-layered mitochondrial control of thrombopoiesis and platelet functionality. We critically assess the translational potential of targeting mitochondria for treating platelet-related disorders, delineating specific molecular targets within MKs and platelets. Furthermore, we propose a framework for developing mitochondrial-based therapeutic strategies to prevent and manage platelet-associated diseases, thereby advancing clinical translation in this field.

Keywords:  Mitochondria; Mitochondrial-targeted therapy; Platelet function; Thrombopoiesis

DOI:  https://doi.org/10.1016/j.redox.2025.103892
Biogerontology. 2025 Oct 13. 26(6): 192

POLR3A mutations cause nucleolus abnormalities and aberrant telomerase RNA metabolism in induced pluripotent stem cells from Wiedemann-Rautenstrauch premature aging syndrome patient.

Evgeniya A Orlova, Vepa K Abdyev, Valeriya Morgunova, Anna A Schukina, Anastasiia L Kungurtseva, Peter A Vasiluev, Vyacheslav Y Tabakov, Ekaterina O Vorontsova, Elena V Zinina, Marina Izvolskaia, Marina E Minzhenkova, Alisa V Vitebskaya, Alla Kalmykova.

  Induced pluripotent stem cells (iPSCs) derived from patients with premature aging disorders are widely regarded as a foundation for both the study of fundamental aging mechanisms and preclinical testing of anti-aging therapies. The most well-studied is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a lamin A gene mutation. Comparing the progeroid phenotype in cell models of distinct premature aging syndromes is critical for identifying early and common aging hallmarks. In this study, using a non-integrative episomal approach we reprogrammed iPSCs from cells of a patient suffering from Wiedemann-Rautenstrauch Syndrome (WRS), which is caused by bi-allelic pathogenic mutations of the RNA polymerase III subunit A gene (POLR3A). In parallel, an iPSC line with the classic HGPS caused by a lamin A mutation was obtained. HGPS and WRS patient fibroblasts showed similar signs of cellular aging; however, unlike HGPS, the causal link between the premature aging phenotype and WRS driving mutations is unclear. RNA polymerase III is required for the transcription of small nuclear RNAs and being a target of TORC1 (Target of Rapamycin kinase Complex 1), it plays a role in longevity and aging in model organisms. Whereas lamin A is downregulated in iPSCs, allowing for regeneration of HGPS iPSCs, we found that POLR3A is upregulated during reprogramming. Enhanced expression of mutant POLR3A in WRS iPSCs led to nucleolus abnormalities and telomerase RNA component (TERC) sequestration in the nucleoli in WRS iPSCs. WRS iPSCs may be an important model for developing new therapeutic approaches affecting premature aging of stem cells.

Keywords:  Hutchinson–Gilford progeria syndrome; Induced pluripotent stem cells; Nucleolus; POLR3A; TERC; Telomeres; Wiedemann-Rautenstrauch progeroid syndrome

DOI:  https://doi.org/10.1007/s10522-025-10333-9