bims-polgdi 2025-09-07 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–09–07
33 papers selected by
Luca Bolliger, lxBio

Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation.
Mitochondrial Quality Control.
Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.
Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs.
MitoTraP: mitochondrial protection for cellular proteostasis.
Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.
Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
Mitochondrial Biogenesis in Skeletal Muscle.
Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
Molecular mechanisms of mitochondrial quality control.
Metformin may alter the course of Leber's hereditary optic neuropathy: a case report.
Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.
Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.
Cerebellum mitochondrial DNA copy number is increased in Parkinson's disease.
MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.
Late-onset Leber's hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?
Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.
Long-term mitochondria-endoplasmic reticulum complexes in the oocytes and early embryos of a matrotrophic pseudoscorpion Chelifer cancroides.
Effects of nutrients and diet on mitochondrial dysfunction: An opportunity for therapeutic approaches in human disease.
Prenatal diagnosis of rare genetic disorders: fourteen years' experience of a tertiary genetic centre from India.
The dual nature of neuroinflammation in networked brain.
Advancements in extracellular vesicle therapy for neurodegenerative diseases.
Interferon gamma applied ex vivo restores function to neutrophils from critically ill patients.
Application of mesenchymal stem cells in ferroptosis-related diseases.
Cutting-edge strategies for delivering drugs to the brain based on nanocarriers.
Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function.
Inflammatory mitochondrial signalling and viral mimicry in cancer.
Contributions of inherited mtDNA to longevity: evidence from extended pedigrees with 176 million kinship pairs.
Exploring the uncharted role of cell senescence in rare diseases.
Calmodulinopathies: The Need for a Registry.

Ageing Res Rev. 2025 Aug 26. pii: S1568-1637(25)00227-2. [Epub ahead of print]112 102881

Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation.

Antonella Girgenti, Laura Palumbo, Gokhan Burcin Kubat, Ibrahim Turkel, Pasquale Picone, Domenico Nuzzo.

  Mitochondrial activity is essential for the proper functioning of higher brain processes, and its impairment has been linked to a wide range of neurological disorders. Increasing evidence shows that under physiological and pathological conditions, mitochondria can be secreted into the extracellular environment to regulate various biological responses, including cellular bioenergetics. Today, the therapeutic modality known as "mitochondrial transplantation" has emerged as a cutting-edge and highly promising intervention for the promotion of cell and tissue regeneration. This innovative approach entails the replacement of dysfunctional mitochondria in the recipient organism with healthy, functional exogenous mitochondria, thereby aiming to restore cellular function and promote tissue repair and recovery. Several studies have demonstrated the beneficial effects of local or systemic administration of mitochondria on in vitro and in vivo models of brain diseases. We discuss the effect of mitochondrial transplantation in various brain diseases and highlight some critical issues. In this regard, we propose vesicles as a delivery system for both whole mitochondria and mitochondrial components to target cells in the central nervous system. Furthermore, the aim of this review is twofold: firstly, to emphasize the significance of brain mitochondrial transplantation, and secondly, to prompt the scientific community to consider the practical applications of brain mitochondrial transplantation. To this end, the text highlights the as yet unresolved issues and challenges that must be addressed and surmounted if this field is to progress. In conclusion, the authors express their support for the development of new potential therapies for mitochondrial diseases of the central nervous system.

Keywords:  Brain diseases; Mitochondrial dysfunction; Mitochondrial transplantation; Vesicles

DOI:  https://doi.org/10.1016/j.arr.2025.102881
Adv Exp Med Biol. 2025 ;1478 51-60

Mitochondrial Quality Control.

Yuntian Guan, Zhen Yan.

  Mitochondria, the power plants of cells, are essential for various cellular functions. In skeletal muscle, mitochondria form a network, called mitochondrial reticulum, which fuels muscle contractile and metabolic functions. The high degree of structure-to-function specialization of mitochondria in skeletal muscle implies that it is closely gauged and regulated to maintain energy production capacity to match the functional demands. The processes that regulate the overall structure and function of mitochondrial reticulum are collectively referred to as mitochondrial quality control. Mitochondrial quality control consists of mitochondrial biogenesis, dynamics (i.e., fission and fusion), and selective degradation via proteolysis and mitophagy. In this chapter, we will discuss different aspects of contemporary understanding of mitochondrial quality control, their respective mechanisms, and their adaptability to exercise training.

Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial reticulum; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1007/978-3-031-88361-3_3
Ageing Res Rev. 2025 Sep 03. pii: S1568-1637(25)00238-7. [Epub ahead of print] 102892

Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.

Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Helio José Coelho-Junior, Vito Pesce, Francesco Landi, Christiaan Leeuwenburgh, Anna Picca.

  Nuclear insertions of mitochondrial DNA (mtDNA) segments (NUMTs) represent an evolutionarily conserved phenomenon originating from the ancient endosymbiotic relationship between mitochondria and host cells. These insertions predominantly localize near intergenic or regulatory regions and are often enriched in tissues with high metabolic activity. Once regarded as inert pseudogenes or genomic artifacts, NUMTs are now recognized as dynamic elements capable of modulating nuclear architecture and cellular function. Advances in whole-genome sequencing have revealed a remarkable diversity of NUMTs across species, including polymorphic variants in humans that suggest ongoing NUMTogenesis. Stress-induced mitochondrial damage promotes mtDNA release and subsequent nuclear integration via non-homologous end joining, a mechanism that may be exacerbated in aging tissues. Studies suggest that NUMTs may intersect with some biological hallmarks of aging. Recently, NUMT accumulation in the brain was shown to correlate with cognitive decline and reduced lifespan, implicating NUMTs in biological aging and associated conditions. Additionally, NUMTs have been observed in oncogenic loci, suggesting potential roles in carcinogenesis. This review synthesizes current evidence on the molecular mechanisms underpinning NUMT generation and explores their intersection with aging biology. We examine how NUMTs may influence mitochondrial-nuclear communication, promote inflammation, and affect telomere dynamics and cellular senescence. We also highlight the relevance of understanding the biological impact of NUMTs across life stages and disease states to inform novel biomarkers and therapeutic strategies.

Keywords:  DNA repair; biological aging; genomic instability; hallmarks of aging; mitochondrial dysfunction; telomeres

DOI:  https://doi.org/10.1016/j.arr.2025.102892
Int J Toxicol. 2025 Aug 28. 10915818251369414

Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.

Nishi Shah, Bhagawati Saxena, Richa Gupta.

  Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.

Keywords:  environmental toxicants; heavy metals; mitochondrial dysfunction; neurodegenerative disorders; pesticides

DOI:  https://doi.org/10.1177/10915818251369414
J Vis Exp. 2025 Aug 15.

Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs.

Sholto de Wet, Rensu Theart, Ben Loos, G Angus McQuibban.

Mitochondria are highly dynamic organelles that are vital to the survival of any animal, undergoing regular fission and fusion events in response to the needs or stresses of the host, leading to the constant remodeling of the mitochondrial network. Because of this, being able to evaluate the mitochondrial network in three dimensions, as well as over time, offers a benefit in understanding how the system responds to factors such as stress or pharmaceutical intervention. Fluorescence imaging of the mitochondrial networks of cells enables the ability to visualize and monitor these changes. However, the mitochondrial network is often described as a two-dimensional and static structure that is defined by unstandardized metrics. Therefore, we set out to describe a pipeline that enables the user to prepare their images for the mitochondrial event localizer (MEL), an ImageJ plugin tool that detects fission and fusion events in the mitochondrial network over time and in a 3-dimensional manner, thus, offering insight into the dynamic changes that this network undergoes. Additionally, we describe the benefits of understanding fission and fusion in light of the changes in the mitochondrial count and morphological changes.

DOI: https://doi.org/10.3791/68478
Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]

MitoTraP: mitochondrial protection for cellular proteostasis.

Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.

  Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.

Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress

DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
World J Methodol. 2025 Sep 20. 15(3): 102709

Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.

Deepak Parchwani, Ragini Singh, Digisha Patel.

  The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer's and Parkinson's, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.

Keywords:  Aging; Cancer; Mitochondrial DNA; Mitochondrial DNA copy number; Neurodegenerative disease; Quantitative polymerase chain reaction

DOI:  https://doi.org/10.5662/wjm.v15.i3.102709
Adv Exp Med Biol. 2025 ;1478 343-363

Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.

Jonathan Wanagat, Robert Musci, Allen Herbst, Judd M Aiken.

  This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.

Keywords:  Mitochondria; Mitochondrial DNA; Mutations; Sarcopenia

DOI:  https://doi.org/10.1007/978-3-031-88361-3_14
Adv Exp Med Biol. 2025 ;1478 19-50

Mitochondrial Biogenesis in Skeletal Muscle.

David A Hood, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, Sabrina Champsi.

  Mitochondrial biogenesis refers to the synthesis of nuclear- and mitochondrially encoded proteins, along with phospholipids, that aid in the expansion of the mitochondrial network. In skeletal muscle, mitochondria are organized as a reticulum, as this ideal morphology complements the elongated shape of a myofibre. This allows for efficient substrate diffusion and supports the vigorously dynamic metabolic capabilities of this tissue type. Mitochondria are central responders to deviations in metabolic homeostasis and are thus required to support acute or chronic bouts of endurance exercise, cold exposure, starvation, or other externally imposed stimuli. This chapter marks the introduction to skeletal muscle mitochondrial adaptability as we discuss the subcellular events that contribute to mitochondrial biogenesis. Topics range from mitochondrial content and subpopulations in different muscle fibre types to signaling cascades and regulatory elements that support this mechanism. The characterization of mitochondrial biogenesis was made possible through clever models of both exercise and muscle disuse, at times with genetic modifications to important regulators, and is incorporated in this discussion. The chapter concludes with reviews on changes to signaling towards biogenesis with age. Altogether, our review attempts to highlight the vast revelations on the targeting, contribution, and significance of mitochondrial biogenesis in skeletal muscle.

Keywords:  Aging; Calcium; Exercise signaling; Exercise training; Gene expression; Mitochondria; Mitochondrial dynamics; Muscle disuse; Protein import; ROS

DOI:  https://doi.org/10.1007/978-3-031-88361-3_2
EMBO Rep. 2025 Aug 29.

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.

  Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing

DOI:  https://doi.org/10.1038/s44319-025-00536-z
Transl Neurodegener. 2025 Sep 01. 14(1): 45

Molecular mechanisms of mitochondrial quality control.

Wensheng Li, Yuran Gui, Cuiping Guo, Yuting Huang, Yi Liu, Xuan Yu, Huiliang Zhang, Jianzhi Wang, Rong Liu, Yacoubou Abdoul Razak Mahaman, Qiuhong Duan, Xiaochuan Wang.

  Mitochondria produce adenosine triphosphate (ATP), the main source of cellular energy. To maintain normal function, cells rely on a complex mitochondrial quality control (MQC) system that regulates mitochondrial homeostasis, including mitochondrial dynamics, mitochondrial dynamic localization, mitochondrial biogenesis, clearance of damaged mitochondria, oxygen radical scavenging, and mitochondrial protein quality control. The MQC system also involves coordination of other organelles, such as the endoplasmic reticulum, lysosomes, and peroxisomes. In this review, we discuss various ways by which the MQC system maintains mitochondrial homeostasis, highlight the relationships between these pathways, and characterize the life cycle of individual mitochondria under the MQC system.

Keywords:  Evidence-based therapies; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Mitochondrial quality control

DOI:  https://doi.org/10.1186/s40035-025-00505-5
Front Med (Lausanne). 2025 ;12 1609941

Metformin may alter the course of Leber's hereditary optic neuropathy: a case report.

Shenoda Abd Elmaseh, Danielle A Gauthier, Maryam Golmohammadi, Nutsa Pargalava, Valerio Carelli, Alfredo A Sadun.

  Leber's hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease caused by variants in mitochondrial DNA (mtDNA) transmitted exclusively through the maternal line. The disease predominantly affects young males and is characterized by progressive bilateral vision loss. Idebenone, a well-studied drug, modestly enhances the mitochondrial function and visual acuity in many patients with LHON. In this study, we report the case of a 48-year-old woman diagnosed with LHON (m.11778G>A/MT-ND4) and type 2 diabetes mellitus who experienced visual field improvement following metformin treatment after 26 months of progressive vision loss unresponsive to idebenone, nicotinamide adenine dinucleotide (NAD+), and hormone replacement therapy (HRT). Our findings offer an intriguing perspective on LHON management but require more investigations, particularly on the molecular effects of metformin on the mitochondrial function in LHON patients.

Keywords:  LHON; NAD+; idebenone; metformin; mitochondrial dysfunction; vision Loss

DOI:  https://doi.org/10.3389/fmed.2025.1609941
Front Neurosci. 2025 ;19 1603292

Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.

Luo Fu, Ting Luo, Zhongnan Hao, Yongli Pan, Wenqiang Xin, Lin Zhang, Zhuhong Lai, Haitao Zhang, Hua Liu, Wei Wei.

  The blood-brain barrier (BBB) is a critical structure that maintains the brain's homeostasis by regulating the transport of molecules and protecting it from harmful substances. However, in neurological diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, the integrity and function of the BBB can be significantly compromised. In these conditions, BBB disruption leads to increased permeability, which facilitates neuroinflammation, exacerbates neuronal damage, and accelerates disease progression. Recent research has highlighted the potential of lipid-based carriers, including liposomes and lipid droplets (LDs), in modulating the BBB's integrity and function in various neurological diseases. Liposomes, with their ability to cross the BBB via mechanisms such as receptor-mediated transcytosis and carrier-mediated transport, are emerging as promising vehicles for the targeted delivery of therapeutic agents to the brain. These properties allow liposomes to effectively reduce infarct size and promote neuroprotection in ischemic stroke, as well as deliver drugs in the treatment of neurodegenerative diseases. Furthermore, LDs-dynamic regulators of lipid metabolism and cellular energy-play an essential role in maintaining cellular homeostasis, particularly during periods of stress when BBB function is compromised. These LDs help sustain cellular energy needs and modulate inflammatory responses, which are key factors in maintaining BBB integrity. Surface modifications of liposomes can further enhance their targeting efficiency, enabling them to selectively bind to specific brain cell types, including neurons, astrocytes, and microglia. This customization improves the precision of therapeutic delivery and supports the development of more tailored treatments. However, challenges such as immune responses, rapid clearance, and complement activation-related toxicity continue to hinder the broader application of liposomes and LDs in clinical settings. This review will focus on the roles of liposomes and LDs in regulating BBB integrity across a range of neurological diseases, discussing their potential for targeted drug delivery, neuroprotection, and the modulation of neuroinflammation. Additionally, we will explore the strategies being developed to address the limitations that currently restrict their clinical use.

Keywords:  blood–brain barrier; lipid droplets; liposomes; neurological disorders; neuroprotection

DOI:  https://doi.org/10.3389/fnins.2025.1603292
Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102678

Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.

Seongho Hong, Sol Pin Kim, Sanghun Kim, Soo Kyung Kang, Sungmo Jung, Yeji Oh, Seung Hee Choi, Su Bin Lee, Hou Cha, Jieun Kim, Jiyoung Bae, Jiyoon Park, Kyoungmi Kim, Chang Geun Choi, Soo-Ji Park, Do Hyun Kim, Lark Kyun Kim, Je Kyung Seong, Hyunji Lee.

  Mitochondrial DNA (mtDNA) base editors are powerful tools for investigating mitochondrial diseases. However, their editing efficiency can vary significantly depending on the target site within the mtDNA. In this study, we developed two improved versions of the mitochondrial adenine base editor (Hifi-sTALED and αnHifi-sTALED) by modifying components other than the TadA8e-V28R deaminase variant. These enhancements significantly increased editing efficiency while preserving minimal off-target effects across the transcriptome. Using these optimized editors, we achieved improved mtDNA editing in mouse embryos and successfully generated mt-Rnr1 mutant mice with high heteroplasmic loads. Functional analyses revealed that the mt-Rnr1 mutation impaired mitochondrial function, as indicated by reduced ATP production and decreased oxygen consumption rate (OCR). These findings demonstrate the utility of the enhanced base editors in generating mitochondrial disease models and advancing research in mitochondrial genetics.

Keywords:  MT: RNA/DNA Editing; TALED; base editing; mitochondria; mitochondrial editing; mtDNA

DOI:  https://doi.org/10.1016/j.omtn.2025.102678
Brain Commun. 2025 ;7(4): fcaf296

Cerebellum mitochondrial DNA copy number is increased in Parkinson's disease.

Talia Beglarian, David R Tyrpak, J Raphael Gibbs, John Andrew MacKay, Sonja W Scholz, Bryan J Traynor, Marilyn S Albert, Liana S Rosenthal, Ted M Dawson, Juan C Troncoso, Dena G Hernandez, Mark R Cookson, Charles H Adler, Geidy Serrano, Andrew B Singleton, Thomas G Beach, Brooke E Hjelm.

  Bioinformatics methods can be used to quantify mitochondrial DNA copy number from whole genome sequencing (WGS) data. We evaluated mitochondrial DNA copy number from human brain-derived WGS data using the fastMitoCalc tool. 341 Parkinson's Disease cerebellum samples were compared with 74 age-matched controls from the North American Brain Expression Consortium. Parkinson's Disease cerebellum had significantly higher mitochondrial DNA copy number compared with controls (P = 4.15e-7), and this effect was reproducible in four of five brain banks when analysis was restricted to each resource that contributed Parkinson's Disease samples to this genetic dataset. Follow-on analyses of 128 Parkinson's Disease cerebellum samples and 33 controls that had paired neuropathology data and clinical scores demonstrated a significant increase in mitochondrial DNA copy number with Unified Staging System for Lewy Body disorders stages and Unified Parkinson's Disease Rating Scale (off meds) motor scores. Analysis of Lewy Body scores from ten brain regions showed cerebellum mitochondrial DNA copy number increased upon pathological infestation of α-synuclein aggregates in the brainstem and limbic system but did not increase after late-stage neocortical involvement. This genetics dataset supports previous observations of cerebellum activation in Parkinson's Disease and suggests mitochondrial DNA copy number may increase to support this regional activation as a compensatory mechanism to pathology or motor symptoms.

Keywords:  Lewy body; Parkinson’s disease; WGS; cerebellum; mitochondrial DNA copy number

DOI:  https://doi.org/10.1093/braincomms/fcaf296
BMC Genomics. 2025 Aug 30. 26(1): 787

MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.

Yoshikazu Furuta, Manami Kakita, Hidenori Tanaka.

   BACKGROUND: Mitochondrial DNA sequences are used for inter- and intra-specific comparison analysis in ecological studies. Instead of using short regions as marker sequences, analyzing longer regions, such as whole mitochondrial DNA sequences, can improve the accuracy of such studies by increasing the likelihood of detecting species or specific sequences. However, current methods for sequencing whole mitochondrial DNA require primer design for each target species or long fragments of genomic DNA as a PCR template. We developed a method and accompanying tool for PCR-based long-read sequencing of whole mitochondrial DNA, named MitoCOMON, which is applicable to wide-target taxonomic clades and partially digested template DNA.
RESULTS: PCR amplification of whole mitochondrial DNA as four fragments facilitates the successful assembly of the whole mitochondrial DNA sequence, even when a sample is a mixture of multiple species or partially degraded. The tool that we developed consists of two modules that can design a primer set for species in a target taxonomic clade and assemble the whole mitochondrial DNA sequence from amplicons which were amplified using the designed primer set. Primer sets were designed for mammal and bird species, which showed a high success rate for whole mitochondrial DNA sequencing with high sequence accuracy. Multiple whole mitochondrial DNA sequences were also assembled from samples mixed with the genomic DNA of several species without forming chimeric sequences. In addition to the accuracy, some assembled sequences also retained a long duplication at the D-loop region, suggesting that the method addresses large rearrangements. Compared with a method that amplifies the whole mitochondrial DNA as a single amplicon, our method was effective for partially degraded samples.
CONCLUSIONS: Our method and accompanying tool, named MitoCOMON, enables an easier acquisition of whole mitochondrial DNA sequences from samples with some DNA degradation without designing species-specific primers. This approach can enhance the accessibility of mitochondrial genomic data and is expected to improve the resolution of ecological analyses, including accurate species identification and individual-level discrimination.

Keywords:   De Novo assembly; Long reads; Structural variation; Whole mitochondrial DNA sequencing

DOI:  https://doi.org/10.1186/s12864-025-12010-0
Cell Mol Life Sci. 2025 Sep 06. 82(1): 337

Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.

Zhongqiang Su, Hui Shu, Xingting Huang, Liuyan Ding, Fengchu Liang, Zongtang Xu, Ziting Zhu, Minshan Chen, Xiaobei Wang, Guihua Li, Huan Xia, Qiannan Cao, Wenlong Zhang, Pingyi Xu, Xinling Yang.

  Microglial activation-induced neuroinflammation and impaired neuronal mitophagy are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.

Keywords:  CGAS-STING; Microglial mitophagy; Mitochondrial DNA; Neuroinflammation; Parkinson's disease; Rhapontigenin

DOI:  https://doi.org/10.1007/s00018-025-05873-9
Front Neurol. 2025 ;16 1616992

Late-onset Leber's hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?

Giulia Amore, Michele Carbonelli, Diego D'Angeli, Luigi Bonan, Marco Faustini-Fustini, Alessandra Maresca, Valerio Carelli, Chiara La Morgia.

   Introduction: Leber's hereditary optic neuropathy (LHON) is a maternally inherited condition due to mitochondrial DNA (mtDNA) mutations usually affecting young men within their thirties, while women seem protected by estrogens with a female-to-male ratio of 1:3. Late-onset cases (over 40 years of age) are usually associated to toxic exposure to tobacco smoke or drugs causing mitochondrial dysfunction.
Results: We describe two cases of LHON remarkable for their late onset (> 60 years) in the absence of classic toxic factors. They were both affected by advanced prostate cancer and developed LHON after introduction of enzalutamide, an antagonist of androgens' receptor, in association with leuprolide, a gonadotropin-releasing hormone (GnRH) analogue, used in the context of Androgen deprivation therapy (ADT). Both patients presented very low serum levels of gonadotropin, estrogens and androgens compatible with hormonotherapy. MtDNA copy number in our probands resulted significantly reduced (like other LHON affected cases), compared to age-matched LHON unaffected mutation carriers and controls.
Discussion: The role of hormones in LHON pathogenesis remains still debated. Recent evidence suggests a protective effect of estrogens in increasing mitochondrial biogenesis (and mtDNA copy number), partially explaining the gender bias of the disease, while the role of androgens is yet to be fully understood. Considering the effect of the ADT on circulating hormonal levels and their reciprocal interactions, we hypothesize that in a context of already low estrogens levels due to GnRH analogue, the block of androgens receptors by Leuprolide further imbalance the estrogens to androgens ratio and eventually trigger the disease.

Keywords:  Leber’s hereditary optic neuropathy; androgen deprivation therapy; estrogens; hormones; mitochondrial disease

DOI:  https://doi.org/10.3389/fneur.2025.1616992
Res Sq. 2025 Aug 18. pii: rs.3.rs-3136613. [Epub ahead of print]

Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.

Xin Jie Chen, Liam Coyne, Arnav Rana, Xiaowen Wang, Sanaea Bhagwagar, Yumiko Umino, Eduardo Solessio, Frank Middleton.

Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease (PD). However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we show that mild mitochondrial protein import stress augments neural damage independent of bioenergetics. We induce protein import stress in a mouse model of PD expressing α-synuclein(A53T). The double mutant mice demonstrate increased size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation and worsened motor defect relative to α-synuclein(A53T) single mutants. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice. These data suggest that mitochondrial protein import stress, which can be induced by many types of mitochondrial injuries, can contribute to neural damage through cytosolic proteostatic stress and possible co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics.

DOI: https://doi.org/10.21203/rs.3.rs-3136613/v1
CNS Neurosci Ther. 2025 Sep;31(9): e70577

Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.

Sevim Isik, Sajeda Osman, Bercem Yeman-Kiyak, Suhair Rami Mohammed Shamshir, Nesrin Majdi Edwan Sanchez.

   AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.
METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.
RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.
CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.

Keywords:  alzheimer's disease; amyotrophic lateral sclerosis; cellular therapy; clinical trials; exosomes; huntington's disease; parkinson's disease; stem cells

DOI:  https://doi.org/10.1111/cns.70577
Dev Biol. 2025 Aug 29. pii: S0012-1606(25)00237-4. [Epub ahead of print]527 318-330

Long-term mitochondria-endoplasmic reticulum complexes in the oocytes and early embryos of a matrotrophic pseudoscorpion Chelifer cancroides.

Izabela Jędrzejowska, Karol Małota, Arnold Garbiec.

  Mitochondria are considered key organelles for proper oocyte growth, maturation, fertilization, and embryo development. During oogenesis, they have been found to be highly dynamic organelles that interact with other cellular components. In this study, we analyzed the morphology and behavior of mitochondria in the oocytes and early embryos of the cosmopolitan pseudoscorpion Chelifer cancroides. Analyses were carried out using light, confocal, and transmission electron microscopy. Our results show that, in the early stages of oocyte growth, mitochondria gather close to the germinal vesicle within an organelle assemblage termed the Balbiani body (Bb). In the Bb, mitochondria increase in number and display a high membrane potential. In advanced previtellogenesis, when the Bb disperses, the mitochondria gradually populate the entire ooplasm and join the endoplasmic reticulum to form mitochondria-endoplasmic reticulum (mt-ER) complexes. Within these complexes, mitochondria significantly change morphology and reduce activity. The mt-ER complexes persist throughout oocyte growth until early embryogenesis. During cleavage, they are unevenly segregated to the micromeres that form the embryo body. Our results suggest that in Chelifer, the Balbiani body plays a role in mitochondrial multiplication. We also discuss the role of the mt-ER complexes and propose that they promote low activity of mitochondria to protect mtDNA and supply the embryo with substantial organelles for the early stages of development.

Keywords:  Balbiani body; Chelicerata; Embryo nutrition; Mitochondria activity; Oogenesis; Organelle interactions

DOI:  https://doi.org/10.1016/j.ydbio.2025.08.020
Biomed Pharmacother. 2025 Aug 28. pii: S0753-3322(25)00687-0. [Epub ahead of print]191 118493

Effects of nutrients and diet on mitochondrial dysfunction: An opportunity for therapeutic approaches in human disease.

Lisa H Do, Renata T Da Costa, Maria E Solesio.

  Mitochondria play a crucial role in multiple cellular processes beyond the regulation of bioenergetics. These processes range from apoptosis to intracellular signaling. Accordingly, mitochondrial dysfunction has been broadly described in the etiopathology of multiple human diseases, including cancer, diabetes, and all the main neurodegenerative disorders. Therapeutic interventions aimed at modulating this dysfunction are promising for preventing and/or delaying the development of these pathologies. Recent research has highlighted the potential of dietary interventions to modulate mitochondrial physiology. In this text, we critically review the scientific literature available regarding the effects of different dietary interventions (such as caloric restriction, ketogenic diets, increased omega-3 fatty acid consumption, etc.) on some key components of mitochondrial physiology. Despite the significant advancements in the field that we present in this review, critical gaps remain regarding the molecular mechanisms that underlie the effects of these dietary interventions on mitochondrial physiology, especially under pathological conditions. Future research in this field could underscore these mechanisms, paving the road for the use of dietary interventions against mitochondrial dysfunction as valid pharmacological strategies in human disease.

Keywords:  Diet; Mitochondria; Mitochondrial physiology; Nutrients; Therapeutic approaches

DOI:  https://doi.org/10.1016/j.biopha.2025.118493
Orphanet J Rare Dis. 2025 Sep 02. 20(1): 471

Prenatal diagnosis of rare genetic disorders: fourteen years' experience of a tertiary genetic centre from India.

Jayesh Sheth, Tejasvi Dhondekar, Manali Ajagekar, Chaitanya Datar, Archana Kher, Jigish Trivedi, Swati Thakkar, Ajit Gandhi, Meenakshi Soni, Mayank Chaudhary, Manish Banker, Anil Jalan, Mamta Muranjan, Sujal Munshi, Ami Munshi, Mili Pandya, Jhanvi Shah, Aadhira Nair, Riddhi Bhavsar, Frenny Sheth, Harsh Sheth.

   BACKGROUND: Rare genetic disorders are increasingly diagnosed due to advancing genetic technology, whilst, treatment for them is challenging. Therefore, their prevention by prenatal diagnosis is a way forward to reduce the overall burden. The present study provides an overview of a cohort of patients who were offered prenatal diagnosis for genetic disorders at a tertiary genetic center in India.
METHODS: The study included 1,738 prenatal samples for the period of 2008 to 2022, identified as being at high risk for rare genetic disorders based on family history, previous affected children, and abnormal ultrasound findings. Participants underwent prenatal diagnostic tests, including chorionic villus sampling or amniocentesis, or fetal blood by various molecular techniques and enzyme-based studies. Data regarding patient demographics, types of disorders screened, and diagnostic outcomes were collected and analyzed.
RESULTS: Of the 1738 cases, 467 (26.87%) prenatal samples were identified as being affected by genetic anomalies. The diagnosed conditions included hematological disorders (n = 735/1738, 42.28%), inborn errors in metabolism (n = 513/1738, 29.52%), neurological disorders (n = 310/1738, 17.84%), musculoskeletal disorders (n = 45/1738, 2.59%), and other rare genetic disorders (n = 135/1738, 7.77%). Early diagnosis facilitated timely medical information and provided options for prevention, such as medical termination of pregnancy (MTP) in affected cases after genetic counseling.
CONCLUSION: Our study demonstrates that prenatal diagnosis for rare genetic disorders is an invaluable step toward reducing the burden of these conditions. The use of advanced genetic techniques, combined with genetic counseling, enables effective prevention strategies. However, challenges such as accessibility, cost, and ethical considerations continue to pose barriers to widespread implementation in India. Increased awareness and government policy support are essential to make these diagnostic services universally available and affordable.

Keywords:  Affordable; Awareness; Diagnosis; Prenatal diagnosis; Prevention; Rare disease; Treatment challenges

DOI:  https://doi.org/10.1186/s13023-025-04003-9
Front Immunol. 2025 ;16 1659947

The dual nature of neuroinflammation in networked brain.

Ludmila Müller, Svetlana Di Benedetto, Viktor Müller.

  Neuroinflammation is a dynamic, context-sensitive process that plays essential roles in brain development, maintenance, and response to injury. It reflects a finely balanced neuroimmune state-facilitating repair and adaptation under homeostatic conditions, while also contributing to dysfunction when dysregulated or chronically activated. In this mini-review, we examine the cellular and molecular mechanisms underlying neuroinflammatory responses, focusing on the roles of microglia and astrocytes, their bidirectional communication with neurons, and their interaction with peripheral immune signals. We describe how various stimuli-including aging, protein aggregates, and cellular stress-modulate glial function and shift immune activity toward protective or deleterious outcomes. Special attention is given to endogenous regulatory pathways, including cytokine signaling, receptor-mediated crosstalk, and immunometabolic cues that determine the resolution or persistence of inflammation. We further discuss shared and disease-specific features of neuroinflammation across neurological disorders, offering a systems-level perspective on how immune activity contributes to neural resilience or degeneration. This integrated view aims to inform future studies on neuroimmune dynamics in health and disease.

Keywords:  CNS; astrocytes; brain; microglia; neuroimmune interactions; neuroinflammation; neurological disorders; neurons

DOI:  https://doi.org/10.3389/fimmu.2025.1659947
Explor Neuroprotective Ther. 2025 ;5

Advancements in extracellular vesicle therapy for neurodegenerative diseases.

Ningyun Hu, Liang Chen, Guoku Hu, Rong Ma.

  Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.

Keywords:  Alzheimer’s disease; Extracellular vesicles; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; exosomes; multiple sclerosis

DOI:  https://doi.org/10.37349/ent.2025.1004104
Thorax. 2025 Aug 28. pii: thorax-2025-223280. [Epub ahead of print]

Interferon gamma applied ex vivo restores function to neutrophils from critically ill patients.

Cameron J Lake, Jonathan Scott, Marie-Hélène Ruchaud-Sparagano, John H Thompson, Fiona Dewar, Polina Yarova, Wendy Funston, Richard Ch Davidson, Kathryn M Musgrave, Stephen E Wright, Ian Clement, Alistair I Roy, Wezi Sendama, Jason Powell, Daniel Brooks, Chung Mun Alice Lin, Kristen Davies, Thomas P Hellyer, Anthony J Rostron, A John Simpson.

   INTRODUCTION: Critically ill patients commonly develop acquired neutrophil dysfunction, which increases susceptibility to intensive care unit-acquired infection (ICU-AI). This study aimed to assess whether interferon gamma (IFN-γ) can restore function in dysfunctional neutrophils from critically ill patients and to uncover potential underlying mechanisms.
METHODS: This was an observational cohort study. Neutrophils were isolated from whole blood donated by critically ill patients (n=31) in four separate teaching hospital intensive care units (ICUs). Neutrophils were subsequently treated with recombinant human IFN-γ or vehicle for 1 hour following either Fc gamma receptor (FcγR) blockade, selective inhibition of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ) or vehicle control for 30 min. Neutrophil phagocytosis, bacterial killing, superoxide generation, phagocytic receptor expression and small Rho GTPase activity were assessed. Neutrophil dysfunction was defined as <50% of cells ingesting 2 or more zymosan particles in a phagocytosis assay.
RESULTS: IFN-γ significantly improved phagocytosis (control 36.5%, IFN-γ 56.0%), bacterial killing (control 31.6%, IFN-γ 82.1%) and superoxide generation (2.8-fold increase relative to control) in dysfunctional neutrophils. IFN-γ also increased the activity of the small GTPases, Rac and Cdc42 (2.4-fold and 1.5-fold increase relative to control, respectively) in dysfunctional neutrophils. Selective inhibition of PI3K-γ prevented the IFN-γ-mediated improvement of phagocytosis (IFN-γ 62.5%, with inhibitor 27.9%), bacterial killing (IFN-γ 82.1%, with inhibitor 30.5%) and superoxide generation (IFN-γ 2.8-fold change relative to control, 0.7 with inhibitor). The IFN-γ-mediated improvement of bacterial killing in dysfunctional neutrophils was also prevented by FcγR blockade (IFN-γ 82.1%, FcγR inhibition 28.7%).
CONCLUSIONS: In critically ill patients with known acquired neutrophil dysfunction, ex vivo application of IFN-γ consistently improved a range of neutrophil effector functions.

Keywords:  Bacterial Infection; Critical Care; Neutrophil Biology

DOI:  https://doi.org/10.1136/thorax-2025-223280
J Mol Med (Berl). 2025 Sep 03.

Application of mesenchymal stem cells in ferroptosis-related diseases.

Xianmei Zhong, Xue Zhang, Yuxuan Zhu, Xi Zheng.

  Modern medicine has achieved groundbreaking advancements in disease diagnosis and treatment, yet significant challenges remain in managing conditions such as age-related diseases, tumors, autoimmune disorders, and neurological conditions. Conventional drug therapies often suffer from inadequate targeting, severe toxic side effects, and limited therapeutic efficacy, leading to adverse clinical outcomes such as disease recurrence and organ dysfunction. In recent years, mesenchymal stem cells (MSCs) have demonstrated transformative potential in regenerative medicine and disease therapy. Leveraging their multipotent differentiation potential, immunomodulatory properties, and paracrine functions, MSCs offer innovative strategies by enhancing tissue repair and microenvironmental homeostasis. Notably, ferroptosis-a newly identified form of regulated cell death-has emerged as a critical research frontier. MSCs and their exosomes exhibit a remarkable ability to modulate ferroptosis by regulating iron ions and lipid peroxide levels. This review provides an in-depth analysis of the molecular pathways through which MSCs influence ferroptosis. Additionally, it explores recent advances in ferroptosis regulation in transplanted MSCs, shedding light on their clinical applicability. In summary, this work underscores the therapeutic promise of MSCs in treating ferroptosis-associated diseases.

Keywords:  Diseases; Ferroptosis; Mesenchymal stem cells

DOI:  https://doi.org/10.1007/s00109-025-02591-4
Drug Dev Ind Pharm. 2025 Sep 05. 1-19

Cutting-edge strategies for delivering drugs to the brain based on nanocarriers.

Tapan Kumar Shaw, Saikat Mollick Shuvo, Paramita Paul, Abhishek Jana, Kazi Asraf Ali.

   OBJECTIVE: This review aims to explore advanced nanotechnology-integrated delivery systems designed to facilitate the transport of therapeutic agents across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) disorders, particularly neurodegenerative diseases.Significance:CNS disorders remain a primary global health concern due to their progressive nature and limited treatment options. Conventional therapies exhibit minimal efficacy, primarily due to the restrictive nature of the BBB, which impedes drug access to brain tissue. Overcoming this barrier is crucial to improving therapeutic outcomes and minimizing systemic side effects.
METHODS: A comprehensive analysis of nanotechnology-based approaches was conducted, focusing on the physicochemical properties of nanocarriers, their interactions with the BBB, and their roles in targeted drug delivery. Strategies involving nanoparticle engineering, ligand-functionalized systems, and gene delivery vectors were critically reviewed.
RESULTS: Nanotechnology has shown considerable promise in facilitating drug delivery across the BBB. Nano-engineered platforms are capable of targeting specific cells, modulating signaling pathways, enhancing neuronal survival, and even inducing regeneration. Various successful nanocarriers, including liposomes, dendrimers, polymeric nanoparticles, and exosomes, demonstrate enhanced drug penetration and specificity.
CONCLUSIONS: Nanotechnology holds transformative potential in treating CNS disorders by addressing the limitations posed by the BBB. Continued research into the design and optimization of brain-targeted nano-systems holds the key to safer, more effective therapies. The manuscript also highlights current challenges and considerations in developing such delivery systems for clinical application.

Keywords:  Blood-brain barrier; Brain targeting; Central nervous system; Nanocarriers; Neurological disorders

DOI:  https://doi.org/10.1080/03639045.2025.2555858
Nat Commun. 2025 Aug 30. 16(1): 8126

Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function.

Nina-Lydia Kazakou, Nadine Bestard-Cuche, Laura J Wagstaff, Kellie Horan, Luise Seeker, Sunniva Bøstrand, Rana Fetit, Rebecca Sherrard Smith, Fabio Baldivia Pohl, Bjorn Neumann, Patrick Keeler, Robin J M Franklin, Anna Williams.

Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin's brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection.

DOI: https://doi.org/10.1038/s41467-025-63279-4
J Transl Med. 2025 Sep 02. 23(1): 982

Inflammatory mitochondrial signalling and viral mimicry in cancer.

Salvatore Nesci, Saverio Marchi, Joyce Hu, Francesco M Marincola, Cristina Algieri.

  Endogenous transposable elements (TEs) are receiving increasing attention as potential targets to develop novel immunostimulatory strategies against cancer. Indeed, the defective epigenetic suppression of TEs in malignant cells offers a therapeutic window to enable their re-activation with at least some degree of selectivity. In line with this notion, multiple clinically employed epigenetic modifiers such as DNA-demethylating agents have been shown to promote the re-expression of TEs in preclinical tumour models, hence driving powerful inflammatory responses that enables increased sensitivity of immunitary immune cells to immunotherapy with immune checkpoint inhibitors (ICIs). This phenomenon is commonly referred to as "viral mimicry" as (at least in part) it impinges on the activation of immunological pathways commonly driven by viral infection, notably the detection of cytosolic nucleic acids by pattern recognition receptors. Here, we critically discuss the molecular mechanisms through which the mitochondria-dependent cGAS-STING and MAVS pathways enable viral mimicry as elicited by the re-activation of TEs in neoplastic cells, as we comment on the therapeutic potential of using epigenetic modifiers to harness these mechanisms in support of restored ICIs sensitivity across cancer types.

Keywords:  Cancer immunotherapy; Endogenous transposable elements; Inflammatory responses; Mitochondria; Pattern recognition receptors; Viral mimicry

DOI:  https://doi.org/10.1186/s12967-025-06931-3
EBioMedicine. 2025 Sep 03. pii: S2352-3964(25)00355-X. [Epub ahead of print]119 105911

Contributions of inherited mtDNA to longevity: evidence from extended pedigrees with 176 million kinship pairs.

S Alexandra Burt, S Mason Garrison, Xuanyu Lyu, Joseph L Rodgers, Sarah L Carroll, Ken R Smith, Michael D Hunter.

   BACKGROUND: Mitochondria are bacteria-like organelles with their own DNA (mtDNA) that exist in the cellular cytoplasm of almost every cell in the human body. Because mitochondria are critical for sustaining life, it follows that inherited mtDNA could be a key aetiologic element underlying longevity. Unfortunately, biometric approaches able to quantify heritable contributions of mtDNA have not been available.
METHODS: We directly leveraged the unique matrilineal inheritance pattern of mtDNA to estimate its effects on longevity (defined as the top 10% oldest survivors within their birth cohort). We employed the Utah Population Database (UPDB) to identify 176,348,110 unique kinship links amongst 1,018,929 individuals born between 1700 and 1925 with information on matrilineal versus patrilineal relatedness.
FINDINGS: Across 1st, 2nd, 3rd, 4th, and 5th degree kin, matrilineal relatives were more similar in their longevity outcomes than were non-maternal relatives. Variance component analyses indicated nuclear DNA heritability of 23-26% and mtDNA heritability of at least 5% - despite mtDNA constituting only ∼16.6 k base pairs (versus 2,875,002 k base pairs for nuclear DNA). Moreover, sharing the maternal line of a longevous relative translated to an average of 11.3 months extra years of life.
INTERPRETATION: Results collectively suggest that mtDNA may be an important element of unusually long lifespans.
FUNDING: This project was supported by RF1-AG073189 and R01-AG022095 from the National Institute on Aging (NIA). We also acknowledge partial support through grant P30-CA2014 from the National Cancer Institute, University of Utah, and from the University of Utah's program in Personalized Health and Utah Clinical and Translational Science Institute.

Keywords:  Extended pedigrees; Heritability; Longevity; Matrilineal relatedness; mtDNA

DOI:  https://doi.org/10.1016/j.ebiom.2025.105911
Orphanet J Rare Dis. 2025 Sep 01. 20(1): 465

Exploring the uncharted role of cell senescence in rare diseases.

Piera Selvaggio, Esi Taci, Alessandra Barassi, Valentina Massa, Cristina Gervasini, Elena Lesma, Clara Bernardelli, Elisabetta Di Fede.

   BACKGROUND: Cellular senescence is a biological process in which the cell cycle is arrested in response to DNA damage caused by different endogenous and exogenous stimuli. In senescent cells, activation of intracellular cascade induces epigenetic, morphological and metabolic changes. Among them, senescent status is characterized by an alteration of the epigenome and the establishment of a peculiar senescence-associated secretory phenotype (SASP), which contributes to the extracellular matrix remodeling and senescence spreading. Growing interest is directed towards senescence relevance both in physiological processes and in pathological ones, including rare progeroid syndromes. However, little is known about senescence contribution to the onset and development of rare diseases in which aging traits are not manifested.
MAIN BODY: Here, we review the current knowledge about senescence involvement in four rare mendelian disorders of the epigenetic machinery (i.e. chromatinopathies) and four rare lung diseases, that can be considered a paradigm for understanding how epigenome alteration and aberrant microenvironment modification in senescence process might drive disease onset and progression. First, we report the main characteristics of chromatinopathies and the relation between the chromatin-related epigenetic defects and the senescence features in Sotos syndrome, Cornelia de Lange syndrome, Rett syndrome, and Kleefstra syndromes. Thereafter, we describe the pathological alteration and senescence involvement in cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension and lymphangioleiomyomatosis, considering them as models of rare lung diseases in which accumulation of senescent cells and their proinflammatory SASP have a central role.
CONCLUSION: Exploring the role of senescence in different and less common diseases might promote the understanding of the senescent process as a novel player in rare disorders, for a more comprehensive vision of their complexity and the suggestion of novel possible therapeutical targets.

Keywords:  Chromatinopaties; Epigenetics; Lung diseases; Lung microenvironment; Senescence; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1186/s13023-025-03778-1
JACC Clin Electrophysiol. 2025 Sep 03. pii: S2405-500X(25)00645-0. [Epub ahead of print]

Calmodulinopathies: The Need for a Registry.

Peter J Schwartz, Lia Crotti.

Calmodulinopathies are very rare genetic disorders associated with a high risk for sudden cardiac death. Disease-causing variants in 1 of the 3 identical CALM genes cause severe forms of long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, or idiopathic ventricular fibrillation, and there are many unanswered questions concerning management and underlying mechanisms. What is currently known depends largely on the initial publications from the ICamR (International Calmodulinopathy Registry). However, progress is delayed because the accrual of patients in ICamR is slow. As we did long ago for long QT syndrome, this is a call for action, requesting doctors all over the world to enroll even their isolated cases in the Registry. This is the only way to obtain, for an adequate number of patients, the data necessary to define the spectrum of clinical manifestations and the genotype-phenotype correlation essential for an improved risk stratification and best therapeutic management. If you are willing to contribute, please contact us.

DOI: https://doi.org/10.1016/j.jacep.2025.08.004