bims-polgdi Biomed News
on POLG disease
Issue of 2025–06–01
seventeen papers selected by
Luca Bolliger, lxBio
  1. Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
  2. Tipping the balance: innate and adaptive immunity in mitochondrial disease.
  3. Mitochondrial DNA transfer between malignant cells and T lymphocytes shapes the cancer-immunity dialogue.
  4. Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.
  5. Actin in mitochondrial regulation and mechanometabolic crosstalk.
  6. Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.
  7. Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
  8. Special Issue "Mitochondrial Metabolism Alterations in Health and Disease".
  9. Mitotherapy in Alzheimer's and Parkinson's diseases: A systematic review of preclinical studies.
  10. Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health.
  11. Telomeres as hallmarks of iPSC aging: A review on telomere dynamics during stemness and cellular reprogramming.
  12. Extracellular vesicles as vital players in drug delivery: a focus on clinical disease treatment.
  13. Neuroprotective effect of folic acid by maintaining DNA stability and mitochondrial homeostasis through the ATM/CHK2/P53/PGC-1α pathway in alcohol-exposed mice.
  14. LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.
  15. Precision exosome engineering for neurological therapeutics: molecular mechanisms and targeted strategies.
  16. Extracellular vesicles in age-related diseases: disease pathogenesis, intervention, and biomarker.
  17. Arginase 1 drives mitochondrial cristae remodeling and PANoptosis in ischemia/hypoxia-induced vascular dysfunction.
  1. Environ Mol Mutagen. 2025 May 26.
    Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
    Ghazal Darfarin, Janice Pluth.
      The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.
    Keywords:  anterograde and retrograde signaling; cellular homeostasis; mitochondrial biogenesis; mitochondrial dynamics; mtDNA maintenance, mitochondrial‐nuclear communication; redox signaling
    DOI:  https://doi.org/10.1002/em.70013
  2. Curr Opin Immunol. 2025 May 26. pii: S0952-7915(25)00042-1. [Epub ahead of print]95 102566
    Tipping the balance: innate and adaptive immunity in mitochondrial disease.
    Andrew Phillip West, Peter J McGuire.
      Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.coi.2025.102566
  3. Oncoimmunology. 2025 Dec;14(1): 2512109
    Mitochondrial DNA transfer between malignant cells and T lymphocytes shapes the cancer-immunity dialogue.
    Liwei Zhao, Peng Liu, Oliver Kepp, Guido Kroemer.
      Nonmutated mitochondrial DNA (mtDNA) from T lymphocytes can be incorporated into cancer cells bearing mutated mtDNA to repair their bioenergetic deficiency. However, a recent paper by Ikeda et al. indicates that mutated mtDNA from malignant cells can also be transferred into tumor-infiltrating T lymphocytes to subvert their function in cancer immunosurveillance.
    Keywords:  Immune checkpoint inhibition; Immunotherapy; immunosuppression
    DOI:  https://doi.org/10.1080/2162402X.2025.2512109
  4. Acta Neuropathol. 2025 May 30. 149(1): 53
    Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.
    Laura A Smith, Elizaveta A Olkhova, Nichola Z Lax, Yi Shiau Ng, Robert W Taylor, Grainne S Gorman, Daniel Erskine, Robert McFarland.
      Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.
    Keywords:  Alpers’ syndrome; DNA polymerase gamma (POLG); MELAS; MERRF; Stroke-like episodes; mtDNA
    DOI:  https://doi.org/10.1007/s00401-025-02891-6
  5. Curr Opin Cell Biol. 2025 May 26. pii: S0955-0674(25)00077-8. [Epub ahead of print]95 102539
    Actin in mitochondrial regulation and mechanometabolic crosstalk.
    Peng Shi, Yuhan Zhang, Congying Wu.
      Mitochondria undergo dynamic adaptations to cellular energy demands, changing morphology and function, through active interactions with other cellular organelles and the cytoskeletons. With advances in light and electron microscopy, actin probes for live-cell imaging, as well as proximity labeling, subtle and transient actin structures associated with mitochondria have been resolved and examined, which opened a new era for the understanding of architectural and mechanical regulation of organelles and metabolism. Here, we first review the recent findings that elucidate the actin-mitochondrion interactions in regulating mitochondrial dynamics (including fission, fusion and trafficking), and cristae architecture. Further, we discuss the functional consequences accompanying these morphological changes, which link cellular metabolism to the cytoskeleton and mechanotransduction through direct or indirect organelle control. Moreover, we summarize the avant-garde techniques for probing mitochondrion-associated actin, including new ways to visualize mitochondria-actin interaction in the cytosol and within the mitochondria, methods to identify the molecular components mediating actin-mitochondria crosstalk, and techniques for reconstructing the 3D ultrastructure of actin-mitochondrion interaction. Finally, we conclude pressing issues in this exciting field, calling for interdisciplinary efforts in examine actin-mitochondrion interactions at micro and macro levels. The dynamics and structural integrity of mitochondria are essential for energy metabolism and signal transduction, while their abnormalities lead to mitochondrial dysfunction and severe disease. This review aims to provide a comprehensive perspective on the emerging roles of the actin cytoskeleton in shaping mitochondrial morphology, structure, and functions, providing new angles to understand mitochondria-related diseases.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102539
  6. Int J Mol Sci. 2025 May 10. pii: 4565. [Epub ahead of print]26(10):
    Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.
    Tatiana Krylova, Yulia Itkis, Polina Tsygankova, Denis Chistol, Konstantin Lyamzaev, Vyacheslav Tabakov, Svetlana Mikhaylova, Natalia Nikitina, Galina Rudenskaya, Aysylu Murtazina, Tatiana Markova, Natalia Semenova, Natalia Buchinskaya, Elena Saifullina, Hasyanya Aksyanova, Peter Sparber, Natalia Andreeva, Natalia Venediktova, Alina Ivanushkina, Daria Eliseeva, Yulia Murakhovskaya, Natalia Sheremet, Ekaterina Zakharova.
      The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber's hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients' phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases.
    Keywords:  LHON; Leigh; MELAS; heteroplasmy; mtDNA; respirometry
    DOI:  https://doi.org/10.3390/ijms26104565
  7. EPMA J. 2025 Jun;16(2): 239-264
    Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
    Qianwen Shao, Marie Louise Ndzie Noah, Olga Golubnitschaja, Xianquan Zhan.
      Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.
    Keywords:  Autophagy and mitophagy; Cancer; Cardio-vascular disease; Chronic Fatigue; Cost-effective tailored treatments; Environment; Health policy; Health-to-disease transition; Individualized patient profile; Metabolic disease; Mitochondrial medicine; Neurodegeneration; Predictive Preventive Personalized Medicine (PPPM / 3PM / 3P medicine); Signaling; Stress; Vital biosensor
    DOI:  https://doi.org/10.1007/s13167-025-00409-4
  8. Int J Mol Sci. 2025 May 18. pii: 4826. [Epub ahead of print]26(10):
    Special Issue "Mitochondrial Metabolism Alterations in Health and Disease".
    Graziantonio Lauria, Rosita Curcio.
      Mitochondria are central hubs of cellular metabolism and signaling that play key roles in stress response, inflammation, calcium homeostasis, mitochondrial quality control, and cell death, with mitochondrial impairment potentially being the underlying cause of several conditions, including metabolic, neurodegenerative, and cardiovascular diseases [...].
    DOI:  https://doi.org/10.3390/ijms26104826
  9. BMC Neurol. 2025 May 27. 25(1): 227
    Mitotherapy in Alzheimer's and Parkinson's diseases: A systematic review of preclinical studies.
    Aynur Modiri, Leila Hosseini, Nasrin Abolhasanpour, Hosein Azizi, Reza Naghdi Sadeh.
       BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are prevalent neurodegenerative disorders and strongly affect both the patients' lives and their caregivers. Strategy to improve and restore mitochondrial function, as well as to treat mitochondria-associated diseases, as observed in the pathophysiology of AD and PD. The current study aimed to investigate the potential of mitotherapy in AD and PD in preclinical studies.
    METHODS: We conducted a systematic search of articles in English related to mitotherapy in AD and PD animal models published until October 2024 in the selected bibliographic databases, including PubMed, Scopus, EMBASE, and Google Scholar, and the reference lists of relevant review articles published. The quality of the final selected studies was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The initial search resulted in 231 studies, and after screening the titles and abstracts, 30 studies were recognized. Finally, 7 studies met the inclusion criteria.
    RESULTS: Despite restricted knowledge of the mitotherapy mechanisms, evidence shows that exogenous mitochondria exert neuroprotective effects via improving mitochondrial function, reducing oxidative stress and inflammation in preclinical models of AD and PD.
    CONCLUSION: This systematic review summarizes the preclinical studies on mitotherapy and provides evidence favoring mitochondria transplantation's protective effects in animal PD and AD models.
    Keywords:  Alzheimer's disease; Mitochondrial dysfunction; Mitochondrial transfer; Parkinson's disease
    DOI:  https://doi.org/10.1186/s12883-025-04241-1
  10. Redox Biol. 2025 May 20. pii: S2213-2317(25)00205-8. [Epub ahead of print]84 103692
    Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health.
    Nawab John Dar, Antonio Currais, Taketo Taguchi, Nick Andrews, Pamela Maher.
      Age-related cognitive decline and neurodegenerative diseases, such as Alzheimer's disease, represent major global health challenges, particularly with an aging population. Mitochondrial dysfunction appears to play a central role in the pathophysiology of these conditions by driving redox dysregulation and impairing cellular energy metabolism. Despite extensive research, effective therapeutic options remain limited. Cannabinol (CBN), a cannabinoid previously identified as a potent inhibitor of oxytosis/ferroptosis through mitochondrial modulation, has demonstrated promising neuroprotective effects. In cell culture, CBN targets mitochondria, preserving mitochondrial membrane potential, enhancing antioxidant defenses and regulating bioenergetic processes. However, the in vivo therapeutic potential of CBN, particularly in aging models, has not been thoroughly explored. To address this gap, this study investigated the effects of CBN on age-associated cognitive decline and metabolic dysfunction using the SAMP8 mouse model of accelerated aging. Our results show that CBN significantly improves spatial learning and memory, with more pronounced cognitive benefits observed in female mice. These cognitive improvements are accompanied by sex-specific changes in metabolic parameters, such as enhanced oxygen consumption and energy expenditure. Mechanistically, CBN modulates key regulators of mitochondrial dynamics, including mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1), while upregulating markers of mitochondrial biogenesis including mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20). Additionally, CBN upregulates key synaptic proteins involved in vesicle trafficking and postsynaptic signaling suggesting that it enhances synaptic function and neurotransmission, further reinforcing its neuroprotective effects. This study provides in vivo evidence supporting CBN's potential to mitigate age-related cognitive and metabolic dysfunction, with notable sex-specific effects, highlighting its promise for neurodegenerative diseases and cognitive decline.
    Keywords:  Age-related cognitive decline; Cannabinol (CBN); Mitochondrial biogenesis; Mitochondrial dysfunction; Neuroprotection; SAMP8 mouse model; Sex-specific effects; Synaptic function
    DOI:  https://doi.org/10.1016/j.redox.2025.103692
  11. Ageing Res Rev. 2025 May 23. pii: S1568-1637(25)00119-9. [Epub ahead of print]109 102773
    Telomeres as hallmarks of iPSC aging: A review on telomere dynamics during stemness and cellular reprogramming.
    Carlota Tavares-Marcos, Magda Correia, Bruno Bernardes de Jesus.
      Telomeres, the protective ends of chromosome, are key to tissue repair and regeneration. Telomere shortening is linked to aging and age-related disorders, while excessive telomerase activity may support tissue regeneration or transformation. Some of the functions of telomeres and telomerase may be mediated by its important role in the process of stemness. Active telomerase, and subsequent telomerase-dependent telomere extension, supports stem-cells self-renewal and pluripotency - essential for tissue healing. During cellular reprogramming, differentiated cells are converted into induced pluripotent stem cells (iPSCs), which resemble embryonic stem cells. During iPSC derivation, telomere length is reset, enhancing iPSCs' regenerative potential. During this process, incomplete telomerase activation and telomere extension can lead to genomic instability and/or haltered cell functionality. Understanding the intricate relation of telomeres, telomerase and stemness may be critical when designing novel cell-based therapies targeting degenerative diseases or to unlock strategies to delay aging. Here, we explore the recent bibliography linking these areas, raising awareness of their important when designing novel breakthroughs in health and longevity.
    Keywords:  Cellular reprogramming; ESC; IPSC; Telomerase; Telomeres
    DOI:  https://doi.org/10.1016/j.arr.2025.102773
  12. Front Bioeng Biotechnol. 2025 ;13 1600227
    Extracellular vesicles as vital players in drug delivery: a focus on clinical disease treatment.
    Tiangang Chen, Dan Chen, Wanting Su, Jianlan Liang, Xiangning Liu, Mingxiang Cai.
      Extracellular vesicles (EVs), a diverse population of bilayer lipid-membrane vesicles secreted by cells, have emerged as ideal drug carriers due to their efficient cellular uptake and targeted delivery capabilities. Advancements in medical and bioengineering collaborations have enabled EVs to be engineered for specific marker expression or therapeutic cargo transport, positioning them as a promising modality for treating cancer, neurological disorders, cardiovascular diseases, and beyond. EV-based drug delivery strategies offer distinct advantages, including facilitation of intercellular communication and immune modulation, high biocompatibility and stability, the ability to traverse the blood-brain barrier, and potential synergistic interactions with encapsulated therapeutics to enhance efficacy. This review explores EV isolation and scalable production, emphasizing cost-effective and reproducible manufacturing strategies, cargo-loading methodologies, and therapeutic applications. Additionally, the current landscape of EV-based targeted drug delivery, clinical translation prospects, and prevailing challenges are examined to provide a comprehensive perspective on their potential in drug delivery systems.
    Keywords:  clinical disease treatment; drug delivery systems; extracellular vesicles; separation and loading technology; targeting
    DOI:  https://doi.org/10.3389/fbioe.2025.1600227
  13. Food Funct. 2025 May 27.
    Neuroprotective effect of folic acid by maintaining DNA stability and mitochondrial homeostasis through the ATM/CHK2/P53/PGC-1α pathway in alcohol-exposed mice.
    Nan Zhang, Huaqi Zhang, Xi Liang, Yan Xu, Guifa Wang, Yixian Bai, Zijian Zhou, Yexin Pu, Yifan Zhou, Meilan Xue, Hui Liang.
      Excessive drinking leads to alcoholic brain injury, which is characterized by neuroinflammation, cognitive decline and motor dysfunction. These pathological features are closely related to chromosomal DNA damage and mitochondrial dysfunction. In this study, we aimed to uncover the neuroprotective effects of folic acid (FA) in mice with alcoholic brain injury. C57BL/6J mice were used to establish the murine model of alcoholic brain injury after 12 weeks of alcohol exposure. FA treatment significantly increased the levels of ATP and mitochondrial DNA (mtDNA) copy number in brain tissues of alcohol-exposed mice, and regulated the imbalance of mitochondrial homeostasis in cortical nerve cells. Furthermore, it could reduce the leakage of mtDNA into the cytoplasm, thereby inhibiting the cGAS/STING/NLRP3 inflammatory pathway and alleviating neuroinflammation. In addition, FA treatment reduced DNA damage in peripheral blood lymphocytes and decreased the expression of 53BP1 and γ-H2AX proteins in brain tissues of alcohol-exposed mice. At the molecular level, FA reduced DNA damage by downregulating the ATM/CHK2/P53 pathway and induced the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which further inversely enhanced mitochondrial function through positive feedback. Collectively, this study provides experimental evidence that FA protects DNA stability and mitochondrial homeostasis in alcohol-exposed mice by downregulating the ATM/CHK2/P53/PGC-1α signaling pathway.
    DOI:  https://doi.org/10.1039/d5fo00260e
  14. Biochem J. 2025 May 28. pii: BCJ20253062. [Epub ahead of print]482(11):
    LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.
    Silas A Buck, Laurie H Sanders.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes an autosomal dominant PD that presents very similarly to sporadic PD. Pathogenic mutations in LRRK2 increase its kinase activity, indicated by both LRRK2 autophosphorylation and phosphorylation of its substrates. To date, the mechanism(s) by which elevated LRRK2 kinase activity induces DA neuron degeneration and PD has not been fully elucidated. One potential mechanism may involve the role of LRRK2 on mitochondria, as mitochondrial dysfunction has been linked to PD pathogenesis, and exciting recent evidence has connected PD pathogenic mutations in LRRK2 to multiple aspects of mitochondrial dysfunction associated with the disease. In this review, we discuss the current knowledge implicating LRRK2 in mitochondrial energetics, oxidative stress, genome integrity, fission/fusion, mitophagy, and ion/protein transport in PD, as well as examine the potential role LRRK2 may play in mediating the effects of mitochondrial therapeutics being investigated for treatment of PD.
    Keywords:  LRRK2; Parkinson’s disease; mitochondria; mitochondrial DNA; mitophagy
    DOI:  https://doi.org/10.1042/BCJ20253062
  15. Mol Biol Rep. 2025 May 30. 52(1): 518
    Precision exosome engineering for neurological therapeutics: molecular mechanisms and targeted strategies.
    Deepika Sharma, Shriyansh Srivastava, Malakapogu Ravindra Babu.
      Exosomes are nanoscale extracellular vesicles which are essential for intercellular communication. They have shown great promise in the delivery of drugs into the brain. Recent developments in the use of exosomes to treat neurological conditions are reviewed in this article. Further, it also focuses on molecular and genetic changes that improve the therapeutic effectiveness of these exosomes. Receptor-specific targeting, stimulus-responsive exosomes, and hybrid nanovesicle systems are the three main approaches investigated for facilitating exosome transport across the blood-brain barrier (BBB). Exosomal microRNAs (miRNAs) and other bioactive molecules have important roles in the brain, and it emphasizes their potential as biomarkers, therapeutic agents and modulators of disease pathogenesis. Additionally, it addresses how biomimetic and synthetic exosomes can enhance focused medication delivery to the brain. It also covers how these exosomes are involved in reducing systemic adverse effects while providing important information for next-generation neurotherapeutic strategies.
    Keywords:  Blood-brain barrier targeting; CNS drug delivery; Exosome engineering; MiRNA biomarkers; Molecular mechanisms; Neurological disease therapy
    DOI:  https://doi.org/10.1007/s11033-025-10639-4
  16. Stem Cell Res Ther. 2025 May 28. 16(1): 263
    Extracellular vesicles in age-related diseases: disease pathogenesis, intervention, and biomarker.
    Puan Haliza Lintang Putri, Samira Husen Alamudi, Xuan Dong, Ying Fu.
      Aging is a multifactorial biological process characterized by the irreversible accumulation of molecular damage, leading to an increased risk of age-related diseases. With the global prominent rise in aging populations, elucidating the mechanisms underlying the aging process and developing strategies to combat age-related diseases have become a pressing priority. Extracellular vesicles (EVs) have gained significant attention due to their role in intercellular communication. EVs are known for their ability to deliver biocargoes, such as miRNA, proteins, and lipids, implicating their involvement in disease pathogenesis and intervention. In this review article, we explore the dual role of EVs in age-related diseases: contributing to the pathogenesis of diseases by transferring deleterious molecules, while also offering therapeutic ability by transferring beneficial molecules. We also highlight the application of EVs as biomarkers for early diagnosis of age-related diseases, paving the way for early intervention and precision medicine. Additionally, we discuss how analysing the composition of EVs cargo can provide insights into disease progression. Finally, we address the challenges and future perspectives of EV-based-therapy in clinical translation, including standardization of EVs isolation methods and improving cargo specificity.
    Keywords:  Age-related disease; Biomarker; Extracellular vesicles; Pathogenesis; Therapy
    DOI:  https://doi.org/10.1186/s13287-025-04374-7
  17. Signal Transduct Target Ther. 2025 May 28. 10(1): 167
    Arginase 1 drives mitochondrial cristae remodeling and PANoptosis in ischemia/hypoxia-induced vascular dysfunction.
    Han She, Jie Zheng, Guozhi Zhao, Yunxia Du, Lei Tan, Zhe-Sheng Chen, Yinyu Wu, Yong Li, Yiyan Liu, Yue Sun, Yi Hu, Deyu Zuo, Qingxiang Mao, Liangming Liu, Tao Li.
      Ischemic/hypoxic injury significantly damages vascular function, detrimentally impacting patient outcomes. Changes in mitochondrial structure and function are closely associated with ischemia/hypoxia-induced vascular dysfunction. The mechanism of this process remains elusive. Using rat models of ischemia and hypoxic vascular smooth muscle cells (VSMCs), we combined transmission electron microscopy, super-resolution microscopy, and metabolic analysis to analyze the structure and function change of mitochondrial cristae. Multi-omics approaches revealed arginase 1 (Arg1) upregulation in ischemic VSMCs, confirmed by in vivo and in vitro knockout models showing Arg1's protective effects on mitochondrial cristae, mitochondrial and vascular function, and limited the release of mtDNA. Mechanistically, Arg1 interacting with Mic10 led to mitochondrial cristae remodeling, together with hypoxia-induced VDAC1 lactylation resulting in the opening of MPTP and release of mtDNA of VSMCs. The released mtDNA led to PANoptosis of VSMCs via activation of the cGAS-STING pathway. ChIP-qPCR results demonstrated that lactate-mediated Arg1 up-regulation was due to H3K18la upregulation. VSMCs targeted nano-material PLGA-PEI-siRNA@PM-α-SMA (NP-siArg1) significantly improved vascular dysfunction. This study uncovers a new mechanism of vascular dysfunction following ischemic/hypoxic injury: a damaging positive feedback loop mediated by lactate-regulated Arg1 expression between the nucleus and mitochondria, leading to mitochondria cristae disorder and mtDNA release, culminating in VSMCs PANoptosis. Targeting VSMCs Arg1 inhibition offers a potential therapeutic strategy to alleviate ischemia/hypoxia-induced vascular impairments.
    DOI:  https://doi.org/10.1038/s41392-025-02255-2
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