bims-polgdi 2025-10-05 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–10–05
28 papers selected by
Luca Bolliger, lxBio

Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.
Exploring the connection between the Mitochondrial DNA and the Circadian Rhythm: Insights into Mitochondrial Biogenesis and its Dynamics.
Mitochondrial and photosynthetic therapy: A crucial strategy for remodeling cellular metabolic function.
Interconnectivity of mitochondrial protein biogenesis and quality control.
Mitochondrial transfer/transplantation in lung injury: mechanism, therapeutic potential, and clinical application.
Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.
Health-related quality of life in patients with mitochondrial disease and their carers.
Mitochondria as a Therapeutic Target in Metabolic Disorders.
Association between mitochondrial DNA copy number and the risk of Parkinson's disease: a meta-analysis and Mendelian randomization study.
The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.
How Human Induced Pluripotent Stem Cells-Derived Models can Advance our Understanding of Secretion Mechanisms in Physiological and Pathological Contexts?
Predizione del tipo di mutazione nelle malattie mitocondriali primarie tramite modelli di machine learning applicati a dati clinici non genetici né istologici.
Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.
Neurodegeneration and aging: pathophysiology, diagnosis, and therapeutic targets.
Ophthalmological signs and sensorimotor evaluation in mitochondrial chronic progressive external ophthalmoplegia: a multidisciplinary prospective study.
Epidemiology of progressive intellectual and neurological deterioration in UK children.
Beyond sequence: A physics-informed machine learning framework for predicting DNA mutations.
Therapeutic Approaches Involving Mitochondria in the Treatment of Acute Kidney Injury.
Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.
Mini review: Gene therapy targets for aging-associated diseases.
Mitochondrial Disruption in Viral-Mediated Neuronal Injury: A Mechanistic Perspective.
Targeting High-Density Aromatic Peptides to Cardiolipin Optimizes the Mitochondrial Membrane Potential and Inhibits Oxidative Stress.
Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.
Illuminating Mitochondrial Dynamics: Ultrahigh Labeling Stability Probe for Long-Term SIM Super-Resolution Imaging of Mitochondria.
Improving quality of life in rare diseases using disease-specific, multidisciplinary online interventions on the example of rare X-linked adrenoleukodystrophy: a randomized-controlled trial.
Safety, Costs, and Ethical Issues in Drug Development and Gene Therapy for Rare Diseases.
Precision Medicine: Design of Immune Inert Exosomes for Targeted Gene Delivery.

Neural Regen Res. 2025 Sep 29.

Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.

Tingting Fu, Xinyi Chen, Shuting Zhang, Ying Fu, Lin Huang, Wandi Xiong.

   ABSTRACT: The mitochondrial genomic homeostasis is essential for the function of the oxidative phosphorylation system and cellular homeostasis. Mitochondrial DNA is particularly susceptible to aging-related oxidative stress due to the lack of a histone coat. Disturbances in mitochondrial DNA may contribute to functional decline during the aging process and in neurodegenerative diseases, leading to further impairment of mitochondrial DNA and initiating a vicious cycle. To date, it remains unclear how disturbed mitochondrial DNA is involved in the etiology of pathological aging and neurodegenerative diseases. The purpose of this review is to clarify the crucial roles of mitochondrial DNA homeostasis in the pathogenesis of neurodegenerative diseases. Mitochondrial DNA is distributed within nucleoids and is then transcribed into polycistronic mitochondrial DNA molecules within the mitochondrial granule region. Within the ultrastructure of the mitochondrial nucleoid and granule, a group of essential mitochondrial proteins involved in DNA replication, DNA transcription, RNA translation, RNA surveillance, and RNA degradation plays a crucial role in maintaining mitochondrial structure, genome integrity, and mitochondrial DNA processing. The uniparentally inherited mitochondrial DNA undergoes heritable polyploid variations, which include homoplasmy and heteroplasmy. Accumulating mitochondrial DNA alterations, such as deletions, point mutations, and methylations, occur during the pathogenic processes of neurodegenerative diseases. The increased mitochondrial DNA alterations can be propagated by the rise of deleterious heteroplasmy in neurodegenerative diseases, ultimately resulting in impairment to the oxidative phosphorylation system, biogenesis defects, and cellular metabolic dysfunction. Therefore, developing appropriate gene editing tools to rectify aberrant alterations in mitochondrial DNA and targeting the key proteins involved in maintaining mitochondrial DNA homeostasis can be considered promising therapeutic strategies for neurodegenerative diseases. Although therapeutic strategies targeting mitochondrial DNA in diseases show great potential, challenges related to efficacy and safety require a better understanding of the mechanisms underlying mitochondrial DNA alterations in aging and neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; heteroplamy; mitochondrial DNA; mitochondrial DNA mutation; mitochondrial genome; mitochondrial haplogroup; mitochondrial homeostasis; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00495
Mol Biol Rep. 2025 Sep 30. 52(1): 971

Exploring the connection between the Mitochondrial DNA and the Circadian Rhythm: Insights into Mitochondrial Biogenesis and its Dynamics.

Sowmya Anand, Piyush Jagdish Balgote, Jayanthi Sivaraman.

  Mitochondrial DNA (mtDNA), inherited exclusively from the mother, encodes genes essential for mitochondrial function, including oxidative phosphorylation (OXPHOS), which generates ATP, the cell's primary energy currency. Circadian rhythm is a crucial biological system that refers to the innate biological clock, whose core is in the suprachiasmatic nucleus (SCN) of the brain. This nucleus regulates various physiological processes, such as sleep-wake cycles, hormone secretion, cellular repair, energy homeostasis, and metabolism, on a roughly 24-hour cycle. Peripheral clocks exist in various tissues, including cells sensitive to external stimuli, and are linked to the circadian rhythm due to mitochondria's role in cellular energy metabolism. Core clock genes like Bmal1 and Clock influence mitochondrial biogenesis, oxidative phosphorylation, and mitophagy, while mitochondrial dysfunction disrupts circadian rhythms, leading to metabolic imbalance and disease progression. Emerging research suggests a bidirectional connection between circadian regulation and mitochondrial dynamics. This review focuses on the complex interplay between the circadian rhythm and mitochondrial processes, as regulated by various cellular proteins, transcription factors, ions, receptors, channels, and the mitochondrial genetic machinery, to understand the harmonious coordination between energy metabolism and timing mechanisms needed to optimize cellular processes and maintain physiological balance. The study of this relationship provides new insights into aging, neurodegenerative disorders, and metabolic diseases, potentially guiding future interventions focusing on chronotherapy and mitochondrial targeting.

Keywords:  BMAL1; Circadian rhythm; Mitochondrial DNA (mtDNA); Mitochondrial biogenesis; PGC1-α; SIRT

DOI:  https://doi.org/10.1007/s11033-025-11010-3
Bioeng Transl Med. 2025 Sep;10(5): e70027

Mitochondrial and photosynthetic therapy: A crucial strategy for remodeling cellular metabolic function.

Muhammad Samee Mubarik, Zizhen Zhao, Mehdi Khoshnamvand, De-Sheng Pei, Ailing Fu.

  Extranuclear organelle transplantation, an emerging field in cell biology and bioengineering, presents innovative therapeutic possibilities by transferring organelles such as mitochondria between cells or across species. In living organisms, mitochondria and chloroplasts are closely related to converting substances and energy within cells. Transplantation therapy of mitochondria seeks to rebuild cell metabolic function in diseased or damaged cells and has broad application potential in treating metabolic diseases. The therapies provide a distinctive technology for cellular restoration by targeting energy generation at the organelle level, which will offer new energy resources for animal cells. At present, mitochondrial transplantation therapy has been applied as a novel approach to rescue patients in clinical settings, and chloroplast-based transplantation endows animal cells to utilize light energy (photosynthetic animal cells). In this review, we discuss the exciting development and application prospects of mitochondrial and photosynthetic therapy in biomedicine. The technology of extranuclear transplantation would exert innovative and profound impacts on biological therapy.

Keywords:  cellular new energy resources; chloroplasts; clinical applications; mitochondria

DOI:  https://doi.org/10.1002/btm2.70027
Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00222-1. [Epub ahead of print]

Interconnectivity of mitochondrial protein biogenesis and quality control.

Abi S Ghifari, Carmela Vazquez-Calvo, Andreas Carlström, Martin Ott.

  Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.

Keywords:  mitochondria; proteases; protein import; proteolysis; proteostasis; translation

DOI:  https://doi.org/10.1016/j.tibs.2025.09.004
Front Immunol. 2025 ;16 1668281

Mitochondrial transfer/transplantation in lung injury: mechanism, therapeutic potential, and clinical application.

Ling-Jie Wang, Peng-Fei Guo, SongOu Zhang, Sai Wang, Yi-Zhao Chen, Hong-Wang Yan, Xue-Lin Zhang.

  Lung injury has become a critical clinical problem that urgently requires resolution due to its high morbidity, high mortality, and the limitations of existing treatment methods. Mitochondrial dysfunction, as the core mechanism of lung injury, promotes disease progression through energy metabolism imbalances, oxidative stress, and exacerbated inflammatory responses. Recent studies have found that intercellular mitochondrial transfer, acting as a "transcellular rescue" mechanism, can deliver functional mitochondria through pathways such as tunneling nanotubes, exosome. This process provides a novel approach to replenish energy for damaged cells, regulate inflammation, and repair tissues. In various lung injury models, mitochondrial transfer/transplantation has been shown to improve alveolar-capillary barrier function, reduce collagen deposition, inhibit the release of inflammatory factors, and restore mitochondrial membrane potential. This is particularly evident in conditions such as acute lung injury, pulmonary fibrosis, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, where it shows significant therapeutic potential. The combination of diverse delivery methods and multi-source mitochondria provide a flexible strategy for clinical application. In summary, mitochondrial transfer, as an emerging intercellular communication and rescue mechanism, provides a promising new direction for the precision treatment of lung injury.

Keywords:  ALI; ARDS; COPD; lung injury; mitochondrial transfer

DOI:  https://doi.org/10.3389/fimmu.2025.1668281
Front Cell Neurosci. 2025 ;19 1635775

Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.

Kota Aoshima, Yuya Takagi, Michinori Funato, Yoshiki Kuse, Shinsuke Nakamura, Masamitsu Shimazawa.

  Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone's therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.

Keywords:  Leber’s hereditary optic neuropathy; in vitro disease modeling; mitochondrial disease; mitophagy; retinal organoid

DOI:  https://doi.org/10.3389/fncel.2025.1635775
J Med Genet. 2025 Sep 27. pii: jmg-2025-110896. [Epub ahead of print]

Health-related quality of life in patients with mitochondrial disease and their carers.

Deborah Schofield, Joshua Kraindler, Katherine Lim, Owen Tan, Sameen Haque, Karen Crawley, Sarah West, Adam Percival, Jayamala Parmar, Rupendra Shrestha, Carolyn Sue.

   BACKGROUND: Mitochondrial diseases are a group of rare, chronic disorders with a significant disease burden; however, there is limited knowledge about their effects on the health-related quality of life (HRQoL) of patients and their carers. This study estimates HRQoL among adult patients with mitochondrial diseases and their carers, using the Assessment of Quality-of-Life 8D (AQoL-8D), a validated instrument for measuring health utilities.
METHODS: Ninety-nine adult patients and 24 carers were recruited to the Economic and Psychosocial Impacts of Caring for Families Affected by Mitochondrial Disease (EPIC-MITO) Study, based in New South Wales, Australia.
RESULTS: Adult patients exhibited significantly lower utility values (0.52) compared with age-adjusted and gender-adjusted population norms (0.80; p<0.001). Regression analysis shows that mental health disorders, sleep disorders, financial stress and female gender were associated with reduced HRQoL. Carers also demonstrated AQoL-8D utility values (0.70) significantly below age-adjusted and gender-adjusted population norms (0.81; p=0.01) reflecting the broader burden of mitochondrial diseases on families.
CONCLUSION: With increasing use of genetic testing and genomic sequencing, as well as hope for gene therapies, health utility values will be necessary for economic evaluations of new interventions for mitochondrial disease. This paper shows the substantial impact on HRQoL of mitochondrial disease measured through utilities. The utility values from this paper can inform future economic evaluations for interventions for patients with mitochondrial disease. Further, the paper demonstrated that mitochondrial disease not only reduces the HRQoL of patients but also impacts the HRQoL of carers.

Keywords:  Economics; Neuromuscular Diseases

DOI:  https://doi.org/10.1136/jmg-2025-110896
Mini Rev Med Chem. 2025 Sep 29.

Mitochondria as a Therapeutic Target in Metabolic Disorders.

Youde Cai, Fang Gan, Yunzhi Chen, Qiansong He, Wei Chen, Zhongyong Peng, Ling Gong.

  Mitochondria, commonly termed the 'cellular powerhouse', produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In addition to their role in energy synthesis, mitochondria are crucial for maintaining calcium homeostasis, mediating cellular signaling, regulating cell proliferation and apoptosis, and supporting various other physiological processes. In recent years, mitochondria have gained prominence as a critical target for the treatment of metabolic disorders. Research has demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of metabolic diseases, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular diseases, and endocrine tumors. Consequently, understanding the mechanisms of mitochondrial homeostatic imbalance and developing mitochondria-targeted therapeutics hold promise for innovative treatments of metabolic disorder-related diseases. This article seeks to elucidate recent advancements in the understanding of mitochondrial dysfunction's role in metabolic diseases and offers a comprehensive overview of current therapeutic strategies and approaches for addressing this dysfunction.

Keywords:  Mitochondria; bioenergetics; cellular signaling; metabolism; redox biology; therapeutic target.

DOI:  https://doi.org/10.2174/0113895575403490250917111723
BMC Neurol. 2025 Sep 29. 25(1): 390

Association between mitochondrial DNA copy number and the risk of Parkinson's disease: a meta-analysis and Mendelian randomization study.

Haoyang Zheng, Duo Zhang, Yong Gan, Yuyi Wu, Wei Xiang.



Keywords:  Copy number; Mendelian randomization; Meta-analysis; Mitochondrial DNA; Parkinson's disease

DOI:  https://doi.org/10.1186/s12883-025-04400-4
Neurochem Res. 2025 Oct 04. 50(5): 317

The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.

Vaishali Walecha, Pratibha M Luthra.

  The medical field has spent many years investigating Parkinson's disease (PD), primarily focusing on its main pathogenic feature, dopaminergic neuronal degeneration. Recent studies indicate that PD develops through a complex pathogenic model that links mitochondria to astrocytes and neurons, creating a destructive metabolic loop, a protein aggregation cycle, and oxidative stress. This review examines how mitochondria integrate with astrocytes and neurons in the "triad hypothesis," offering a multifaceted perspective on PD progression. Despite being previously overlooked, we have observed that astrocytic mitochondria play a central role in maintaining neuroprotection and homeostasis. Given that, dysfunctional mitochondria in astrocytes and neurons lead to metabolic failure, compromised glutamate regulation, while also enhancing α-synuclein aggregation, amplifying neuroinflammation, ferroptotic vulnerability and oxidative stress. Henceforth, this report discusses current insights into astrocyte-neuron metabolic coupling, mitochondrial quality control, and lipid redox imbalance, highlighting the role of astrocytic mitochondria as a strong therapeutic strategy. We discuss experimental and translational approaches that aim to restore triad integrity, including mitophagy enhancement, metabolic reprogramming, mitochondrial transfer, and astrocyte-to-neuron reprogramming. By positioning astrocytic mitochondria at the core of PD pathogenesis, this review advocates novel interventions focused on glial metabolic resilience. This integrated approach addresses three major pathogenic axes. It offers promising potential for disease modification and developing effective therapeutics beyond symptomatic dopamine replacement to correct neurodegenerative conditions.

Keywords:  Astrocytic mitochondria; Calcium signalling; Ferroptosis; Mitochondrial dysfunction; Mitochondrial transfer; Neurodegeneration; Neuroinflammation; Neuron-astrocyte interaction; Oxidative stress; Parkinson’s disease (PD); α-Synuclein aggregation

DOI:  https://doi.org/10.1007/s11064-025-04559-9
Biol Cell. 2025 Oct;117(10): e70035

How Human Induced Pluripotent Stem Cells-Derived Models can Advance our Understanding of Secretion Mechanisms in Physiological and Pathological Contexts?

Lou Fourriere, Gaelle Boncompain.

  The molecular architecture of differentiated cells is essential to ensure their specific functions and is supported by membrane trafficking. Defects in the intracellular organization and/or in protein transport contribute to various diseases such as neurological and cardiac diseases. In the recent years, human induced pluripotent stem cells (hiPSCs) have been used to model diseases. Indeed, pluripotent stem cells represent a powerful model to reveal differences in the organization and functional capacity of the secretory trafficking routes responsible for the complex morphology and specialized functions of differentiated cells. This review focuses on the need to conduct investigations of the membrane trafficking mechanisms, their regulation and defects in hiPSCs-derived models, such as neurons and cardiomyocytes, and highlights how powerful these models are to unravel cell-type specific properties. Some studies conducted in hiPSCs-derived models deciphering trafficking defects in pathological conditions are cited as examples. New advances in genome editing, intracellular tools, high-resolution microscopy and fast imaging are essential for studying membrane trafficking in hiPSCs, which will be discussed, as well as their current limitations and areas of improvement. Altogether, this review is intended to pave the way for interconnected comparative studies required to understand the mechanisms regulating protein transport in health and disease.

Keywords:  Golgi apparatus; cardiomyocyte; differentiated cells; hiPSC; membrane trafficking; neuron; protein secretion

DOI:  https://doi.org/10.1111/boc.70035
Recenti Prog Med. 2025 Oct;116(10): 613-614

Predizione del tipo di mutazione nelle malattie mitocondriali primarie tramite modelli di machine learning applicati a dati clinici non genetici né istologici.

Sara Mazzucato, Piervito Lopriore, Francesco Daddoveri, Costanza Lamperti, Valerio Carelli, Olimpia Musumeci, Serenella Servidei, Silvestro Micera, Michelangelo Mancuso, Andrea Bandini.

This study shows that machine learning can accurately distinguish between mitochondrial and nuclear DNA mutations in primary mitochondrial diseases using only non-genetic and non-histological clinical data. While language models underperform in comparison, they show potential as complementary diagnostic tools.

DOI: https://doi.org/10.1701/4573.45801
Exp Gerontol. 2025 Oct 01. pii: S0531-5565(25)00242-6. [Epub ahead of print] 112913

Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.

Ziyue Xie, Xinyu Zhang, Yu Li, Ruigong Zhu.

  Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.

Keywords:  Cellular senescence; Mitochondrial dysfunction; Molecular mechanism; Organelle

DOI:  https://doi.org/10.1016/j.exger.2025.112913
Inflammopharmacology. 2025 Oct 02.

Neurodegeneration and aging: pathophysiology, diagnosis, and therapeutic targets.

Abhay Thakur, Rahul Sharma, Rohit Sharma, Anjana Devi.

  Aging is the greatest risk factor for AD, ALS, PD, FTD, and HD. Neurons in the brain experience many changes as people age, negatively affecting their structure and function. It examines the key processes behind brain aging, such as age-related death of cells, failure of the cells' powerhouses, oxidative stress, incorrect protein shapes, brain inflammation, difficulty in cleaning the brain, and deterioration of blood vessels, and shows their impact on neurodegeneration. With age, there are difficulties in brain-blood circulation, less synaptic change, and fewer new neurons, which make the disease even worse. Informed by human and animal trials, we see that mitochondria work less efficiently in aging brain cells, while oxidative damage to DNA increases doubly to triply. In addition, too much tau, amyloid-β, and α-synuclein building up is tied to declining mental abilities in the elderly. We further evaluate new tests that help with early detection and classification, for example, using biomarkers in cerebrospinal fluid (CSF), blood panels, detailed brain scans, and AI algorithms. It stresses that more aging-specific trials, better integration of multi-omics, and increased interest in research on the gut-brain axis are important. The communication between the aging of the body and the brain is also explained. This article covers the main cellular, molecular, and clinical issues linked to brain aging and highlights important future research areas needed to develop effective treatments for aging people.

Keywords:  Brain aging; Cognitive decline; Mitochondrial dysfunction; Neurodegenerative diseases; Protein aggregation

DOI:  https://doi.org/10.1007/s10787-025-01991-9
BMC Ophthalmol. 2025 Sep 30. 25(1): 520

Ophthalmological signs and sensorimotor evaluation in mitochondrial chronic progressive external ophthalmoplegia: a multidisciplinary prospective study.

Gustavo Savino, Federico Giannuzzi, Valentina Cima, Davide Brando, Claudia Fossataro, Serenella Servidei, Maria Cristina Savastano, Guido Primiano.

   BACKGROUND: Primary mitochondrial myopathies (PMM) are disorders that involve defects in oxidative phosphorylation (OXPHOS) and impair mainly, but not exclusively, skeletal muscles. Progressive external ophthalmoplegia (PEO), eyelid ptosis, exercise intolerance and skeletal muscle weakness are the most common symptoms of myopathy in mitochondrial diseases, impairing ocular motility and visual abilities.
METHODS: Twenty-five patients underwent complete ophthalmological examination, including best corrected visual acuity (BCVA), ptosis evaluation, dilated fundus examination, and orthoptic examinations, including cover and cover-uncover test, ocular motility analysis, fusional amplitude (FA) vergence for near and for distance, Bagolini striated glasses test (BSGs) and Worth four-dot lights test (WFDT).
RESULTS: Mean age at evaluation was of 47,2 ± 16.07 years. Twenty-two (88%) out of 25 patients had a PEO disease, while three (12%) of them a Kearn-Sayre syndrome (KSS). Ocular motility impairment was found in 92% of the population. Fifteen patients (60%) didn't complain of double vision in casual seeing condition despite some of them showed manifest strabismus both at far (53%) and at near (60%). A compensation sensorial mechanism, mainly suppression, was detected through sensory tests. The near and distance fusional capabilities in convergence and in divergence (CFAs and DFAs) were absent in 68 and 72% of the whole sample respectively. PEO manifests at an older age than KSS (p = 0.003), diplopia does not correlate with disease duration (p = 0.06) and no predictive factors for diplopia can be identified.
CONCLUSIONS: A significant number of patients not complaining of double vision in casual seeing state showed manifest or latent/manifest strabismus at FAoD and NAoD. Most strabismic patients had a monocular suppression or alternate diplopia and suppression at sensory tests (BSGs and WFDT). The pathophysiology of these sensory adaptations in an adult visual system can only be hypothesized. A multidisciplinary approach is essential for proper clinical management and to analyze an understand clinical features pathogenesis.

Keywords:  Mitochondrial diseases; Mitochondrial diseases diplopia; Mitochondrial diseases eyelid ptosis; Mitochondrial diseases strabismus; Neurological strabismus; Ophthalmological abnormalities in mitochondrial diseases

DOI:  https://doi.org/10.1186/s12886-025-04194-6
Dev Med Child Neurol. 2025 Sep 29.

Epidemiology of progressive intellectual and neurological deterioration in UK children.

Christopher M Verity, Polly J Maunder, Anne Marie Winstone, Suvankar Pal.

AIM: To study the neurodegenerative diseases that cause progressive intellectual and neurological deterioration (PIND) in children in the UK.
METHOD: This active prospective epidemiological study asked UK paediatricians to notify all childhood cases of PIND via the British Paediatric Surveillance Unit. Clinical data were obtained using a questionnaire or via a site visit. An independent PIND study Expert Group classified the cases.
RESULTS: Between May 1997 and April 2024 (27 years), 2373 children with PIND were identified who had an underlying diagnosis to explain their deterioration. There were six cases of variant Creutzfeldt-Jakob disease plus 2367 children (1265 males, 1102 females) with other diseases. The lifetime risk of having a diagnosed disease causing PIND was 0.1 in 1000 live births. Asian British children made up 28.6% of the 2183 cases with known ethnicity. Excluding variant Creutzfeldt-Jakob disease, diagnosed children had 259 diseases, identified before death in 99% of children (only 39 were known to have had postmortems). Increasingly, diagnosis was made using genetic studies. Sixty-one per cent (157 of 259) of the diseases were inborn errors of metabolism, affecting 78% of diagnosed children. There were 43 lysosomal diseases.
INTERPRETATION: This unique epidemiological study of many rare childhood neurodegenerative diseases provides valuable practical information about the presentation, clinical features, and inheritance of these complex disorders.

DOI: https://doi.org/10.1111/dmcn.70008
Comput Struct Biotechnol J. 2025 ;27 3985-3992

Beyond sequence: A physics-informed machine learning framework for predicting DNA mutations.

M Suárez-Villagrán, N Mitsakos, J H Miller.

  This paper investigates how incorporating information from a quantum tight-binding model can enhance the predictive capability of machine learning models for identifying mutation-prone sites in mitochondrial DNA (mtDNA). We employ quantum Hamiltonian techniques and machine learning to explore mutations in mitochondrial DNA's hypervariable segment 1 (HVR1). This region is recognized for its high variability and is frequently used in genealogical DNA testing and research. Our approach considers the local energy associated with each base pair, as well as the interactions among electrons within the DNA chain. For this study, we analyze data from the Mitomap database. Our findings suggest that both the local ionization energies and the context-dependent nature of the base pairs significantly influence the locations of mutations within DNA. Specifically, our machine learning model can extract valuable insights when examining homopolymeric runs-regions where a single base pair repeats multiple times within a sequence.

Keywords:  DNA; Homopolymeric runs; Hypervariable region 1; Machine learning; Mitochondrial DNA; Mutations; Quantum biology

DOI:  https://doi.org/10.1016/j.csbj.2025.08.033
Semin Nephrol. 2025 Sep 29. pii: S0270-9295(25)00154-8. [Epub ahead of print] 151676

Therapeutic Approaches Involving Mitochondria in the Treatment of Acute Kidney Injury.

Prisha S Patel, Navjot S Pabla, Amandeep Bajwa.

  Acute kidney injury (AKI) continues to pose a significant clinical burden, characterized by high morbidity and mortality rates. Emerging evidence has established mitochondrial dysfunction as a central driver in the pathogenesis of AKI, encompassing deficits in bioenergetics, excessive production of reactive oxygen species, and disruption of mitochondrial dynamics. Therapeutic interventions targeting mitochondrial pathways-most notably peptide-based agents such as SS-31-have demonstrated promising results in preclinical models. Recent discoveries have identified phospholipid scramblase 3 (PLSCR3) as an essential mediator of SS-31's mitochondrial protective effects, positioning it as a novel therapeutic target. This review synthesizes current mitochondrial-directed approaches for AKI, with a particular emphasis on the mechanistic role of PLSCR3 in maintaining mitochondrial homeostasis and injury responses. Despite encouraging data, mitochondrial therapies face several translational hurdles, including limited bioavailability, challenges in establishing effective dosing regimens, incomplete mechanistic understanding, and variability in efficacy across different experimental models. Moreover, concerns regarding cost, accessibility, and long-term safety remain unresolved, contributing to inconsistent outcomes in clinical trials. Herein we evaluate the emerging role of PLSCR3 as a potentially druggable mitochondrial target, supported by recent genetic, biochemical, and in vivo evidence, and discuss translational strategies that may bridge the gap between experimental promise and clinical application. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Keywords:  SS-31 (Elamipretide); acute kidney injury; cardiolipin; mitochondria-targeted antioxidants; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; phospholipid scramblase 3 (PLSCR3); reactive oxygen species

DOI:  https://doi.org/10.1016/j.semnephrol.2025.151676
Pharmacol Res. 2025 Sep 25. pii: S1043-6618(25)00398-6. [Epub ahead of print]221 107973

Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.

Bernard Ribalet, Scott John, Madeleine G Milner, Leia Salongo, Ambre M Bertholet.

  In mitochondria, the energy derived from the proton gradient across the mitochondrial inner membrane (IMM) is converted into ATP and heat. For these conversions to occur, H+ is pumped out of the matrix via the electron transport chain (ETC) and then re-enters either via the ATP synthase to produce ATP or via the ADP/ATP carrier (AAC) to release heat. Due to its dual functions of ADP/ATP exchange and H+ transport, AAC may be considered a major regulator of the energy distribution of mitochondria between ATP synthesis and thermogenesis. Using real-time imaging of pH with a fluorescent pH probe targeted to the mitochondrial matrix, we investigated in a myoblast cell model how H+ fluxes across the IMM are regulated by AAC and the ATP synthase. Our data show that activation of AAC-dependent H+ transport by the mitochondrial uncoupler BAM15 causes an acidification of the matrix followed by a re-alkalization phase due to the reversed activity of the ATP synthase. Similar re-alkalization and reversal of ATP synthase activity were observed after acidification caused by inhibition of the electron transport chain. Lastly, the discovery that strong protonophoric activity independent of AAC suppresses the re-alkalization phase and consequently the reverse action of the ATP synthase, suggests the need for strict control of the H+ flux through the IMM by AAC. Thus, real-time imaging of matrix pH reveals a functional interaction between AAC and the ATP synthase for the control of H+ fluxes across the IMM.

Keywords:  ADP/ATP carrier; ATP synthase; BAM15; Electron transport chain; FCCP; Mitochondria; PH sensor; Proton transport; Uncoupling protein

DOI:  https://doi.org/10.1016/j.phrs.2025.107973
Biochem Biophys Res Commun. 2025 Sep 25. pii: S0006-291X(25)01424-X. [Epub ahead of print]785 152708

Mini review: Gene therapy targets for aging-associated diseases.

Shchukina Elza, Eremin Ilya, Mazunin Ilya, Moskalev Alexey.

  Contemporary gene therapy approaches represent a promising avenue for intervening in aging mechanisms and treating age-associated diseases. This review analyzes findings from preclinical and clinical studies of gene therapeutic strategies targeting age-related pathologies, including neurodegenerative, cardiovascular, metabolic, and ophthalmological disorders. We examine how specific aging mechanisms - DNA damage accumulation, telomere attrition, mitochondrial dysfunction, and chronic inflammation - can be addressed through targeted gene therapies. Key therapeutic targets include telomerase reactivation through TERT overexpression for genomic stability, KLOTHO supplementation for anti-inflammatory effects, metabolic regulation via SIRT family genes and FoxO3, and protein homeostasis modulation through APOE variants. Additional approaches encompass growth differentiation factors such as GDF11 for tissue regeneration, senolytic strategies for eliminating senescent cells, and epigenetic reprogramming techniques for tissue rejuvenation. Rather than characterizing these as universal 'longevity genes,' we emphasize their context-dependent effects, disease-specific applications, and associated benefit-risk profiles. Current methodological limitations and promising directions for developing personalized gene therapy interventions targeting the biological processes underlying aging are discussed.

Keywords:  Age-related diseases; Aging mechanisms; Cellular senescence; Delivery systems; Gene therapy

DOI:  https://doi.org/10.1016/j.bbrc.2025.152708
J Med Virol. 2025 Oct;97(10): e70626

Mitochondrial Disruption in Viral-Mediated Neuronal Injury: A Mechanistic Perspective.

Shuqi Shi, Mingzhu Zhai, Benqing Wu, Wuping Sun.

  Neuronal injury is a major pathological issue that cannot be ignored during viral infections. Mitochondria, the energy factories of the cell, play a unique role in this scenario and are severely impacted when viruses infect host cells. Viruses invade and infect cells via specific mechanisms, causing changes in cellular structure and function. These changes not only directly affect mitochondria but also disrupt their normal function through indirect pathways. This paper reviews the mechanisms of mitochondrial damage induced by infections with SARS-CoV-2, herpesviruses, human immunodeficiency virus (HIV), and hepatitis C virus (HCV), providing new insights and strategies for preventing and treating neuronal injury.

Keywords:  HCV; HIV; HSV; Neuron injury; SARS‐CoV‐2; VZV; mitochondria

DOI:  https://doi.org/10.1002/jmv.70626
FASEB Bioadv. 2025 Oct;7(10): e70052

Targeting High-Density Aromatic Peptides to Cardiolipin Optimizes the Mitochondrial Membrane Potential and Inhibits Oxidative Stress.

Alexander Birk, Sara Arain, Daniele Musumeci, Virginia Garcia-Marin, Margaret A MacNeil.

  Cardiolipin (CL), a mitochondria-specific non-bilayer phospholipid, plays an essential role in the assembly and structural dynamics of the respiratory chain, affecting the membrane morphology and functional activity of inner mitochondria membrane (IMM)-embedded proteins. CL forms CL-rich domains on the IMM where negative curvature is required to increase the stability of cristae. However, CL constantly transitions between lamellar bilayer and non-bilayer phases, such as inverted CL hexagonal phases and inverted CL micelles. Non-bilayer phases of CL promote mitochondrial fission and fragmentation, transition of CL to the outer mitochondrial membrane (OMM), and mitophagy. In addition, non-bilayer phases of CL can increase proton leakage, which leads to mitochondrial depolarization and decreased mitochondrial ATP synthesis. Thus, therapeutic applications for minimizing non-bilayer CL phases should be able to optimize mitochondrial stability during various stresses. We have developed a novel, high-density aromatic peptide (HDAP2) that targets CL and enhances the stability of CL within the lipid core of bilayers in CL-POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) liposomes. We also demonstrated that HDAP2 interacts with inverted CL micelles, forming HDAP2-CL micelles. This suggests that HDAP2 interacts with the non-bilayer phase of CL, thereby stabilizing CL in the bilayer configuration. Scanning electron microscopy confirmed that HDAP2 assembles into spherical micelles approximately 1-3 μm in diameter. We have also demonstrated that this novel, water-soluble peptide is cell-permeable and targets mitochondria without causing cell toxicity. Furthermore, we used a well-known mitochondrial toxicity model of serum starvation to demonstrate that HDAP2 significantly promoted cell survival in a dose-dependent manner in mitochondria-dependent Madin-Darby bovine kidney (MDBK) cells. Importantly, HDAP2 preserved mitochondrial membrane potential and mitigated oxidative stress during serum deprivation. These protective effects suggest that, through its unique mechanism of action, HDAP2 can enhance cellular homeostasis, which would offer broad therapeutic potential for the prevention, recovery, and reversal of many acute and chronic disease conditions, including neurodegeneration, ischemia-reperfusion injury, and inflammation.

Keywords:  cardiolipin; cell survival; mitochondria; mitochondrial potential; oxidative stress

DOI:  https://doi.org/10.1096/fba.2024-00061
Nat Commun. 2025 Sep 30. 16(1): 8685

Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.

Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.

Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

DOI: https://doi.org/10.1038/s41467-025-63813-4
Front Cell Dev Biol. 2025 ;13 1646072

Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.

Qingzhi Ran, Chen Gao, Chunrong Xiang, Xuanhui He, Yongkang Zhang, Yin Zhang, Hengwen Chen.

  Mitochondrial fission process 1 (MTFP1) has emerged as a central regulator of mitochondrial dynamics, playing indispensable roles in maintaining organellar integrity, bioenergetic homeostasis, and stress adaptation - particularly in high-energy-demand tissues such as cardiac and skeletal muscle. Mounting evidence implicates MTFP1 dysfunction in the pathogenesis of diverse diseases including cardiovascular disorders, myopathies, and cancer. Beyond its canonical role in mediating mitochondrial fusion-fission balance, recent studies have unveiled MTFP1's multifaceted involvement in calcium signaling modulation, ROS metabolism, and mitochondria-ER communication networks, substantially expanding its functional repertoire in cellular physiology. The protein's pleiotropic effects stem from its ability to integrate metabolic status with organelle dynamics and quality control mechanisms. Particularly noteworthy is MTFP1's cell-type-specific regulation of the ROS-calcium axis, which appears critical for its differential impacts in disease states. These discoveries position MTFP1 as both a mechanistic linchpin connecting mitochondrial dynamics to cellular homeostasis and a promising but challenging therapeutic target requiring precise contextual modulation. Current research frontiers focus on elucidating tissue-specific regulatory mechanisms of MTFP1 activity, developing microenvironment-sensitive targeting strategies, and exploring its potential as a biomarker for mitochondrial dysfunction-related pathologies. This evolving understanding of MTFP1's integrative functions opens new avenues for developing precision therapies targeting mitochondrial dynamics in energy-metabolism-linked diseases.

Keywords:  Mitochondria; Tumor; autophagy; cardiovascular disease; drug Targets; inflammation; mitochondrial fission process 1 protein

DOI:  https://doi.org/10.3389/fcell.2025.1646072
ACS Cent Sci. 2025 Sep 24. 11(9): 1700-1714

Illuminating Mitochondrial Dynamics: Ultrahigh Labeling Stability Probe for Long-Term SIM Super-Resolution Imaging of Mitochondria.

Xiangpeng Lin, Xuelei Pang, Yue Huang, Xinxin Duan, Yunfei Wei, Ning Jing, Meng Zhang, Yu-Hui Zhang.

Delineating intricate mitochondrial dynamic changes over extended time scales through combined fluorescent probes and super-resolution microscopy is pivotal for deciphering the pathogenesis of mitochondrial-related diseases. However, a major challenge lies in the scarcity of probes that simultaneously exhibit robust labeling stability, exceptional photostability, and minimal cytotoxicity. Herein, rational design and screening yielded a novel covalent mitochondrial probe, HZ Mito Red. Due to its exceptional covalent labeling efficiency, HZ Mito Red exhibits superior mitochondrial labeling stability, with a 10-fold improvement compared to Mito Tracker Red (MTR). Furthermore, it exhibits remarkable photostability, retaining over 80% fluorescence after 300 SIM images, and negligible phototoxicity, preserving mitochondrial integrity even after 400 SIM images of continuous imaging. These advantageous properties facilitated the pioneering of high signal-to-noise, long-term dynamic SIM super-resolution imaging of mitochondria during ferroptosis, apoptosis, and autophagy, achieving unprecedented detailed delineation of mitochondrial morphology. Additionally, engineered for multichannel mitochondrial imaging, HZ Mito Deep Red mirrors the exceptional labeling stability of HZ Mito Red, achieving near-phototoxicity-free dynamic tracking with 60% fluorescence retention after 300 SIM images. Significantly, both HZ Mito Red and HZ Mito Deep Red are compatible with cell immunofluorescence staining. This study provides a robust and versatile tool for the in-depth analysis of mitochondrial dynamics in disease states.

DOI: https://doi.org/10.1021/acscentsci.5c00695
Ther Adv Neurol Disord. 2025 ;18 17562864251376109

Improving quality of life in rare diseases using disease-specific, multidisciplinary online interventions on the example of rare X-linked adrenoleukodystrophy: a randomized-controlled trial.

Lisa Schäfer, Astrid Unterlauft, Brit Froebrich-Andreß, Carolin Wollny, Marie Rößler, Ronja Fischer, Carla Bähr, Julia Lier, Daniel T Wasmus, Christa-Caroline Bergner, Wolfgang Köhler.

   Background: People with rare diseases (RDs) often require intensive multidisciplinary care in disease-specific centers of excellence (CoE). However, access is limited for most patients living remotely. X-linked adrenoleukodystrophy (X-ALD) is a genetic RD leading to demyelination of the central and peripheral nervous system.
Objectives: This randomized-controlled trial tested the feasibility, acceptance, and effectiveness of a multidisciplinary online intervention provided by a CoE on the quality of life (QoL) and well-being of symptomatic women with X-ALD.
Design: Single-center, randomized-controlled clinical trial involving 68 German-speaking women with symptomatic X-ALD.
Methods: Participants were randomized into an experimental group (EG, n = 34) receiving 12-month online intervention SMART-ALD and a waiting-list control group (WL-CG, n = 34) receiving 6-month SMART-ALD after a 6-month waiting period. Within SMART-ALD, participants were offered regular web-based neurological, social, psychological, and nutritional counseling and fitness training provided by the Leukodystrophy Outpatient Clinic at Leipzig, Germany. Group, time, and interaction effects on primary (self-reported QoL) and secondary (physical and mental health) outcomes after 6-month SMART-ALD were tested by repeated measures ANOVAs.
Results: One WL-CG participant dropped out after the waiting period and was excluded from the final analysis. Significant QoL improvements in the EG versus WL-CG were found on self-reported mental health (mean difference (MD): 5.4, 95% confidence interval (CI) (2.8, 13.6), p = 0.020, η2 = 0.08) and vitality (MD: 8.8, 95% CI (0.1, 17.4), p = 0.002, η2 = 0.14). Further significant interaction effects emerged for improved knowledge about nutrition (MD: 0.4, 95% CI (-0.7, 1.4), p = 0.002, η2 = 0.15), socio-medical benefits (MD: 1.8, 95% CI (0.5, 3.0), p = 0.033, η2 = 0.07), and intense physical activity (MD: 2.2, 95% CI (-3.9, 8.4), p = 0.024, η2 = 0.10).
Conclusion: The study shows that easily accessible, multidisciplinary online interventions provided by the CoE have the potential to improve the QoL in people with RDs by providing regular access to specialized care.
Trial registration: This study was registered on ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT04687007).

Keywords:  adrenoleukodystrophy (X-ALD); multidisciplinary online intervention; myeloneuropathy; quality of life (QoL); rare diseases (RDs); symptomatic women

DOI:  https://doi.org/10.1177/17562864251376109
Continuum (Minneap Minn). 2025 Oct;31(5): 1486-1500

Safety, Costs, and Ethical Issues in Drug Development and Gene Therapy for Rare Diseases.

Nicholas Johnson, A Gordon Smith.

Scientific advances have provided the ability to modify the course of genetic diseases through the use of genetic therapies. These therapies include RNA-based approaches that either reduce the translation of a toxic protein or skip exons to produce a more functional protein. Adeno-associated virus-based delivery of missing gene products has also been demonstrated to modify the overall course of diseases. The science has advanced beyond the ability of our health system infrastructure to keep pace. Challenges with drug pricing, manufacturing, regulatory pathways, and patient access remain. The ability to overcome these challenges will directly influence the ability to deliver these highly promising therapies to patients waiting for them.

DOI: https://doi.org/10.1212/cont.0000000000001619
Curr Gene Ther. 2025 09 30.

Precision Medicine: Design of Immune Inert Exosomes for Targeted Gene Delivery.

Fawzy A Saad.

  Exosomes represent the smallest size among extracellular vesicles, which also include apoptotic bodies and microvesicles. Exosomes are natural nanocarriers that play a key role in intracellular communication, consisting of a hydrophobic lipid bilayer membrane and a hydrophilic core. The membrane compositions of exosomes are similar to those of the parent cells from which they are generated. Normally, the exosome membrane contains diacylglycerol, ceramide, cholesterol, and various surface proteins, including tetraspanins and Lamb2. Almost all cell types secrete exosomes into body fluids through exocytosis, including stem cells, epithelial cells, endothelial cells, immune cells, tumor cells, neurons, mast cells, oligodendrocytes, reticulocytes, macrophages, platelets, and astrocytes. Every cell type expresses a distinct type of exosomes carrying various bioactive molecules. Exosomes are major transporters of bioactive cargo, including enzymes, receptors, growth and transcription factors, nucleic acids, lipids, and other metabolites, which strongly affect the physiology of recipient cells. Exosomes are not only potent drug and gene delivery nanocarriers, but also have potential for disease diagnosis, tissue regeneration, and immunomodulation. Exosomes are present in various body fluids, including plasma, serum, saliva, milk, nasal secretions, urine, amniotic fluid, semen, and cerebrospinal fluid, among others. Stem cell-made exosomes are potential natural therapeutics, which is due to their rejuvenating cargo and ability to cross biological barriers. However, natural exosomes' inefficient cargo transfer and short lifespan in the bloodstream have hindered their progress in therapeutic interventions. Genetic engineering of the parent cell allows for loading specific therapeutic cargo into the lumen of newly generated exosomes and/or displaying certain homing peptides or ligands at their surface, leading to extension of their lifespan and precise delivery to specific organs or tissues. This minireview explores the creation of designer exosomes through parent cell engineering and their utilization for guiding the delivery of tailored therapeutic cargo to specific organs while evading the host's innate immune response.

Keywords:  Designer exosomes; extracellular vesicles; invisible exosomes; smart exosomes.; tailored cargos

DOI:  https://doi.org/10.2174/0115665232409032250908114520