bims-polgdi 2025-07-13 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–07–13
27 papers selected by
Luca Bolliger, lxBio

The Role of Estrogen in Mitochondrial Disease.
Mitochondrial topoisomerases, nucleoid architecture and mtDNA repair in human disease.
Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies.
Extremely low-frequency electromagnetic field (ELF-EMF) enhances mitochondrial energy production in NARP cybrids.
Mitochondrial curation for the next generation.
Unlocking the potential of mitochondrial transplantation: overcoming challenges and paving the way for routine therapeutic application.
Organelles share the load.
Understanding the mechanisms of mitochondrial rewiring during viral infections.
A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.
Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies.
A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions.
Mitochondrion in Pulmonary Disease: Small Organelle but Big Function.
Exosomes as Next-Generation Carriers for Brain Drug Delivery: Engineering, Formulation, Characterization, and Neurotherapeutic Applications.
MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
Crosstalk between mitochondrial quality control and novel programmed cell death in pulmonary diseases.
Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.
Shape, membrane morphology, and morphodynamic response of metabolically active human mitochondria revealed by scanning ion conductance microscopy.
Mitochondrial Delivery of Molecular Drugs Bypassing Endocytosis.
Molecular Mechanisms of Extracellular Vesicle Biogenesis and Their Impact on the Design of Custom EVs.
Exosomes as Future Therapeutic Tools and Targets for Corneal Diseases.
Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration.
Recent Advances in the Application of Mitochondria-targeted Fluorescent Probes.
The potential role of extracellular vesicles as hepatic diagnostic and therapeutic tools: Can the dream come true?
The role of ginseng in aging: Insights into regulatory T cells activation and mitochondrial regulation.
Induced Pluripotent Stem Cells for the Treatment of Lysosomal Storage Disorders.
Research progress on mRNA drug delivery strategies in the nervous system.
Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.

Cell Mol Neurobiol. 2025 Jul 11. 45(1): 68

The Role of Estrogen in Mitochondrial Disease.

Xi Huang, Cun-Hui Pan, Fei Yin, Jing Peng, Li Yang.

  This review aims to investigate the potential role of estrogen in various mitochondrial diseases, such as Leber's Hereditary Optic Neuropathy and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes, focusing on its effects on aging, oxidative stress, mitochondrial biogenesis, and mitophagy. Mitochondrial diseases have become important in modern medical research due to their complex genetic background and diverse clinical manifestations. Studies in recent years have shown that estrogen plays an essential role in physiological regulation and may also affect the health status of cells by regulating mitochondrial function, which in turn affects the occurrence and development of diseases. However, there is still a lack of systematic review of estrogen's specific mechanisms and roles in these diseases. This review will synthesize the relevant literature to explore the association between estrogen and mitochondrial diseases and its possible therapeutic prospects, aiming to provide a theoretical basis and reference for future research.

Keywords:  Aging; Estrogen; Mitochondrial biogenesis; Mitochondrial disease; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1007/s10571-025-01592-8
J Cell Sci. 2025 Jul 01. pii: jcs263638. [Epub ahead of print]138(13):

Mitochondrial topoisomerases, nucleoid architecture and mtDNA repair in human disease.

Sangheeta Bhattacharjee, Benu Brata Das.

  DNA topoisomerases are essential for maintaining DNA topology, gene expression and the accurate transmission of genetic information. Mitochondria possess circular DNA (mtDNA), which, unlike nuclear chromosomes, lacks protective histones and exists in nucleoprotein complexes called nucleoids, which are vital for mtDNA stability. Although the mitochondrial genome encodes essential genes involved in ATP production via oxidative phosphorylation, it does not encode crucial mtDNA maintenance genes and depends entirely on nuclear-encoded proteins for mtDNA maintenance. These include nuclear-encoded topoisomerases (i.e. Top1mt, Top2α, Top2β and Top3α), which alleviate topological stress during mtDNA transcription and replication, and mitochondrial transcription factor A (TFAM), are crucial for ensuring proper nucleoid structure and mtDNA packaging. Furthermore, tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) participate in the repair of mtDNA damage associated with trapped topoisomerase-mtDNA complexes, which can compromise mtDNA integrity and contribute to neurodegeneration, cancer and premature aging. Drugs that stabilize these protein-DNA adducts (PDAs) to induce mtDNA damage and mitochondrial dysfunction are promising new strategies for cancer therapy. This Review explores the essential roles of mitochondrial topoisomerases, overviews mechanisms involved in mtDNA repair and discusses how mitochondrial fission and mitophagy are employed as a survival strategy for clearing damaged mtDNA.

Keywords:  DNA repair; Mitochondria; Mitochondrial DNA; Neurological diseases; TDP1; TFAM; Topoisomerase 1

DOI:  https://doi.org/10.1242/jcs.263638
Front Aging. 2025 ;6 1585508

Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies.

Dalia M Miller, Stephen L Archer, Kimberly J Dunham-Snary.

  Mitochondrial-driven diseases encompass a diverse group of single-gene and complex disorders, all linked to mitochondrial dysfunction, with significant impacts on human health. While there are rare mitochondrial diseases in which the primary defect resides in mutations in mitochondrial DNA, it is increasingly clear that acquired mitochondrial dysfunction, both genetically- and epigenetically-mediated, complicates common complex diseases, including diabetes, cardiovascular disease and ischemia reperfusion injury, cancer, pulmonary hypertension, and neurodegenerative diseases. It is also recognized that mitochondrial abnormalities not only act by altering metabolism but, through effects on mitochondrial dynamics, can regulate numerous cellular processes including intracellular calcium handling, cell proliferation, apoptosis and quality control. This review examines the crucial role of preclinical models in advancing our understanding of mitochondrial genetic contributions to these conditions. It follows the evolution of models of mitochondrial-driven diseases, from earlier in vitro and in vivo systems to the use of more innovative approaches, such as CRISPR-based gene editing and mitochondrial replacement therapies. By assessing both the strengths and limitations of these models, we highlight their contributions to uncovering disease mechanisms, identifying therapeutic targets, and facilitating novel discoveries. Challenges in translating preclinical findings into clinical applications are also addressed, along with strategies to enhance the accuracy and relevance of these models. This review outlines the current state of the field, the future trajectory of mitochondrial disease modeling, and its potential impact on patient care.

Keywords:  CRISPR/Cas9; conplastic mouse; cybrid; mitochondrial replacement therapy (MRT); mitochondrial-driven diseases; mitochondrial-nuclear eXchange (MNX) mice; organoid; preclinical models

DOI:  https://doi.org/10.3389/fragi.2025.1585508
Sci Rep. 2025 Jul 08. 15(1): 24369

Extremely low-frequency electromagnetic field (ELF-EMF) enhances mitochondrial energy production in NARP cybrids.

Mikako Ito, Zhizhou Huang, Kosaku Nomura, Masaki Teranishi, Fei Zhao, Hiroyuki Mino, Makoto Yoneda, Masashi Tanaka, Kinji Ohno.

  A mutation (m.8993T > G) in MT-ATP6 in mitochondrial DNA (mtDNA) causes the neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome by impairing mitochondrial energy production. Extremely low-frequency electromagnetic field (ELF-EMF) suppresses mitochondrial oxidative phosphorylation (OXPHOS) Complex II and induces mitohormetic activation of mitochondrial OXPHOS activities. We examined the effects of ELF-EMF on normal cybrids carrying 100% wild-type mtDNA (2SA cybrids) and NARP cybrids carrying 40% wild-type and 60% mutant mtDNA (NARP3-2 cybrids). We found that ELF-EMF had no effect on the copy number of mtDNA either in 2SA or NARP3-2 cybrids, or the ratio of wild-type-to-mutant mtDNA in NARP3-2 cybrids. Instead, ELF-EMF increased the transcription of mtDNA and the transcription ratio of wild-type-to-mutant mtDNA in NARP3-2 cybrids. In addition, ELF-EMF increased the expression of mitochondrial OXPHOS proteins and the mitochondrial OXPHOS Complex V activity in NARP3-2 cybrids. ELF-EMF upregulated fission-promoting phosphorylation of DRP1, as well as the expression of fusion-promoting MFN1 and MFN2, in NARP3-2 cybrids. ELF-EMF also increased ATP production estimated by oxygen consumption rates (OCR) and by a biochemical assay in NARP3-2 cybrids. Hormetic activation of mitochondria by ELF-EMF is likely to be effective to ameliorate defective mitochondrial energy production in NARP and other mitochondrial diseases.

Keywords:  And mitohormesis; Extremely low-frequency electromagnetic field (ELF-EMF); Mitochondrial DNA; Mitochondrial biogenesis; Mitophagy; Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome

DOI:  https://doi.org/10.1038/s41598-025-10536-7
Curr Opin Genet Dev. 2025 Jul 04. pii: S0959-437X(25)00068-1. [Epub ahead of print]93 102376

Mitochondrial curation for the next generation.

Gregory C Gundberg, Jeremy Nance.

The mitochondrial genome (mtDNA) can accumulate deleterious mutations that lead to disease. Animals have evolved strategies to eliminate mtDNA mutations in the maternal germ line, increasing the likelihood that their progeny inherit healthy mitochondria. Here, we provide an overview of mitochondrial quality control in the germ line, focusing on recent findings in mammals, Drosophila, and C. elegans. We discuss three strategies for quality control: elimination of sperm mtDNA, which prevents transmission of paternal mtDNA to progeny; the genetic bottleneck, which reduces the effective number of mtDNAs in germ cells, potentially exposing mutations to selection; and purifying selection, which selects for healthier mtDNAs. Finally, we discuss outstanding questions in the field and technical advances needed to address them.

DOI: https://doi.org/10.1016/j.gde.2025.102376
Cytotechnology. 2025 Aug;77(4): 139

Unlocking the potential of mitochondrial transplantation: overcoming challenges and paving the way for routine therapeutic application.

Amaneh Mohammadi Roushandeh, Kazuo Tomita, Yoshikazu Kuwahara, Nima Najafi-Ghalehlou, Tomoaki Sato, Mehryar Habibi Roudkenar.

  Mitochondrial medicine has shown great promise as a therapeutic approach for treating currently incurable diseases. Preclinical studies highlight its safety and efficacy, but significant challenges remain in translating these therapies from bench to bedside. Key unresolved issues include understanding the mechanisms behind the reparative potential of transplanted mitochondria, such as their viability and functionality in an extracellular environment, especially under elevated calcium ion concentrations. Additionally, challenges related to mitochondrial sourcing, delivery methods, and ethical considerations need to be addressed for broader clinical adoption. This review analyses these challenges and explores strategies to overcome them, including refining mitochondrial sourcing, delivery techniques, and storage solutions. We also emphasise the need for rigorous ethical guidelines and regulatory frameworks to ensure safe and global implementation, paving the way for mitochondrial medicine's broader clinical use.

Keywords:  Mitochondrial biology; Mitochondrial dysfunction; Mitochondrial medicine; Mitochondrial transplantation; Regenerative medicine

DOI:  https://doi.org/10.1007/s10616-025-00805-8
Science. 2025 Jul 10. 389(6756): 130-131

Organelles share the load.

Marc Fransen.

Peroxisome-mitochondria contact sites manage mitochondrial oxidative stress.

DOI: https://doi.org/10.1126/science.adz0109
J Gen Virol. 2025 Jul;106(7):

Understanding the mechanisms of mitochondrial rewiring during viral infections.

Marta Lopez-Nieto, Nicolas Locker.

  As intracellular parasites, viruses must hijack and often rewire organelles, signalling pathways and the bioenergetics machinery of the infected cell to replicate their genome, produce viral proteins and assemble new viral particles. Mitochondria are key eukaryotic organelles often referred to as the cell's powerhouse. They control many fundamental cellular processes, from metabolism and energy production to calcium homeostasis and programmed cell death. Importantly, mitochondrial membranes are also critical sites for the integration and amplification of antiviral innate immune responses. Overall, mitochondria are therefore both supporting the virus life cycle by sustaining energy production, metabolism and synthesis of macromolecules and part of the cell's first line of defence against viruses. This review summarizes recent findings on viral manipulations of mitochondria and their functions. We explore the evolving understanding of how mitochondrial dynamics is targeted to regulate innate immunity, evasion strategies used to avoid mitochondrial-associated mechanisms that impair replication and the role of mitochondrial functions such as generating reactive oxygen species or regulating the electron transport chain during infection. Overall, we provide a comprehensive view of how viruses modulate mitochondrial function to promote replication.

Keywords:  innate immunity; mitochondria; mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1099/jgv.0.002128
Am J Med Genet A. 2025 Jul 09. e64177

A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.

Vittoria Rossi, Dan Brooks, Hongzheng Dai, Elizabeth Mizerik, Karla Salazar, Daniel Davila-Williams, Yishay Ben-Moshe, Seema R Lalani, Sarah H Elsea, Charul Gijavanekar, Daryl A Scott, Keren Machol, Mir Reza Bekheirnia, Fernando Scaglia.

  POLG2 encodes an accessory subunit in DNA polymerase gamma that is required for mitochondrial DNA synthesis. Monoallelic pathogenic variants in POLG2 are associated primarily with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4 (PEOA4, MIM #610131). We report a rare case of severe infantile hepatocerebral syndrome associated with biallelic variants in POLG2. The proband, a 5-week-old female infant, presented with seizures and acute liver failure. Extensive metabolic workup, including untargeted metabolomics analysis and elevated plasma growth differentiation factor 15, was suggestive of mitochondrial dysfunction. Rapid trio genome sequencing identified compound heterozygous variants, a likely pathogenic variant and a variant of uncertain significance in POLG2. This case expands the clinical phenotype associated with POLG2-related mitochondrial disease to include a severe hepatocerebral syndrome manifesting in early childhood. This case underscores the utility of integrated genomic and metabolomic analyses in diagnosing rare and complex mitochondrial disorders. These findings also emphasize the importance of considering POLG2-related mitochondrial disease in the differential diagnosis of infants presenting with liver failure and neurological symptoms and enhance our understanding of the phenotypic spectrum associated with this disorder.

Keywords:   POLG2 ; liver failure; mitochondrial DNA replication; mitochondrial disorder; untargeted metabolomics analysis

DOI:  https://doi.org/10.1002/ajmg.a.64177
Biogerontology. 2025 Jul 09. 26(4): 142

Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies.

Pei Wei, Xiaoyan Zhang, Chi Yan, Siyu Sun, Zhigang Chen, Fei Lin.

  Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53-PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Keywords:  Aging; Autophagy; Epigenetic regulation; Metabolic reprogramming; Mitochondria; Telomere dysfunction

DOI:  https://doi.org/10.1007/s10522-025-10273-4
Mol Genet Metab. 2025 Jun 28. pii: S1096-7192(25)00175-1. [Epub ahead of print]145(4): 109184

A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions.

Olivia Sniezek Carney, Kodi Harris, Madison Santizo, Valeria Silva, Jhanay Davis, Kyuna Lee, Sharada Vishwanath, Anne Hamacher-Brady, Hilary J Vernon.

  Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodeling are mediated by a coordinated set of enzymes, and disruptions in this pathway are increasingly recognized as causes of inherited mitochondrial diseases. This review provides a comprehensive overview of the genetic disorders associated with defects in cardiolipin metabolism, highlighting genetic and molecular characteristics, clinical manifestations, and available models with which to study these diseases. We examine the roles of key genes involved in cardiolipin biosynthesis (PGS1, CRLS1) and remodeling (TAZ, AGK, among others), and describe how pathogenic variants disrupt mitochondrial function. The prototypical disorder, Barth syndrome, is discussed in depth alongside recently identified conditions linked to defects in related enzymes.

Keywords:  Barth syndrome; Cardiolipin; Lipid biosynthesis; Mitochondrial disease

DOI:  https://doi.org/10.1016/j.ymgme.2025.109184
Small Methods. 2025 Jul 06. e2500674

Mitochondrion in Pulmonary Disease: Small Organelle but Big Function.

Jiawen Wang, Honghui Wu, Jianqing Gao, Tianyuan Zhang.

  Mitochondria are micrometer-sized organelles, yet are pivotal for the activity, function, and fate of mammalian cells. Recent findings further reveal that mitochondrial homeostasis plays an active role in regulating lung cell disorders, inspiring a novel strategy to treat pulmonary disease by restoring the imbalanced mitochondrial homeostasis. Pioneering studies have shown the potentials of this strategy for the treatment of pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS), which currently lack efficient medicines. However, there has been no comprehensive summary of this innovative strategy in pulmonary disease treatment. Therefore, the present review aims to provide an overview of the mechanism and advances in pulmonary disease treatment by restoring mitochondrial homeostasis. Particularly, some of the latest therapeutic strategies, including antioxidant therapy, mitochondrial quality controlling, and mitochondrial replenishment therapy (MRT), are introduced to show the potent capability of mitochondria to regulate cellular disorders in different types of lung cells. This review is believed to provide a general understanding of the mitochondria involved in pathogenesis and is intended to inspire the development of novel therapeutic methods against pulmonary diseases, focusing on regulating impaired mitochondrial homeostasis.

Keywords:  antioxidants; homeostasis; mitochondria; mitochondria transfer; pulmonary diseases

DOI:  https://doi.org/10.1002/smtd.202500674
Pharm Nanotechnol. 2025 Jul 03.

Exosomes as Next-Generation Carriers for Brain Drug Delivery: Engineering, Formulation, Characterization, and Neurotherapeutic Applications.

Vani D, Ethiraj T, Sutha Ponnusamy, Devi R, Aswathi Elisabeth Philip.

   BACKGROUND: Exosomes, nanoscale extracellular vesicles, have emerged as promising drug delivery carriers due to their ability to cross the blood-brain barrier (BBB) and deliver therapeutic cargo efficiently. Their biocompatibility and capacity for engineering make them ideal candidates for treating neurological disorders.
METHODS: This review examines various strategies for exosome engineering, including donor cell selection, isolation techniques, and cargo loading methods. Key characterization techniques such as nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), electron microscopy, and biomarker profiling are discussed. Additionally, in-vitro and in-vivo models used to evaluate exosome- mediated drug delivery efficacy are analyzed.
RESULTS: Exosomes have demonstrated significant potential in neurotherapeutic applications, including targeted drug delivery for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, glioblastoma therapy, and neural repair in stroke models. Clinical studies and experimental models confirm their ability to encapsulate and protect therapeutic molecules, enhance drug stability, and ensure precise targeting. However, challenges such as large-scale production, reproducibility, and safety concerns remain.
CONCLUSION: Exosomes represent a transformative approach to overcoming BBB-related drug delivery challenges, providing a natural, non-invasive platform for neurological therapies. Advances in engineering techniques and characterization will be critical to optimizing their therapeutic potential and clinical translation.

Keywords:  Blood-brain barrier (BBB) penetration; Brain drug delivery; Exosome engineering; Exosome formulation; Exosomes; Neurological disorders.

DOI:  https://doi.org/10.2174/0122117385383438250526063154
J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):

MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.

Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.

  Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.

Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH

DOI:  https://doi.org/10.1242/jcs.263701
Biomed Pharmacother. 2025 Jul 09. pii: S0753-3322(25)00529-3. [Epub ahead of print]189 118335

Crosstalk between mitochondrial quality control and novel programmed cell death in pulmonary diseases.

Qian Gao, Xiaoyu Han, Jun Wang, Xiaodan Liu, Weibing Wu.

  Dysfunctional mitochondrial quality control (MQC) and dysregulated programmed cell death (PCD) are increasingly recognized as key drivers of pulmonary diseases. This review explores the intricate crosstalk between MQC mechanisms, encompassing mitochondrial biogenesis, dynamics, mitophagy, and mitocytosis, and novel PCD pathways such as pyroptosis, ferroptosis, necroptosis, PANoptosis, cuproptosis, and disulfidptosis. We highlight how mitochondrial dysfunction triggers PCD and how PCD exacerbates mitochondrial damage, creating a vicious cycle that amplifies lung injury and inflammation. Emerging therapeutic strategies targeting these interconnected pathways show promise in mitigating pulmonary diseases. However, challenges remain in understanding the context-dependent roles and translating preclinical findings into clinical applications. Further research is still needed to elucidate the precise regulatory mechanisms governing MQC and PCD, identify novel therapeutic targets, and develop biomarkers for early disease detection and prognosis. This review underscores the potential of targeting MQC and PCD as a therapeutic direction for pulmonary diseases, offering new insights into disease pathogenesis and treatment.

Keywords:  Mitochondrial quality control; programmed cell death; pulmonary diseases

DOI:  https://doi.org/10.1016/j.biopha.2025.118335
J Biol Chem. 2025 Jul 08. pii: S0021-9258(25)02314-2. [Epub ahead of print] 110464

Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.

Meiheriayi Yasheng, Yanchun Ji, Yunfan He, Qiuzi Yi, Huanhuan Zhang, Wenqi Shan, Kai Wang, Juanjuan Zhang, Ya Li, Feilong Meng, Minglian Zhang, Jun Qin Mo, Shihui Wei, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying LHON-linked mtDNA mutations, especially their impact on mitochondrial and cellular integrity, is not well understood. Recently, the ND1 3733G>C (p.E143Q) mutation was identified in three Chinese pedigrees with suggestively maternal inheritance of LHON. In this study, we investigated the pathogenic mechanism of m.3733G>C mutation using cybrids generated by fusing mtDNA-less ρ0 cells with enucleated cells from a Chinese patient carrying the m.3733G>C mutation and control subject. Molecular dynamics simulations showed that p.E143Q mutation destabilized these interactions between residues E143 and S110/Y114, or between S141 and W290 in the ND1. Its impact of ND1 structure and function was further evidenced by reduced levels of ND1 in mutant cells. The m.3733G>C mutation caused defective assembly and activity of complex I, respiratory deficiency, diminished mitochondrial ATP production, and increased production of mitochondrial ROS in the mutant cybrids carrying the m.3733G>C mutation. These mitochondrial dysfunctions regulated mitochondrial quality control via mitochondrial dynamics and mitophagy. The m.3733G>C mutation-induced dysfunction yielded elevating mitochondrial localization of DRP1, decreasing network connectivity and increasing fission with abnormal morphologies. Furthermore, the m.3733G>C mutation downregulated ubiquitin-dependent mitophagy pathway, evidenced by decreasing the levels of Parkin and Pink, but not ubiquitin-independent mitophagy pathway. The m.3733G>C mutation-induced deficiencies reshaped the cellular homeostasis via impairing autophagy process and promoting intrinsic apoptosis. Our findings provide new insights into pathophysiology of LHON arising from the m.3733G>C mutation-induced mitochondrial dysfunctions and reprograming organellular and cellular homeostasis.

DOI: https://doi.org/10.1016/j.jbc.2025.110464
Beilstein J Nanotechnol. 2025 ;16 951-967

Shape, membrane morphology, and morphodynamic response of metabolically active human mitochondria revealed by scanning ion conductance microscopy.

Eric Lieberwirth, Anja Schaeper, Regina Lange, Ingo Barke, Simone Baltrusch, Sylvia Speller.

  Mitochondrial network dynamics play a key role in enabling cells to adapt to environmental changes. Fusion and fission of mitochondria, as well as their contact with other organelles, are central processes. Consequently, the outer membrane, which separates the mitochondrion from the cytoplasm, has become a focus of investigation. We analysed metabolically active mitochondria from HeLa cells using scanning ion conductance microscopy to generate nanoscopically resolved, three-dimensional topographies. Our measurements reveal the diversity of mitochondrial shapes. Moreover, a morphodynamic effect was identified, the magnitude of which depends on mitochondrial viability. This method, applied for the first time to mitochondria, shows potential for visualising the morphodynamic responses of mitochondria to their local environment. The similarities between the nanopipette in the measurement setup and the microtubules in the cellular context are discussed as the basis for the hypothesis.

Keywords:  HeLa; metabolically active; mitochondria; morphodynamics; scanning ion conductance microscopy

DOI:  https://doi.org/10.3762/bjnano.16.73
ACS Appl Mater Interfaces. 2025 Jul 11.

Mitochondrial Delivery of Molecular Drugs Bypassing Endocytosis.

Reeddhi Ray, Soumi Das, Abu Raihan Sarkar, Nikhil R Jana.

  Although mitochondria are potential therapeutic target for various diseases, the targeted delivery of drugs to mitochondria is challenging. Conventional carrier-based drug delivery utilizes an endocytic uptake pathway that results in partial and delayed mitochondrial targeting due to complicated endosomal trafficking followed by endosomal escape roots. Here, we report a nonendocytic approach for preferential and rapid mitochondrial delivery of molecular drugs using a designed nanocarrier. The drug-loaded nanocarrier rapidly enters into the cell via temporary membrane pore formation, releases molecular drugs into cytosol without any vesicular entrapment, and labels mitochondria within 5 min. In contrast, control nanocarrier-based delivery of the same molecule via endocytic root leads to lysosomal trafficking. This result demonstrates the advantage of the nonendocytic approach for efficient mitochondrial targeting of drugs with potential therapeutic advantages.

Keywords:  cell therapy; endocytosis; lysosome; mitochondrial targeting; nanocarrier; nanoparticle; quantum dot

DOI:  https://doi.org/10.1021/acsami.5c06774
Adv Healthc Mater. 2025 Jul 08. e2501349

Molecular Mechanisms of Extracellular Vesicle Biogenesis and Their Impact on the Design of Custom EVs.

Luís Carvalho Ferraz, Paulo Pereira, João Vasco Ferreira.

  Extracellular Vesicles (EVs) are nanosized lipid-bound particles that are pivotal for intercellular communication and actively participate in diverse physiological processes, including immune modulation, proteostasis, and tissue repair. EVs have emerged as promising therapeutic targets and biomarkers because of their significant roles in the pathogenesis of diseases, including cancer, neurodegeneration, and cardiovascular disorders. Despite extensive research on EVs as diagnostic tools and mediators of cellular signaling, the fundamental mechanisms underlying their biogenesis remain unclear. Consequently, this understanding of how the composition of EVs dynamically changes in response to physiological and pathological conditions is often limited, leading to lower diagnostic utility and slower advancements in clinical interventions and EVs engineering. This review explores the intricate mechanisms underlying EVs biogenesis and payload selection, emphasizing how these processes vary across EVs subclasses, thereby underpinning their functional versatility. The biogenetic pathways are highlighted from the ectocytosis-driven generation of microvesicles and apoptotic body (ApoBDs) formation via membrane blebbing to the formation of exosomes within the endosomal compartments and their regulated release via exocytosis.

Keywords:  apoptotic bodies; exocytosis; exosomes; extracellular vesicles; microvesicles

DOI:  https://doi.org/10.1002/adhm.202501349
Cells. 2025 Jun 23. pii: 959. [Epub ahead of print]14(13):

Exosomes as Future Therapeutic Tools and Targets for Corneal Diseases.

Joshua Gamez, Daxian Zha, Shaghaiegh M Ebrahimi, Seok White, Alexander V Ljubimov, Mehrnoosh Saghizadeh.

  The therapeutic potential of exosomes (Exos), a subpopulation of extracellular vesicles (EVs) secreted by various cell types, has been broadly emphasized. Exos are endosome-derived membrane-bound vesicles 50-150 nm in size. Exos can be general or cell type-specific. Their contents enable them to function as multi-signaling and vectorized vehicles. Exos are important for maintaining cellular homeostasis. They are released into extracellular spaces, leading to uptake by neighboring or distant cells and delivering their contents to modulate cell signaling. Exos influence tissue responses to injury, infection, and disease by fusion with the target cells and transferring their cargo, including cytokines, growth and angiogenic factors, signaling molecules, lipids, DNA, mRNAs, and non-coding RNAs. They are implicated in various physiological and pathological conditions, including ocular surface events, such as corneal scarring, wound healing, and inflammation. Their biocompatibility, stability, low immunogenicity, and easy detectability in bodily fluids (blood, tears, saliva, and urine) make them promising tools for diagnosing and treating ocular diseases. The potential to engineer specific Exo cargos makes them outstanding therapeutic delivery vehicles. The objective of this review is to provide novel insights into the functions of Exo cargos and their applications as biomarkers and therapeutics, or targets in the cornea.

Keywords:  biomarkers; cell–cell communication; cornea; crosstalk; exosome blockers; exosomes; miRNAs; therapeutic tools; therapeutics targets

DOI:  https://doi.org/10.3390/cells14130959
Cell Death Dis. 2025 Jul 07. 16(1): 499

Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration.

Gaoshang Chai, Yuming Mao, Juan Gong, Shuguang Bi, Yuqi Zhang, Jiajun Wu, Liu Yang, Tianlong Gao, Haitian Fu, Chunjing Yu, Caili Ren, Guofu Zhang, Xuming Zhu, Xin Guan, Haoting Yu, Caijing Tang, Yunjuan Nie, Haitao Yu.

Mitochondrial defects are early pathological changes in neurodegenerative disease (ND). Homocysteine (Hcy) is an independent risk factor for ND. However, whether and how Hcy induces mitochondrial defects during the process of neurodegeneration is unclear. Here, we revealed that Hcy interfered with mitochondrial oxidative phosphorylation (OXPHOS) by inhibiting the mitochondrial electron transport chain (ETC) complex I, resulting in increased levels of reactive oxygen species (ROS) in the hippocampus of rats. Specifically, Hcy suppressed Ndufa1 expression, which is essential for complex I assembly and activation, by interfering with its transcription factor Creb1. Moreover, we found that Hcy induced neurodegeneration-like pathological changes in mitochondria in the brain via the inhibition of the NAD+/Sirt1 pathway, including defects in mitochondrial morphology, mitochondrial biogenesis, and mitophagy, ultimately leading to impairments in synapses and cognition, all of which were reversed by Ndufa1 upregulation. Thus, Ndufa1 is a key molecular switch of Hcy-induced mitochondrial damage, and appropriately targeting Ndufa1 or NAD+ replenishment may serve as a novel therapeutic strategy for Hcy-induced neurodegeneration and cognitive impairment.

DOI: https://doi.org/10.1038/s41419-025-07834-3
Curr Med Chem. 2025 Jul 04.

Recent Advances in the Application of Mitochondria-targeted Fluorescent Probes.

Merve Inel, Ayşe Yildirim, Bahadir Ozturk, Mustafa Yilmaz.

  Mitochondria, the complex powerhouses of eukaryotic cells, lie at the core of energy production, metabolism, and signaling. Mitochondrial dysfunctions underlie a wide range of human diseases, and there is a need for simple and effective tools to target and study these organelles. This review focuses on the applications of mitochondria-targeted cationic probes. It provides an up-to-date review of recent publications investigating the effects of these cationic probes, which are designed to manipulate mitochondrial function and detect dysfunction in different cell lines. In addition, it analyzes the effects of mitochondria-targeted fluorescence cationic probes in vivo and in vitro studies, and their effects in probe studies.

Keywords:  MMP; Mitochondria; ROS; cancer; cell death; fluorescent probe; pH.; viscosity

DOI:  https://doi.org/10.2174/0109298673368188250613112621
ILIVER. 2024 Mar;3(1): 100078

The potential role of extracellular vesicles as hepatic diagnostic and therapeutic tools: Can the dream come true?

Nourhan Badwei.

  Chronic liver disease of various aetiologies with underlying cirrhosis is a serious cause of liver-related morbidity and mortality globally. The emerging role of non-invasive diagnostic/therapeutic tools in different stages of liver disease represents a challenge and an area of great interest for many researchers, which could differ in the clinical outcome of liver disease patients. Over a decade, several studies have evaluated the emerging role of circulating extracellular vesicles (EVs) as biomarkers and therapeutic targets in different liver diseases; They are small membrane-encapsulated particles that can act as potent vehicles via their cargos between different hepatic cell types and also between organs, because of their ability to transfer proteins, lipids, and nucleic acids to affect the recipient cells' related physiological functions. Hence, the issues related to the potential use of EVs as biomarkers in liver disease diagnosis, prognosis, and even to assess the response to treatment, have been handled in our review concluding that EVs have shown promising results as potential diagnostic tools and for further evaluation as therapeutic targets.

Keywords:  Diagnosis; Extracellular vesicles; Liver diseases; Prognosis; Therapeutic targets

DOI:  https://doi.org/10.1016/j.iliver.2024.100078
J Ginseng Res. 2025 Jul;49(4): 376-388

The role of ginseng in aging: Insights into regulatory T cells activation and mitochondrial regulation.

Hamid Iqbal, Dong-Kwon Rhee.

  A hallmark of aging is the progressive decline in resilience to stress and mitochondrial activity. As mitochondrial function decreases with aging, mitochondrial DNA (mtDNA) is shed under apoptotic stress, resulting in a persistent low-level of sterile inflammation (called inflammaging) that induces the aging program. In response to inflammaging, the body activates a compensatory anti-inflammatory response, including the activation of regulatory T (Treg) cells, to prevent excessive tissue damage. Recent studies have highlighted the dysfunction of Treg cells in elderly patients, suggesting that their critical role in the mitigation of aging. Additionally, mitochondrial electron transport chain (ETC) complexes, particularly complexes II and III, are essential for the function of Th1 and Treg cells, respectively. Since centenarians experience less inflammaging, this review aims to explore the anti-aging properties of ginseng. Research has shown that ginseng and its active compounds, ginsenosides, increase Treg cells population in aged mice and convert pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages. Furthermore, ginseng enhances antioxidant protein expression, decreases reactive oxygen species (ROS) production, restores mitochondrial ATP and membrane potential, and exerts anti-aging effects. Ginseng has been shown to extend lifespan, promote beneficial gut bacteria, and slow cognitive decline through its influence on immune cell circulation. Future research, including clinical trials, is needed to clarify the regulatory effects of ginseng on Treg cells, mitochondrial complexes, and their associated metabolites, as well as the interconnected mechanisms between them.

Keywords:  Aging; Ginseng; Inflammaging; Mitochondria; Regulatory T cells

DOI:  https://doi.org/10.1016/j.jgr.2025.05.005
J Inherit Metab Dis. 2025 Jul;48(4): e70064

Induced Pluripotent Stem Cells for the Treatment of Lysosomal Storage Disorders.

Maryann Lorino, Bei Qiu, Brian Bigger.

Lysosomal disorders (LSDs) are a group of rare metabolic disorders, with an overall incidence of 1:4800 to 1:8000 live births. LSDs are primarily caused by dysfunctional lysosomal enzymes, which typically lead to the progressive accumulation of substrates within cellular lysosomes. As a result, patients experience a wide array of somatic symptoms such as visceromegaly, cardiopulmonary abnormalities, and respiratory and urinary infections. Additionally, over two-thirds of LSD subtypes have a neurological component, and without treatment, patients experience neurodegeneration, cognitive decline, and life expectancies spanning infancy to adulthood. At present, there is no therapy that rescues the degenerative neuropathology of LSDs, and current developments, such as brain-targeted enzyme replacement therapy, hematopoietic stem cell transplantation, and even gene therapy, can only prevent further neurodegeneration. However, recent advancements involving induced pluripotent stem cells (iPSCs) have demonstrated that stem cells may harbor the potential to both recapitulate the phenotype of neuropathic LSDs in vitro, as well as serve as a vector for regeneration in vivo, by replacing cells and neurons damaged by disease progression. This review reports the current state of iPSC technology in LSD research, and the pathway by which iPSCs are translated from disease modeling to serving as a regenerative therapeutic for neuropathic LSDs in the clinic.

DOI: https://doi.org/10.1002/jimd.70064
Nanomedicine (Lond). 2025 Jul 07. 1-16

Research progress on mRNA drug delivery strategies in the nervous system.

Bo Yang, Anqi Liu, Xiaojing Li, Zhigang Miao.

  There has been little progress in the treatment of central nervous system (CNS) disorders in recent decades. To date, new therapeutic agents such as small molecule drugs, cytokines, monoclonal antibodies and vaccines targeting specific antigens are still in the research and development stage and have not yet entered clinical use. With the discovery of gene-editing technology and the development of new therapeutic strategies, mRNA has been developed and used as a new type of drug, showing potential application value in the treatment of various neurological diseases. However, mRNA drugs face difficulties in being delivered to the CNS to exert therapeutic effects. We conducted a review by searching the PubMed database for relevant literature up to now, focusing on the research progress of mRNA drug delivery systems in the nervous system and their applications in neurological diseases, explore the challenges and prospects of mRNA drugs in neurological diseases, and provide reference for the development and implementation of mRNA drugs for neurological diseases.

Keywords:  CNS; delivery; drugs; mRNA; nano

DOI:  https://doi.org/10.1080/17435889.2025.2530242
Nature. 2025 Jul 09.

Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.

Guangbin Shi, Claire Miller, Sota Kuno, Alejandro G Rey Hipolito, Salsabiel El Nagar, Giulietta M Riboldi, Megan Korn, Wyatt C Tran, Zixuan Wang, Lia Ficaro, Tao Lin, Quentin Spillier, Begoña Gamallo-Lana, Drew R Jones, Matija Snuderl, Soomin C Song, Adam C Mar, Alexandra L Joyner, Roy V Sillitoe, Robert S Banh, Michael E Pacold.

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA or 4-HB supplementation promotes CoQ10 headgroup synthesis in vivo, here we administered 4-HMA and 4-HB to Hpdl-/- mice, which model an ultra-rare, lethal mitochondrial encephalopathy in humans. Both 4-HMA and 4-HB were incorporated into CoQ9 and CoQ10 in the brains of Hpdl-/- mice. Oral treatment of Hpdl-/- pups with 4-HMA or 4-HB enabled 90-100% of Hpdl-/- mice to live to adulthood. Furthermore, 4-HB treatment stabilized and improved the neurological symptoms of a patient with progressive spasticity due to biallelic HPDL variants. Our work shows that 4-HMA and 4-HB can modify the course of mitochondrial encephalopathy driven by HPDL variants and demonstrates that CoQ10 headgroup intermediates can restore CoQ10 synthesis in vivo.

DOI: https://doi.org/10.1038/s41586-025-09246-x