bims-polgdi Biomed News
on POLG disease
Issue of 2025–05–04
forty papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.
  2. Ramping up mitochondrial DNA replication.
  3. Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.
  4. High Content Analysis of Mitochondrial Function in Induced Pluripotent Stem Cell-Derived Neurons.
  5. Advances in research on mitochondrial dysfunction in neurodegenerative diseases.
  6. Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress.
  7. Modulation of Lonp1 Activity by Small Compounds.
  8. Enhancing Mitochondrial Function Through Pharmacological Modification: A Novel Approach to Mitochondrial Transplantation in a Sepsis Model.
  9. Mitochondrial Dysfunction in Endothelial Cells: A Key Driver of Organ Disorders and Aging.
  10. Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
  11. Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
  12. Uncovering the role of mitochondrial genome in pathogenicity and drug resistance in pathogenic fungi.
  13. Label-Free Visualization and Segmentation of Endothelial Cell Mitochondria Using Holotomographic Microscopy and U-Net.
  14. Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
  15. Harnessing Nur77's mitochondrial apoptotic pathway: A promising therapeutic strategy for targeted disease intervention.
  16. Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions.
  17. Haplogroup Structure and Genetic Variation Analyses of Mitochondrial Genome SNPs in the Iranian Population.
  18. Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  19. The copper ionophore disulfiram improves mitochondrial function in various yeast and human cellular models of mitochondrial diseases.
  20. Recent advances in mitochondrial transplantation to treat disease.
  21. Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.
  22. Contemporary insights into elamipretide's mitochondrial mechanism of action and therapeutic effects.
  23. Cell-Based Assays Using Derived Human-Induced Pluripotent Cells in Drug Discovery and Development.
  24. Cytoplasmic Inheritance: The Transmission of Plastid and Mitochondrial Genomes Across Cells and Generations.
  25. Mitochondria - the CEO of the cell.
  26. GPCRs With mTOR Signaling Expressed in Gut-Brain-Immune Axis-Cells Could Contribute to the Treatment of Neurodegenerative Diseases and Immune-Related Diseases.
  27. Differential effects of lifespan-extending genetic manipulations in an animal model of MJD/SCA3.
  28. Human Organoids as an Emerging Tool for Genome Screenings.
  29. Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.
  30. Platelet Extracellular Vesicles as Natural Delivery Vehicles for Mitochondrial Dysfunction Therapy?
  31. The Dual Role of Exogenous Hydrogen Sulfide (H2S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions.
  32. Sulforaphane and Brain Health: From Pathways of Action to Effects on Specific Disorders.
  33. Pluripotent Stem Cells: Recent Advances and Emerging Trends.
  34. Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies-A Comprehensive Narrative Review.
  35. Coenzyme Q10 and the Blood-Brain Barrier: An Overview.
  36. Decoding the role of microtubules: a trafficking road for vesicle.
  37. Replicative Senescence in Mesenchymal Stem Cells: An In Vitro Study on Mitochondrial Dynamics and Metabolic Alterations.
  38. Sodium thiosulfate mitigates PM2.5-induced cardiotoxicity by preservation of mitochondrial function.
  39. Pediatric Systemic Autoinflammatory Disorders: An Overview.
  40. Mitochondrial quality control disorder in neurodegenerative disorders: Potential and advantages of traditional Chinese medicines.
  1. Genes Dis. 2025 Jul;12(4): 101437
    Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.
    Ye Hong, Ying Song, Wenjun Wang, Jinghui Shi, Xi Chen.
      Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.
    Keywords:  Base editor; CRISPR-Cas9; Mitochondrial DNA; Neurodegenerative diseases; mitoTALENs; mitoZFNs
    DOI:  https://doi.org/10.1016/j.gendis.2024.101437
  2. Nat Rev Drug Discov. 2025 May 02.
    Ramping up mitochondrial DNA replication.
    Katie Kingwell.
      
    DOI:  https://doi.org/10.1038/d41573-025-00079-x
  3. Am J Hum Genet. 2025 Apr 23. pii: S0002-9297(25)00144-2. [Epub ahead of print]
    Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.
    Solve-RD Consortium
      The diagnosis of mitochondrial DNA (mtDNA) diseases remains challenging with next-generation sequencing, where bioinformatic analysis is usually more focused on the nuclear genome. We developed a workflow for the evaluation of mtDNA diseases and applied it in a large European rare disease cohort (Solve-RD). A semi-automated bioinformatic pipeline with MToolBox was used to filter the unsolved Solve-RD cohort for rare mtDNA variants after validating this pipeline on exome datasets of 42 individuals previously diagnosed with mtDNA variants. Variants were filtered based on blood heteroplasmy levels (≥1%) and reported association with disease. Overall, 10,157 exome and genome datasets from 9,923 affected individuals from 9,483 families within Solve-RD met the quality inclusion criteria. 136 mtDNA variants in 135 undiagnosed individuals were prioritized using the filtering approach. A focused MitoPhen-based phenotype similarity scoring method was tested in a separate genetically diagnosed "phenotype test cohort" consisting of nuclear gene and mtDNA diseases using a receiving operator characteristic evaluation. We applied the MitoPhen-based phenotype similarity score of >0.3, which was highly sensitive for detecting mtDNA diseases in the phenotype test cohort, to the filtered cohort of 135 undiagnosed individuals. This aided the prioritization of 34 out of 37 (92%) individuals who received confirmed and likely causative mtDNA disease diagnoses. The phenotypic evaluation was limited by the quality of input data in some individuals. The overall pipeline led to an additional diagnostic yield of 0.4% in a cohort where mitochondrial disease was not initially suspected. This highlights the value of our mtDNA analysis pipeline in diverse datasets.
    Keywords:  Solve-RD; bioinformatics; mitochondrial DNA; phenotype similarity; reanalysis
    DOI:  https://doi.org/10.1016/j.ajhg.2025.04.003
  4. Methods Mol Biol. 2025 ;2924 259-268
    High Content Analysis of Mitochondrial Function in Induced Pluripotent Stem Cell-Derived Neurons.
    Daniel Little, Christin Luft, Olukunbi Mosaku, Robin Ketteler, Michael J Devine, Paul Gissen.
      Mitochondrial dysfunction is linked to many neurological diseases; therefore, the ability to measure mitochondrial function is of great use for researching disease and testing potential therapeutics. Here we describe a high-content assay to simultaneously measure mitochondrial membrane potential, morphology, and cell viability in iPSC-derived neurons. Neurons are seeded into plates suitable for fluorescent microscopy, and stained with the mitochondrial membrane potential-dependent dye TMRM, cytoplasmic dye Calcein-AM, and nuclear stain Hoechst-33,342. Images are acquired in live cells and analyzed using automated image analysis software.
    Keywords:  High content screening; Image analysis; Induced pluripotent stem cells; Mitochondria; Neurons
    DOI:  https://doi.org/10.1007/978-1-0716-4530-7_19
  5. J Neurol. 2025 Apr 28. 272(5): 364
    Advances in research on mitochondrial dysfunction in neurodegenerative diseases.
    Yao Zhang, Xiao-Wen Li, Yuan Zhang, Xing Li.
      Given the high energy demand of the nervous system, mitochondrial dysfunction is a key factor in the pathogenesis of neurodegenerative diseases. Thus, a comprehensive understanding of its mechanisms and potential therapeutic targets is essential. This review discusses the roles of mitochondrial oxidative stress, mitochondrial dynamics alterations, and mtDNA damage in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). In addition, it summarizes the contributions of novel technological approaches in detecting mitochondrial dysfunction, which assist in disease diagnosis. We also emphasize emerging therapeutic strategies and drugs aimed at enhancing mitochondrial quality control and reducing oxidative stress, thereby laying the groundwork for innovative therapeutic approaches in neurodegenerative disease treatment.
    Keywords:  Detection technology; Mitochondrial dysfunction; Neurodegenerative diseases; Therapeutic targets
    DOI:  https://doi.org/10.1007/s00415-025-13101-4
  6. medRxiv. 2025 Apr 12. pii: 2025.04.09.25325473. [Epub ahead of print]
    Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress.
    Caroline Trumpff, David Shire, Jeremy Michelson, Natalia Bobba-Alves, Temmie Yu, Richard P Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.
      Human blood contains cell-free mitochondrial DNA (cf-mtDNA) that dynamically increases in concentration in response to acute mental stress. Like other neuroendocrine stress markers, we previously found that cf-mtDNA is also detectable in saliva, calling for studies examining saliva cf-mtDNA reactivity to mental stress. In healthy women and men from the MiSBIE (Mitochondrial Stress, Brain Imaging, and Epigenetics) study (n=68, 66% women), a brief socio-evaluative stressor induced a striking 280% or 2.8-fold increase in saliva cf-mtDNA concentration within 10 minutes (g=0.55, p<0.0001). In blood drawn concurrently with saliva sampling, stress increased cf-mtDNA by an average 32% at 60 min in serum (g=0.20), but not in anticoagulated plasma where cf-mtDNA decreased by 19% at 60 min (g=0.25). Examining the influence of mitochondrial health on cf-mtDNA reactivity in participants with rare mitochondrial diseases (MitoD), we report that a subset of MitoD participants exhibit markedly blunted saliva cf-mtDNA stress reactivity, suggesting that bioenergetic defects within mitochondria may influence the magnitude of saliva, and possibly blood cf-mtDNA responses. Our results document robust saliva cf-mtDNA stress reactivity and provide a methodology to examine the psychobiological regulation of cell-free mitochondria in future studies.
    DOI:  https://doi.org/10.1101/2025.04.09.25325473
  7. Biomolecules. 2025 Apr 09. pii: 553. [Epub ahead of print]15(4):
    Modulation of Lonp1 Activity by Small Compounds.
    Giada Zanini, Giulia Micheloni, Giorgia Sinigaglia, Valentina Selleri, Anna Vittoria Mattioli, Milena Nasi, Ciro Leonardo Pierri, Marcello Pinti.
      The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizing them into inhibitors and activators. Inhibitors such as CDDO and its derivatives selectively target LONP1, impairing mitochondrial proteolysis, inducing protein aggregation, and promoting apoptosis, particularly in cancer cells. Compounds like Obtusilactone A and proteasome inhibitors (e.g., MG262) demonstrate potent cytotoxicity, further expanding the therapeutic landscape. Conversely, LONP1 activators, including Artemisinin derivatives and 84-B10, restore mitochondrial function and protect against conditions such as polycystic ovary syndrome (PCOS) and acute kidney injury (AKI). Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance.
    Keywords:  CDDO; Lon protease; artemisinin; bardoxolone; bortezomib; cancer therapy; proteasome inhibitors; protein quality control; proteostasis
    DOI:  https://doi.org/10.3390/biom15040553
  8. Biomedicines. 2025 Apr 10. pii: 934. [Epub ahead of print]13(4):
    Enhancing Mitochondrial Function Through Pharmacological Modification: A Novel Approach to Mitochondrial Transplantation in a Sepsis Model.
    Bomi Kim, Yun-Seok Kim, Kyuseok Kim.
      Background/Objectives: Sepsis continues to be a significant global health issue, with current treatments primarily focused on antibiotics, fluid resuscitation, vasopressors, or steroids. Recent studies have started to explore mitochondrial transplantation as a potential treatment for sepsis. This study aims to evaluate the effects of enhanced mitochondrial transplantation on sepsis. Methods: We examined various mitochondrial-targeting drugs (formoterol, metformin, CoQ10, pioglitazone, fenofibrate, and elamipretide) to improve mitochondrial function prior to transplantation. Mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) and analyzing the expression of genes related to mitochondrial biogenesis. Additionally, the effects of enhanced mitochondrial transplantation on inflammation were investigated using an in vitro sepsis model with THP-1 cells. Results: Formoterol significantly increased mitochondrial biogenesis, as evidenced by enhanced oxygen consumption rates and the upregulation of mitochondrial-associated genes, including those related to biogenesis (PGC-1α: 1.56-fold, p < 0.01) and electron transport (mt-Nd6: 1.13-fold, p = 0.16; mt-Cytb: 1.57-fold, p < 0.001; and mt-Co2: 1.44-fold, p < 0.05). Furthermore, formoterol-enhanced mitochondrial transplantation demonstrated a substantial reduction in TNF-α levels in LPS-induced hyperinflammatory THP-1 cells (untreated: 915.91 ± 12.03 vs. formoterol-treated: 529.29 ± 78.23 pg/mL, p < 0.05), suggesting its potential to modulate immune responses. Conclusions: Mitochondrial transplantation using drug-enhancing mitochondrial function might be a promising strategy in sepsis.
    Keywords:  formoterol; mitochondrial transplantation; proinflammation; sepsis
    DOI:  https://doi.org/10.3390/biomedicines13040934
  9. Antioxidants (Basel). 2025 Mar 21. pii: 372. [Epub ahead of print]14(4):
    Mitochondrial Dysfunction in Endothelial Cells: A Key Driver of Organ Disorders and Aging.
    Elena Grossini, Sakthipriyan Venkatesan, Mohammad Mostafa Ola Pour.
      Mitochondria are of great importance in cell biology since they are major sites of adenosine triphosphate (ATP) production and are widely involved in different cellular pathways involved in the response to stress. During ATP production, reactive oxygen species (ROS) can be produced. While a small amount of ROS may be important for the regulation of physiological processes, at elevated levels they can turn into harmful agents leading to cellular damage. From a pathological perspective, it could be particularly interesting to focus on mitochondrial function in endothelial cells since they may be involved in the development of aging and in the onset of different diseases, including renal, cardio-metabolic, liver and neurodegenerative ones. However, to date, there are no surveys which address the above issues. To fill this gap, it may be valuable to collect recent findings about the role of mitochondria in the regulation of endothelial function, not only to increase knowledge about it but also for clinical applications. Here, we overview the most recent knowledge about the above issues in the view of characterizing the role of mitochondria in endothelial cells as an innovative potential target for the prevention of aging, as well as the treatment of the above pathological conditions.
    Keywords:  ageing; endothelial cells; liver diseases; mitochondria; neurodegenerative disorders; reactive oxygen species; renal diseases
    DOI:  https://doi.org/10.3390/antiox14040372
  10. Neural Regen Res. 2025 Apr 29.
    Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
    Min Zhou, Min Zheng, Siyao Liang, Maomao Li, Jiarui Ma, Shiyu Zhang, Xinyao Song, Yonglin Hu, Yuhong Lyu, Xingkun Ou, Changwu Yue.
       ABSTRACT: The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; calcium homeostasis; intervention strategy; mitochondria; mitochondrial dysfunction; mitochondrial membrane permeability transition pore; mitophagy; neurodegenerative diseases; oxidative stress; targeted therapy
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01507
  11. Res Sq. 2025 Apr 09. pii: rs.3.rs-6330979. [Epub ahead of print]
    Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
    David Sherwood, Siddharthan Balachandar Thendral, Sasha Bacot, Katherine Morton, Qiuyi Chi, Isabel Kenny-Ganzert, Joel Meyer.
      The quality of mitochondria inherited from the oocyte determines embryonic viability, metabolic health throughout progeny lifetime, and future generation endurance. High levels of endogenous reactive oxygen species and exogenous toxicants are threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in developed oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here we discover that in C. elegans, the onset of oocyte-to-zygote transition (OZT) developmentally triggers a rapid mitophagy event. We show that mitophagy at OZT (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway, and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Impaired MOZT leads to increased deleterious mtDNA inheritance and decreases embryonic survival. Inherited mtDNA damage accumulates across generations, leading to the extinction of descendent populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity.
    DOI:  https://doi.org/10.21203/rs.3.rs-6330979/v1
  12. Front Cell Infect Microbiol. 2025 ;15 1576485
    Uncovering the role of mitochondrial genome in pathogenicity and drug resistance in pathogenic fungi.
    Yue Ni, Xindi Gao.
      Fungal infections are becoming more prevalent globally, particularly affecting immunocompromised populations, such as people living with HIV, organ transplant recipients and those on immunomodulatory therapy. Globally, approximately 6.55 million people are affected by invasive fungal infections annually, leading to serious health consequences and death. Mitochondria are membrane-bound organelles found in almost all eukaryotic cells and play an important role in cellular metabolism and energy production, including pathogenic fungi. These organelles possess their own genome, the mitochondrial genome, which is usually circular and encodes proteins essential for energy production. Variation and evolutionary adaptation within and between species' mitochondrial genomes can affect mitochondrial function, and consequently cellular energy production and metabolic activity, which may contribute to pathogenicity and drug resistance in certain fungal species. This review explores the link between the mitochondrial genome and mechanisms of fungal pathogenicity and drug resistance, with a particular focus on Cryptococcus neoformans and Candida albicans. These insights deepen our understanding of fungal biology and may provide new avenues for developing innovative therapeutic strategies.
    Keywords:  Candida albicans; Cryptococcus neoformans; drug resistance; mitochondrial genome; pathogenicity
    DOI:  https://doi.org/10.3389/fcimb.2025.1576485
  13. Chem Biomed Imaging. 2025 Apr 28. 3(4): 225-231
    Label-Free Visualization and Segmentation of Endothelial Cell Mitochondria Using Holotomographic Microscopy and U-Net.
    Raul Michael, Tallah Modirzadeh, Tahir Bachar Issa, Patrick Jurney.
      Understanding the physiological processes underlying cardiovascular disease (CVD) requires examination of endothelial cell (EC) mitochondrial networks, because mitochondrial function and adenosine triphosphate production are crucial in EC metabolism, and consequently influence CVD progression. Although current biochemical assays and immunofluorescence microscopy can reveal how mitochondrial function influences cellular metabolism, they cannot achieve live observation and tracking changes in mitochondrial networks through fusion and fission events. Holotomographic microscopy (HTM) has emerged as a promising technique for real-time, label-free visualization of ECs and their organelles, such as mitochondria. This nondestructive, noninterfering live cell imaging method offers unprecedented opportunities to observe mitochondrial network dynamics. However, because existing image processing tools based on immunofluorescence microscopy techniques are incompatible with HTM images, a machine-learning model is required. Here, we developed a model using a U-net learner with a Resnet18 encoder to identify four classes within HTM images: mitochondrial networks, cell borders, ECs, and background. This method accurately identifies mitochondrial structures and positions. With high accuracy and similarity metrics, the output image successfully provides visualization of mitochondrial networks within HTM images of ECs. This approach enables the study of mitochondrial networks and their effects, and holds promise in advancing understanding of CVD mechanisms.
    DOI:  https://doi.org/10.1021/cbmi.4c00100
  14. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251332141
    Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
    Jason C Casler, Matilde V Neto, Thomas Burgoyne, Laura L Lackner.
      Sites of close apposition between organelles, known as membrane contact sites (MCSs), are critical regulators of organelle function. Mitochondria form elaborate reticular networks that perform essential metabolic and signaling functions. Many mitochondrial functions are regulated by MCSs formed between mitochondria and other organelles. In this review, we aim to bring attention to an understudied, but physiologically important, MCS between mitochondria and the plasma membrane (PM). We first describe the molecular mechanism of mitochondria-PM tethering in budding yeast and discuss its role in regulating multiple biological processes, including mitochondrial dynamics and lipid metabolism. Next, we discuss the evidence for mitochondria-PM tethering in higher eukaryotes, with a specific emphasis on mitochondria-PM contacts in retinal cells, and speculate on their functions. Finally, we discuss unanswered questions to guide future research into the function of mitochondria-PM contact sites.
    Keywords:  cell biology; electron microscopy; interorganelle (inter-organelle); membrane contact sites (MCSs)‌; mitochondrion (mitochondria); plasma membrane
    DOI:  https://doi.org/10.1177/25152564251332141
  15. Biomed Pharmacother. 2025 Apr 25. pii: S0753-3322(25)00285-9. [Epub ahead of print]187 118091
    Harnessing Nur77's mitochondrial apoptotic pathway: A promising therapeutic strategy for targeted disease intervention.
    Ruihai Fu, Dandan Ling, Qiqi Zhang, Aifang Jiang, Haiyan Pang.
      The role of mitochondria in disease development cannot be overlooked, and the targeting of mitochondria for the treatment of disease has emerged as a significant area of research in recent years. Mitochondria are the control center of the intrinsic apoptotic pathway, and their normal functions are finely regulated by a series of complex mechanisms. The nuclear receptor Nur77 is closely related to the functions of the mitochondria and is an active pro-apoptotic member of the nuclear receptor superfamily. The translocation of Nur77 to the mitochondria can promote the conversion of the anti-apoptotic protein Bcl-2 to a pro-apoptotic state, disrupt the balance between mitochondrial fission and fusion, and inhibit mitophagy. These effects lead to irreversible damage to mitochondria and apoptosis, ultimately accelerating the progression of the disease. Here, we review the mechanism and targeted drug development of the mitochondrial apoptosis pathway activated by Nur77 in human diseases, helping to understand the new advances in disease treatment.
    Keywords:  Apoptosis; Bcl-2; Mitochondria; Mitochondrial dynamics; Mitophagy; Nur77
    DOI:  https://doi.org/10.1016/j.biopha.2025.118091
  16. J Clin Med. 2025 Apr 08. pii: 2537. [Epub ahead of print]14(8):
    Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions.
    Michael Otakhor Erhunmwunse, Pushpa Raj Joshi.
      Introduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the 'common' 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.
    Keywords:  CPEO; common deletion (CD); mitochondrial DNA; ptosis
    DOI:  https://doi.org/10.3390/jcm14082537
  17. Arch Iran Med. 2025 Mar 01. 28(3): 140-148
    Haplogroup Structure and Genetic Variation Analyses of Mitochondrial Genome SNPs in the Iranian Population.
    Masoumeh Ghasemi, Marzieh Mohseni, Zohreh Fattahi, Masoud Edizadeh, Maryam Beheshtian, Fatemeh Keshavarzi, Khadijeh Jalalvand, Mohammadamin Omrani, Ali Khanbazi, Yasser Riazalhosseini, Mohammad Reza Akbari, Kimia Kahrizi, Hossein Najmabadi.
       BACKGROUND: Mitochondrial DNA (mtDNA) is a valuable marker for population studies and forensic investigations. Recent advancements in massively parallel sequencing technologies enable whole mitochondrial genome sequencing. This study collected blood samples from unrelated Iranian participants from four ethnic groups: Persian, Kurd, Lur, and Azeri. We mapped mtDNA haplogroups according to genetic ancestry and investigated the ethnic similarities within the Iranian population.
    METHODS: Complete mtDNA sequences were generated with targeted mtDNA sequencing method and haplogroups were determined on the base of mitogenome polymorphisms. Additionally, we used data from the whole exome sequencing (WES) of the current samples to compare the variants identified by two different mitochondrial testing methods. Principal component analysis (PCA) calculations were performed using the R software to determine diversity between unrelated individuals of various ethnicities.
    RESULTS: A total of 129 sub-haplogroups were identified in 15 main haplogroups. The findings revealed high frequencies of haplogroups U and H (22.4% and 20.3%, respectively) in the Iranian population. The PCA scatter plots revealed overlapping diversity, with no distinct trends separating the groups in these four groups within the Iranian population. In the present samples, the WES method identified only 57.8% of the variants detected by the targeted mtDNA sequencing method.
    CONCLUSION: Variant studies do not show much difference, which indicate a small genetic difference between the central ethnic groups of Iran. Furthermore, comparing the targeted whole mitochondrial genome to mitochondrial data from WES in our study samples highlights the notion that targeted entire mitochondrial genome is a gold standard method for variant detection.
    Keywords:  Genomic diversity; Haplogroup; Mitochondrial DNA; Targeted mtDNA sequencing method; Whole exome sequencing
    DOI:  https://doi.org/10.34172/aim.33639
  18. Nat Commun. 2025 Apr 29. 16(1): 4029
    Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
    DOI:  https://doi.org/10.1038/s41467-025-59427-5
  19. Hum Mol Genet. 2025 Apr 29. pii: ddaf061. [Epub ahead of print]
    The copper ionophore disulfiram improves mitochondrial function in various yeast and human cellular models of mitochondrial diseases.
    Claire Almyre, Nolwenn Bounaix, François Godard, Olivier R Baris, Anne-Louise Cayer, Elodie Sardin, Marine Bouhier, Anaïs Hoarau, Laetitia Dard, Jérémy Richard, Vanessa Bergeron, Aurélie Renaud, Nadege Loaëc, Naïg Gueguen, Valérie Desquiret-Dumas, Bénédicte Lelievre, Aurore Inisan, Cristina Panozzo, Genevève Dujardin, Marc Blondel, Agnes Rötig, Véronique Paquis-Flucklinger, Stéphane Azoulay, Nathalie Bonnefoy, Carole H Sellem, Agnès Delahodde, Vincent Procaccio, Déborah Tribouillard-Tanvier.
      The copper ionophore disulfiram (DSF) is commonly used to treat chronic alcoholism and has potential anti-cancer activity. Using a yeast-based screening assay of FDA-approved compounds, DSF was herein identified for its ability to improve oxidative phosphorylation-dependent growth of various yeast models of mitochondrial diseases caused by a wide range of defects in ATP synthase, complexes III and IV, cardiolipin remodeling, maintenance and translation of the mitochondrial genome. This compound also showed beneficial effects in cells derived from patients suffering from Barth or MELAS syndromes, two mitochondrial diseases associated respectively with a lack in cardiolipin remodeling and protein synthesis inside the organelle. We provide evidence that the rescuing activity of DSF results from its ability to transport copper ions across biological membranes. Indeed, other copper ionophores (pyrithione and elesclomol) and supplementation of the growth media with copper ions had also beneficial effects in yeast and human cells with dysfunctional mitochondria. Our data suggest that the copper-dependent rescuing activity in these cells results from a better capacity to assemble cytochrome c oxidase. Altogether, our findings hold promise for the development of new therapeutic strategies for mitochondrial disorders.
    Keywords:  Mitochondrial diseases; copper; disulfiram; drug repositioning; oxidative phosphorylation
    DOI:  https://doi.org/10.1093/hmg/ddaf061
  20. Biomater Transl. 2025 ;6(1): 4-23
    Recent advances in mitochondrial transplantation to treat disease.
    Xiangling Li, Yanjun Guan, Chaochao Li, Haofeng Cheng, Jun Bai, Jinjuan Zhao, Yu Wang, Jiang Peng.
      Mitochondrial transplantation (MT), an innovative regenerative technique widely used to treat diseases caused by mitochondrial dysfunction, shows great promise for clinical application. This procedure can increase the number of mitochondria and improve the function of damaged mitochondria, resulting in increased adenosine triphosphate levels, decreased reactive oxygen species production, improved Ca2+ buffering capacity, modulated inflammatory response, and reduced apoptosis to protect cells, thus promoting tissue repair. In this review, we describe research advances in MT over the last five years, focusing on its application in treating various diseases, including ischaemic injuries (of the kidney, heart, lung, and liver), neurodegenerative disorders, spinal cord injury, sepsis, diabetes mellitus, stroke, and ultraviolet radiation injuries, as well as in procedures such as organ transplantation, focusing on instances where MT demonstrated good efficacy. We also cover the application of engineered mitochondria and mitochondrial combination therapies and present the latest advances in improving MT efficiency, as well as the current clinical applications and shortcomings of MT, aiming to provide a theoretical foundation for enhanced MT utilisation in the future.
    Keywords:  cardiovascular diseases; ischaemia/reperfusion injury; mitochondrial dysfunction; mitochondrial transplantation; neurodegenerative diseases
    DOI:  https://doi.org/10.12336/biomatertransl.2025.01.002
  21. Curr Stem Cell Res Ther. 2025 Apr 25.
    Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.
    Jingyi Chen, Zhilang Xie, Huayin Zhou, Yingxin Ou, Wenwen Tan, Aizhen Zhang, Yuying Li, Xingliang Fan.
      Mesenchymal stem cells (MSCs) hold transformative potential in translational medicine due to their versatile differentiation abilities and regenerative properties. Notably, MSCs can transfer mitochondria to unrelated cells through intercellular mitochondrial transfer, offering a groundbreaking approach to halting the progression of mitochondrial diseases and restoring function to cells compromised by mitochondrial dysfunction. Although MSC mitochondrial transfer has demonstrated significant therapeutic promise across a range of diseases, its application in clinical settings remains largely unexplored. This review delves into the novel mechanisms by which MSCs execute mitochondrial transfer, highlighting its profound impact on cellular metabolism, immune modulation, and tissue regeneration. We provide an in-depth analysis of the therapeutic potential of MSC mitochondrial transfer, particularly in treating mitochondrial dysfunction-related diseases and advancing tissue repair strategies. Additionally, we propose innovative considerations for optimizing MSC mitochondrial transfer in clinical trials, emphasizing its potential to reshape the landscape of regenerative medicine and therapeutic interventions.
    Keywords:  Mesenchymal stem cells; immunomodulation; mitochondrial transfer; oxidative stress; therapeutic potential.
    DOI:  https://doi.org/10.2174/011574888X362739250416153254
  22. Biomed Pharmacother. 2025 Apr 27. pii: S0753-3322(25)00250-1. [Epub ahead of print]187 118056
    Contemporary insights into elamipretide's mitochondrial mechanism of action and therapeutic effects.
    Hani N Sabbah, Nathan N Alder, Genevieve C Sparagna, James E Bruce, Brian L Stauffer, Luke H Chao, Robert D S Pitceathly, Christoph Maack, David J Marcinek.
      Mitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide's MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide's ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide's MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions.
    Keywords:  Barth syndrome; Cardiolipin; Elamipretide; MOA; Mechanism; Mitochondria
    DOI:  https://doi.org/10.1016/j.biopha.2025.118056
  23. Methods Mol Biol. 2025 ;2924 1-14
    Cell-Based Assays Using Derived Human-Induced Pluripotent Cells in Drug Discovery and Development.
    James A Ross, Carl-Fredrik Mandenius.
      The use of human-induced pluripotent cell lines in the differentiation of specific cell types and assay development has in recent years progressed significantly. In this introduction to the field, the rationale for using induced pluripotent stem cells in drug development is described and some of the advantages and drawbacks are discussed. The prospect of facilitating drug development by using stratified sources of cells from diverse patient groups and differentiating these to organ and tissue cells for their use in disease models, screening assays, and ADME testing is highlighted. The variety of methodologies and protocols presented in this volume provides a selected collection of experiences and practice. Here, these are discussed in a general perspective with references and comments to other similar protocols in the literature.
    Keywords:  Differentiation protocols; Disease models; Drug screening; Induced pluripotent cell; iPSC
    DOI:  https://doi.org/10.1007/978-1-0716-4530-7_1
  24. Plant Physiol. 2025 Apr 30. pii: kiaf168. [Epub ahead of print]
    Cytoplasmic Inheritance: The Transmission of Plastid and Mitochondrial Genomes Across Cells and Generations.
    Kin Pan Chung.
      In photosynthetic organisms, genetic material is stored in the nucleus and the two cytoplasmic organelles: plastids and mitochondria. While both the nuclear and cytoplasmic genomes are essential for survival, the inheritance of these genomes is subject to distinct laws. Cytoplasmic inheritance differs fundamentally from nuclear inheritance through two unique processes: vegetative segregation and uniparental inheritance. To illustrate the significance of these processes in shaping cytoplasmic inheritance, I will trace the journey of plastid and mitochondrial genomes, following their transmission from parents to progeny. The cellular and molecular mechanisms regulating their transmission along the path are explored. By providing a framework that encompasses the inheritance of both plastid and mitochondrial genomes across cells and generations, I aim to present a comprehensive overview of cytoplasmic inheritance and highlight the intricate interplay of cellular processes that determine inheritance patterns. I will conclude this review by summarizing recent breakthroughs in the field that have significantly advanced our understanding of cytoplasmic inheritance. This knowledge has paved the way for achieving the first instance of controlled cytoplasmic inheritance in plants, unlocking the potential to harness cytoplasmic genetics for crop improvement.
    DOI:  https://doi.org/10.1093/plphys/kiaf168
  25. J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):
    Mitochondria - the CEO of the cell.
    Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.
      As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.
    Keywords:  Mitochondria; Organelle; mtDNA
    DOI:  https://doi.org/10.1242/jcs.263403
  26. Discov Med. 2025 Apr;37(195): 608-617
    GPCRs With mTOR Signaling Expressed in Gut-Brain-Immune Axis-Cells Could Contribute to the Treatment of Neurodegenerative Diseases and Immune-Related Diseases.
    Akari Fukumoto, Naoko Suga, Moeka Nakashima, Satoru Matsuda.
      The central nervous system (CNS) and the immune system might cooperate with each other on various levels in a body. Interestingly, signaling pathways linked to several G protein-coupled receptors (GPCRs) have been shown to be involved in the pathology both of CNS disorders including neurodegenerative diseases and/or immune-related diseases. Oxidative stress and inflammation are likely to contribute to cell damage and death in these disorders, which in turn could cause mitochondrial injury. Interestingly, it has been revealed that gut microbiota could play a significant role in changing the phenotype of various neuron and/or immune-related disorders. Remarkably, GPCR signaling has been recognized as a key upstream regulator for autophagy/mitophagy via the action of the mammalian/mechanistic target of rapamycin (mTOR) signaling. In addition, adjusting the composition of gut microbiota could be applied to modulate the autophagy/mitophagy by the alteration of GPCR signaling to ameliorate the mitochondrial injury. Collectively, this approach may contribute to the innovative development of promising therapeutics for neurodegenerative diseases and/or immune-related diseases. This review describes that concept, highlighting the intracellular mTOR signaling from the cell surface GPCRs within cells of Gut-brain-immune axis.
    Keywords:  GPCR; autophagy; gut microbiota; immune-related disease; mTOR; mitophagy; neurodegenerative disease
    DOI:  https://doi.org/10.24976/Discov.Med.202537195.53
  27. Mech Ageing Dev. 2025 Apr 24. pii: S0047-6374(25)00040-5. [Epub ahead of print] 112064
    Differential effects of lifespan-extending genetic manipulations in an animal model of MJD/SCA3.
    Marta Daniela Costa, Jorge Diogo Da Silva, Dulce Almeida, Joana Pereira-Sousa, Daniela Vilasboas-Campos, Jorge Humberto Fernandes, Andreia Teixeira-Castro, Patrícia Maciel.
      Aging is a natural biological process, but evidence suggests that some aspects of aging can be delayed and reduce the prevalence of neurodegenerative diseases, for which aging is a key risk factor. In a neuronal Caenorhabditis elegans model of a Polyglutamine disease-Spinocerebellar Ataxia Type 3 (SCA3), or Machado-Joseph disease (MJD)- we assessed the hypothesis that delaying aging is neuroprotective, investigating the effect of genetically manipulating multiple lifespan-determinant mechanisms. Lifespan-increasing mutations causing insulin/IGF-1 signaling downregulation, mitochondrial dysfunction, germline ablation and dietary restriction/innate immune activation had distinct impacts on MJD/SCA3 phenotypes, suggesting that not all genetic strategies of stalling aging are equally neuroprotective and challenging the idea that delaying aging is a guaranteed therapy for these diseases. Lifespan-extension improved the SCA3/MJD motor phenotype only when induced by altered nutrient-sensing pathways such as those mediated by insulin/IGF-1 and eat-2 signaling, but their effects on neuronal aggregation differed. These pathways exhibited differential proteostasis profiles, but both activated the heat shock response suggesting that they operate through partially independent mechanisms to confer neuroprotection. The therapeutic value of the insulin/IGF-1 downregulation was demonstrated through the chronic treatment of the SCA3/MJD model with an insulin/IGF-1 signaling inhibitor, underscoring the relevance of aging manipulations in guiding therapeutic strategies for these diseases.
    Keywords:  C. elegans; MJD/SCA3; aging; dietary restriction; germline signaling; insulin/IGF-1; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.mad.2025.112064
  28. Annu Rev Biomed Eng. 2025 May;27(1): 157-183
    Human Organoids as an Emerging Tool for Genome Screenings.
    Francesco Andreatta, Delilah Hendriks, Benedetta Artegiani.
      Over the last decade, a plethora of organoid models have been generated to recapitulate aspects of human development, disease, tissue homeostasis, and repair. Organoids representing multiple tissues have emerged and are typically categorized based on their origin. Tissue-derived organoids are established directly from tissue-resident stem/progenitor cells of either adult or fetal origin. Starting from pluripotent stem cells (PSCs), PSC-derived organoids instead recapitulate the developmental trajectory of a given organ. Gene editing technologies, particularly the CRISPR-Cas toolbox, have greatly facilitated gene manipulation experiments with considerable ease and scalability, revolutionizing organoid-based human biology research. Here, we review the recent adaptation of CRISPR-based screenings in organoids. We examine the strategies adopted to perform CRISPR screenings in organoids, discuss different screening scopes and readouts, and highlight organoid-specific challenges. We then discuss individual organoid-based genome screening studies that have uncovered novel genes involved in a variety of biological processes. We close by providing an outlook on how widespread adaptation of CRISPR screenings across the organoid field may be achieved, to ultimately leverage our understanding of human biology.
    Keywords:  CRISPR-Cas; genetic engineering; genome screening; human organoids; pluripotent stem cells; tissue-derived organoids
    DOI:  https://doi.org/10.1146/annurev-bioeng-103023-122327
  29. Exerc Sport Sci Rev. 2025 May 01.
    Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.
    Maya Semel, Cole Lukasiewicz, Russell T Hepple.
       ABSTRACT: Our Perspective for Progress highlights sex differences in skeletal muscle mitochondrial function that evolve with aging, with an influence of denervation emerging in advanced age. Gaps include knowledge about mitochondrial alterations in microdomains of muscle fibers, plasticity of the mitochondrial reticulum to acute muscle contractions, and advanced age of both sexes.
    Keywords:  Mitochondria; aging; denervation; heterogeneity; skeletal muscle
    DOI:  https://doi.org/10.1249/JES.0000000000000364
  30. ACS Biomater Sci Eng. 2025 Apr 25.
    Platelet Extracellular Vesicles as Natural Delivery Vehicles for Mitochondrial Dysfunction Therapy?
    Hsien Chang Yeh, Kirti Gupta, Ya-Hsuan Lu, Abinaya Srinivasan, Liling Delila, Nguyen Tran Hai Yen, Ariunjargal Nyam-Erdene, Thierry Burnouf.
      Mitochondria are vital for energy production, metabolic regulation, and cellular signaling. Their dysfunction is strongly implicated in neurological, cardiovascular, and muscular degenerative diseases, where energy deficits and oxidative stress accelerate disease progression. Platelet extracellular vesicles (PEVs), once called "platelet dust", have emerged as promising agents for mitigating mitochondrial dysfunction. Like other extracellular vesicles (EVs), PEVs carry diverse molecular cargo and surface markers implicated in disease processes and therapeutic efficacy. Notably, they may possibly contain intact or partially functional mitochondrial components, making them tentatively attractive for targeting mitochondrial damage. Although direct research on PEVs-mediated mitochondrial rescue remains limited, current evidence suggests that PEVs can modulate diseases associated with mitochondrial dysfunction and potentially enhance mitochondrial health. This review explores the therapeutic potential of PEVs in neurodegenerative and cardiovascular disorders, highlighting their role in restoring mitochondrial health. By examining recent advancements in PEVs research, we aim to shed light on novel strategies for utilizing PEVs as therapeutic agents. Our goal is to underscore the importance of further fundamental and applied research into PEVs-based interventions, as innovative tools for combating a wide range of diseases linked to mitochondrial dysfunction.
    Keywords:  exosomes; extracellular vesicles; microvesicles; oxidative stress; platelet
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00473
  31. Antioxidants (Basel). 2025 Mar 25. pii: 384. [Epub ahead of print]14(4):
    The Dual Role of Exogenous Hydrogen Sulfide (H2S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions.
    Domenica Mallardi, Guglielmina Chimienti, Fatima Maqoud, Antonella Orlando, Simona Drago, Eleonora Malerba, Caterina De Virgilio, Hamid I Akbarali, Francesco Russo.
      Hydrogen sulfide (H2S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H2S exert cytoprotective effects, excessive concentrations can lead to toxicity, oxidative stress, and inflammation. The aim of this study was to investigate the dose-dependent effects of exogenous H2S on mitochondrial functions and biogenesis in intestinal epithelial cells under non-stressed conditions. Using a Caco-2 monolayer model, we evaluated the impact of sodium hydrosulfide (NaHS) at concentrations ranging from 1 × 10-7 M to 5 × 10-3 M on mitochondrial metabolism, redox balance, antioxidant defense, inflammatory responses, autophagy/mitophagy, and apoptosis. Our results demonstrated a biphasic response: low-to-moderate H2S concentrations (1 × 10-7 M-1.5 × 10-3 M) enhance mitochondrial biogenesis through PGC-1α activation, upregulating TFAM and COX-4 expression, and increasing the mtDNA copy number. In contrast, higher concentrations (2 × 10-3-5 × 10-3 M) impair mitochondrial function, induce oxidative stress, and promote apoptosis. These effects are associated with elevated reactive oxygen species (ROS) production, dysregulation of antioxidant enzymes, and COX-2-mediated inflammation. H2S-induced autophagy/mitophagy is a protective mechanism at intermediate concentrations but fails to mitigate mitochondrial damage at toxic levels. This study underscores the delicate balance between the cytoprotective and cytotoxic effects of exogenous H2S in intestinal cells, helping to develop new therapeutic approaches for gastrointestinal disorders.
    Keywords:  Caco-2 monolayer model; cytoprotection; gastrointestinal tract; hydrogen sulfide; mitochondria/metabolism; oxidation reduction
    DOI:  https://doi.org/10.3390/antiox14040384
  32. Nutrients. 2025 Apr 15. pii: 1353. [Epub ahead of print]17(8):
    Sulforaphane and Brain Health: From Pathways of Action to Effects on Specific Disorders.
    Jed W Fahey, Hua Liu, Holly Batt, Anita A Panjwani, Petra Tsuji.
      The brain accounts for about 2% of the body's weight, but it consumes about 20% of the body's energy at rest, primarily derived from ATP produced in mitochondria. The brain thus has a high mitochondrial density in its neurons because of its extensive energy demands for maintaining ion gradients, neurotransmission, and synaptic activity. The brain is also extremely susceptible to damage and dysregulation caused by inflammation (neuroinflammation) and oxidative stress. Many systemic challenges to the brain can be mitigated by the phytochemical sulforaphane (SF), which is particularly important in supporting mitochondrial function. SF or its biogenic precursor glucoraphanin, from broccoli seeds or sprouts, can confer neuroprotective and cognitive benefits via diverse physiological and biochemical mechanisms. SF is able to cross the blood-brain barrier as well as to protect it, and it mitigates the consequences of destructive neuroinflammation. It also protects against the neurotoxic effects of environmental pollutants, combats the tissue and cell damage wrought by advanced glycation end products (detoxication), and supports healthy glucose metabolism. These effects are applicable to individuals of all ages, from the developing brains in periconception and infancy, to cognitively, developmentally, and traumatically challenged brains, to those in later life as well as those who are suffering with multiple chronic conditions including Parkinson's and Alzheimer's diseases.
    Keywords:  autism; broccoli; cognition; detoxication; glucoraphanin; neurologic; nutrition; psychiatric; schizophrenia
    DOI:  https://doi.org/10.3390/nu17081353
  33. Biomedicines. 2025 Mar 21. pii: 765. [Epub ahead of print]13(4):
    Pluripotent Stem Cells: Recent Advances and Emerging Trends.
    Aline Yen Ling Wang, Ana Elena Aviña, Yen-Yu Liu, Huang-Kai Kao.
      The field of induced pluripotent stem cells (iPSCs) continues to evolve, offering unprecedented potential for regenerative medicine, disease modeling, and therapeutic applications [...].
    DOI:  https://doi.org/10.3390/biomedicines13040765
  34. Genes (Basel). 2025 Apr 18. pii: 465. [Epub ahead of print]16(4):
    Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies-A Comprehensive Narrative Review.
    Consolato M Sergi.
      Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene is located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have the associated condition, while female individuals who inherit the TAFAZZIN pathogenic variant generally do not experience the condition. There are several organs that may be affected, but striking is the cardiological involvement. Cardiovascular disease, which may be the trigger starting the diagnostic procedure in a proband, may include a range of diseases from a severely dilated heart to a hypertrophic heart in the spectrum of anomalies encountered. Left ventricular non-compaction of the heart is also occasionally encountered. This cardiac event may reveal the prognosis of the affected patients. In this narrative review, we highlight the gene's characteristics, the reactome, the cardiological features of the cardiovascular disease observed in patients affected with BTHS, emphasize the most current studies on BTHS cardiomyopathy, and delineate the biological underlying mechanisms supporting the proposal of new therapeutic options.
    Keywords:  BTHS; Barth syndrome; TAFAZZIN; TAZ; cardiac surgery; cardiovascular disease; left ventricular non-compaction; metabolic disease; outcome; prognosis
    DOI:  https://doi.org/10.3390/genes16040465
  35. J Clin Med. 2025 Apr 16. pii: 2748. [Epub ahead of print]14(8):
    Coenzyme Q10 and the Blood-Brain Barrier: An Overview.
    David Mantle, Iain Hargreaves.
      Mitochondrial dysfunction is a common factor known to be involved in the pathogenesis of a number of neurological disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Given the importance of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, and the deficiency of CoQ10 reported in such neurological disorders, there is a rationale for investigating the potential therapeutic role of supplementary CoQ10. However, while there is evidence for the efficacy of CoQ10 supplementation in animal models of the above disorders, randomised controlled clinical trials supplementing CoQ10 in PD, AD, or ALS have had disappointing outcomes. This in turn may be a reflection of the current uncertainty as to whether CoQ10 can access the blood-brain barrier in human subjects. In an attempt to further elucidate the disparity in outcomes of such preclinical and clinical studies, in this article we have reviewed evidence from the peer-reviewed literature to establish the ability of CoQ10 to access the brain via the BBB.
    Keywords:  blood CSF barrier; blood–brain barrier; coenzyme Q10; intranasal drug delivery; mitochondrial dysfunction; neurological disorders
    DOI:  https://doi.org/10.3390/jcm14082748
  36. Theranostics. 2025 ;15(11): 5138-5152
    Decoding the role of microtubules: a trafficking road for vesicle.
    Jiaorong Qu, Jianan Li, Hong Wang, Jianhang Lan, Zixuan Huo, Xiaojiaoyang Li.
      Background: In eukaryotic cells, intracellular and extracellular vesicle transport systems are ubiquitous and tightly linked. This process involves well-defined initiation and termination points, as well as mechanisms for vesicle recycling. During transport, cytoskeletal components serve as "roads" to prevent disordered vesicular movement and to ensure efficient transport, particularly through microtubules. Microtubules primarily facilitate the long-distance transport of vesicles. The dynamic nature of microtubule structure makes its stability sensitive to proteins, drugs, and post-translational modifications such as acetylation, which in turn regulate microtubule-dependent vesicular transport. Furthermore, motor proteins interact with microtubules and bind to cargoes via their tail domains, driving vesicle transport along microtubules and determining the directionality of movement. Aim of review: To elucidate the detailed processes and mechanisms of microtubules-regulated long-distance vesicle transport, providing a comprehensive overview of current research in this area. Key scientific concepts of review: This review provides an in-depth analysis of microtubule-mediated vesicle transport, emphasizing the molecular mechanisms involved. It examines vesicle transport between organelles, the impact of microtubule characteristics on this process, and the role of motor proteins in vesicle dynamics. Additionally, it summarizes diseases associated with abnormal microtubule-mediated vesicle transport, aiming to offer insights for the treatment of related conditions.
    Keywords:  cytoskeleton; microtubule acetylation; microtubules; motor protein; vesicle transport
    DOI:  https://doi.org/10.7150/thno.110120
  37. Antioxidants (Basel). 2025 Apr 08. pii: 446. [Epub ahead of print]14(4):
    Replicative Senescence in Mesenchymal Stem Cells: An In Vitro Study on Mitochondrial Dynamics and Metabolic Alterations.
    Beatrice Casorati, Isabella Zafferri, Sara Castiglioni, Jeanette A Maier.
      Mesenchymal stem cells (MSCs) are multipotent progenitors capable of self-renewal and differentiation into various cell lineages, making them essential for tissue repair and regenerative medicine. However, their regenerative potential is constrained by replicative senescence, an irreversible growth arrest that occurs after a finite number of cell divisions. In this study, we serially passaged human bone marrow-derived MSCs (bMSCs) and compared young, pre-senescent, and senescent cells. The onset of senescence was accompanied by progressive alterations in mitochondrial dynamics, leading to a decline in mitochondrial membrane potential, and increased reactive oxygen species (ROS) production, alongside a diminished cellular antioxidant capacity. These mitochondrial defects play a role in metabolic reprogramming in senescent bMSCs. Our findings underscore the intricate interplay between ROS, mitochondrial dysfunction, and replicative senescence, offering valuable insights to guide the development of therapeutic strategies for preserving MSC functionality in aging and MSC-based therapies.
    Keywords:  ROS; mesenchymal stem cells; mitochondria; replicative senescence
    DOI:  https://doi.org/10.3390/antiox14040446
  38. Fundam Clin Pharmacol. 2025 Jun;39(3): e70010
    Sodium thiosulfate mitigates PM2.5-induced cardiotoxicity by preservation of mitochondrial function.
    Bhavana Sivakumar, Gino A Kurian.
       BACKGROUND: Exposure to PM2.5 triggers changes in myocardial structure and function, leading to a decline in the ability of heart to withstand further oxidative stress. This manuscript addresses the absence of a endogenous agent capable of counteracting the cardiac toxicity associated with PM2.5 exposure. Consequently, we investigated the potential of sodium thiosulfate (STS) to elevate thiosulfate levels, given its known antioxidant, anti-inflammatory, metal chelation, and mitochondrial preservation properties, in order to mitigate PM2.5 induced cardiac damage.
    METHODS: Female Wistar rats were exposed to PM2.5 (250 μg/m3) for 3 hours daily for 21 days, after which their hearts were excised and mounted on Langendorff apparatus for ischemia-reperfusion (IR) induction. We implemented both preventive and curative investigation protocols for STS: the preventive group received STS thrice weekly for 3 weeks during the exposure regimen, while the curative group received STS after 21 days of PM2.5 exposure for 3 weeks (thrice per week).
    RESULTS: Treatment with STS exhibited cardioprotective potential against the detrimental effects of PM2.5 exposure, as evidenced by improved cardiac hemodynamic performance, reduced tissue damage, attenuation of structural remodeling associated with hypertrophy and fibrosis, and a significant reduction in metal deposition. Moreover, it demonstrated an ability to enhance the resilience against IR. Cellular and subcellular level analyses revealed improved mitochondrial function. The protective efficacy of STS was more significant when administered as a preventive measure compared to its curative application.
    CONCLUSION: In summary, our results indicate that STS effectively alleviates PM2.5-induced toxicity due to its antioxidative, metal-chelating, and preservation of mitochondrial function capabilities.
    Keywords:  PM2.5; cardiovascular disease; mitochondria; myocardial ischemia–reperfusion injury; sodium thiosulphate
    DOI:  https://doi.org/10.1111/fcp.70010
  39. Curr Allergy Asthma Rep. 2025 Apr 29. 25(1): 23
    Pediatric Systemic Autoinflammatory Disorders: An Overview.
    Julisa M Patel.
       PURPOSE OF REVIEW: Systemic autoinflammatory disorders (SAIDs) are a group of diseases that are characterized by recurrent or persistent unprovoked attacks of inflammation resulting from innate immunity dysregulation and leading to significant sequelae in many cases. The concept of autoinflammatory disorders has been widely studied in the last 28 years since the genetic mutation responsible for familial Mediterranean fever (FMF) was discovered. These disorders are mainly hereditary autoinflammatory diseases with key immunological pathways affected and particularly involving inflammasomes, nuclear factor-κB dysregulation and interferon upregulation. This article serves as an overview of pediatric systemic autoinflammatory disorders, their presentation, workup, complications, and therapeutic management.
    RECENT FINDINGS: Advances in genetic analysis have allowed for the rapid identification of mutations responsible for many autoinflammatory disorders. Advances in biomolecular techniques, which have allowed for identifying key players such as inflammasomes, have led to treatment options that have significantly improved morbidity and mortality in affected patients. This review provides an overview of the proposed pathogenesis, presenting features, potential complications and suggested therapies of systemic autoinflammatory disorders. Providers should have a high clinical suspicion for autoinflammatory disorders in children who present with fever, a heightened inflammatory response and negative evaluation for an infectious, malignant, and autoimmune etiology. Understanding and identifying these disorders in a timely manner and implementing prompt treatment allow for the best possible outcome for these patients.
    Keywords:  Autoinflammatory disorders; Inflammasome; Innate immunity; Pediatric; Periodic fevers
    DOI:  https://doi.org/10.1007/s11882-025-01203-y
  40. J Pharm Anal. 2025 Apr;15(4): 101146
    Mitochondrial quality control disorder in neurodegenerative disorders: Potential and advantages of traditional Chinese medicines.
    Lei Xu, Tao Zhang, Baojie Zhu, Honglin Tao, Yue Liu, Xianfeng Liu, Yi Zhang, Xianli Meng.
      Neurodegenerative disorders (NDDs) are prevalent chronic conditions characterized by progressive synaptic loss and pathological protein alterations. Increasing evidence suggested that mitochondrial quality control (MQC) serves as the key cellular process responsible for clearing misfolded proteins and impaired mitochondria. Herein, we provided a comprehensive analysis of the mechanisms through which MQC mediates the onset and progression of NDDs, emphasizing mitochondrial dynamic stability, the clearance of damaged mitochondria, and the generation of new mitochondria. In addition, traditional Chinese medicines (TCMs) and their active monomers targeting MQC in NDD treatment have been demonstrated. Consequently, we compiled the TCMs that show great potential in the treatment of NDDs by targeting MQC, aiming to offer novel insights and a scientific foundation for the use of MQC stabilizers in NDD prevention and treatment.
    Keywords:  Mitochondrial quality control; Neurodegenerative disorder; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jpha.2024.101146
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