bims-polgdi Biomed News
on POLG disease
Issue of 2025–06–22
25 papers selected by
Luca Bolliger, lxBio



  1. Mol Biomed. 2025 Jun 19. 6(1): 42
      Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.
    Keywords:  Cancer; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Therapy
    DOI:  https://doi.org/10.1186/s43556-025-00284-5
  2. J Neuromuscul Dis. 2025 Jun 19. 22143602241307198
      Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases.In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.
    Keywords:  induced pluripotent stem cells; neuronal models; primary mitochondrial diseases
    DOI:  https://doi.org/10.1177/22143602241307198
  3. Sci Rep. 2025 Jun 19. 15(1): 18717
      Mitochondrial genome mutations are associated with various diseases and gene therapy targeted to mitochondria has the potential to effectively treat such diseases. Here, we targeted a point mutation in mitochondrial DNA (mtDNA) that can cause mitochondrial diseases via delivery of the clustered, regularly interspaced, short palindromic repeats/Cas9 (CRISPR/Cas9) system to mitochondria using an innovative lipid nanoparticle (LNP) delivery system. To overcome the major barrier of the mitochondrial membrane structure, we investigated a strategy to deliver ribonucleoprotein (RNP) directly to mitochondria via membrane fusion using MITO-Porter, a mitochondria-targeting lipid nanoparticle. First, we constructed RNP-MITO-Porter, in which an RNP was loaded into MITO-Porter using a microfluidic device. Sequence-specific double-strand breaks were confirmed when the constructed RNP-MITO-Porter was applied to isolated mitochondria. Next, the RNP-MITO-Porter was applied to HeLa cells, and a portion of the RNP-MITO-Porter was colocalized with mitochondria and caused sequence-specific double-strand breaks in mtDNA. Finally, RNP-MITO-Porter was successfully delivered to mitochondria of cells derived from a mouse carrying a point mutation (m.7778G > T) in mtDNA (mt-Atp8) (LMSF-N-MTFVB cells), and created double-strand breaks at the target sequence. RNP-MITO-Porter is expected to contribute significantly to the clinical application of mitochondrion-targeted gene therapy.
    Keywords:  CRISPR/Cas9 ribonucleoprotein (RNP); Lipid nanoparticle (LNP); MITO-Porter; Mitochondrial genome editing; Mitochondrial-targeted delivery
    DOI:  https://doi.org/10.1038/s41598-025-03671-8
  4. Neural Regen Res. 2025 Jun 19.
       ABSTRACT: Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.
    Keywords:  autism spectrum disorders; autophagic clearance; cellular homeostasis; fusion and fission; mitochondrial dynamics; mitophagy; neural regeneration; neurodevelopmental disorders; neuronal energy metabolism; oxidative stress
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01422
  5. Neural Regen Res. 2025 Jun 19.
       ABSTRACT: Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and nonsynaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.
    Keywords:  aging; hippocampus; memory; mitochondria; synaptic mitochondria
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01571
  6. Commun Biol. 2025 Jun 17. 8(1): 936
      VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
    DOI:  https://doi.org/10.1038/s42003-025-08311-5
  7. Aging Dis. 2025 Jun 18.
      Mitochondria are dynamic organelles vital for neuronal function due to their ability to generate ATP, sequester cytosolic calcium (Ca2+), regulate lipid metabolism, and modulate apoptosis signaling. In order to maintain these essential functions in healthy neurons, mitochondria must be continuously replenished through mitochondrial turnover and biogenesis. Conversely, the dysregulation of mitochondrial homeostasis can lead to oxidative stress and contribute to the neuropathology of Parkinson's disease (PD). This review will provide an updated in-depth review of mitochondrial processes such as mitophagy, biogenesis, trafficking, oxidative phosphorylation, Ca2+ sequestration, mitochondrial transfer, and their relevance to PD pathophysiology. We provide an extensive overview of the neuroprotective molecular signaling pathways regulated by PD-associated proteins that converge at the mitochondrion. Importantly, in this review we highlight aspects of mitochondrial pathology that converge across multiple models including iPSCs, patient-derived fibroblasts, cell culture models, rodent models and chemical and genetic models of PD. Finally, we provide a comprehensive update on the molecular toolbox used to interrogate these signaling pathways using in vitro and in vivo models of PD and provide insight into the downstream protein targets that can be leveraged to develop novel therapies against PD.
    DOI:  https://doi.org/10.14336/AD.2025.0440
  8. Exp Cell Res. 2025 Jun 13. pii: S0014-4827(25)00247-2. [Epub ahead of print]450(2): 114647
      Subcellular disorders are linked with several diseases, specifically mitochondrial dysfunction linked to age, metabolic disorders, cancer, cardiovascular disease, and other mitochondrial diseases (MDs). Intracellular medication delivery is a promising option for effective therapy. This study aims to highlight subcellular delivery with focus on mitochondrial pharmacology, gene therapy, transplantation, and drug targeting. PubMed, Google Scholar, Scopus, and other scholarly sources were leveraged to prepare this narrative review. According to current studies, intermittent fasting, consistent exercise, well-balanced diets, and proper sleep can all help to increase mitochondrial quality. Molecular therapies improve mitochondrial bioenergetics, redox status, biogenesis, dynamics, mitophagy, bioenergetic, and sirtuins. The antioxidant supplementation restores endogenous antioxidants such as alpha-lipoic acid, tocopherols, L-carnitine, and coenzyme Q10 to prevent mitochondrial damage. Mdivi-1, melatonin, resveratrol, PGC-1α agonists, metformin, and Opa1 activators modify the dynamics and biogenesis of mitochondria. Bioactive phytochemicals, including curcumin, berberine, quercetin, and capsaicin, affect OXPHOS and mitochondrial sirtuins. These agents affect gene expression, antioxidant defenses, inflammation, and mitochondrion functions. Therefore, bioactive phytochemicals limit oxidative damage, increase insulin sensitivity, and improve extended cell longevity. Mitochondrial transplantation and gene therapy using mRNA and gene editing technologies are promising treatment options for MDs. Mitoquidone, triphenylphosphine, mitochondrial-targeting peptides, and nanocarriers localize medicines within mitochondrial compartments. In conclusion, a good lifestyle and bioactive materials, alongside mitochondrial medications, gene therapy, transplantation, and drug targeting, could restore overall cellular health.
    Keywords:  Bioactive compounds; Gene therapy; MDT; Mitochondrial biogenesis; Sirtuins; Uncouplers
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114647
  9. Cell Commun Signal. 2025 Jun 19. 23(1): 290
      Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
    Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-025-02308-7
  10. EMBO J. 2025 Jun 16.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
  11. Mol Cells. 2025 Jun 12. pii: S1016-8478(25)00062-7. [Epub ahead of print] 100238
      Mitochondria play a central role in cellular energy metabolism and signaling, and their dysfunction is associated with a wide range of diseases. Therefore, assessing mitochondrial function is essential for understanding their role in various cellular processes and disease progression. Here, we describe the principles and methodologies for analyzing mitochondrial membrane potential, reactive oxygen species, and calcium levels using the fluorescent probes TMRM, MitoSOX, and Rhod-2AM, respectively. This work provides a practical guide for researchers investigating mitochondrial function under physiological and pathological conditions.
    Keywords:  Calcium; MitoSOX; Mitochondria; ROS; Rhod-2AM; TMRM; membrane potential
    DOI:  https://doi.org/10.1016/j.mocell.2025.100238
  12. Mitochondrion. 2025 Jun 18. pii: S1567-7249(25)00058-3. [Epub ahead of print] 102061
      Diagnosing mitochondrial diseases remains challenging because of the heterogeneous symptoms. This study aims to use machine learning to predict mitochondrial diseases from phenotypes to reduce genetic testing costs. This study included patients who underwent whole exome or mitochondrial genome sequencing for suspected mitochondrial diseases. Clinical phenotypes were coded, and machine learning models (support vector machine, random forest, multilayer perceptron, and XGBoost) were developed to classify patients. Of 103 patients, 43 (41.7%) had mitochondrial diseases. Myopathy and respiratory failure differed significantly between the two groups. XGBoost achieved the highest accuracy (67.5%). In conclusion, machine learning improves patient prioritization and diagnostic yield.
    Keywords:  Machine learning; Mitochondrial diseases; Phenotype
    DOI:  https://doi.org/10.1016/j.mito.2025.102061
  13. Psychoneuroendocrinology. 2025 Jun 06. pii: S0306-4530(25)00227-6. [Epub ahead of print]179 107504
       BACKGROUND: Early life stress (ELS) is a well-established risk factor for psychiatric conditions across the lifespan. A growing body of evidence indicates that alterations to mitochondrial DNA may result from chronic activation of physiological stress responses in ELS and may be associated with psychiatric outcomes. Several studies have found relationships between a number of psychiatric conditions and mtDNA copy number (mtDNAcn), with emerging evidence for a role of early life stress in these associations. This study examined mtDNAcn in physically healthy young adults with and without ELS and a broad range of psychiatric conditions.
    METHODS: Participants (N = 181; 69.1 % female) included those with ELS and psychiatric conditions (n = 59; ELS+Psych), ELS and no psychiatric conditions (n = 49; ELS-Psych), and with neither ELS nor psychiatric conditions (n = 73; Controls). Standardized interviews and self-reports assessed demographics, stress, and mental health. DNA from PBMCs was used as input for ultra-low coverage whole genome sequencing (ULC-WGS); mtDNAcn was quantified using the fastMitoCalc tool. ANOVAs were used to examine group differences and negative binomial regression models assessed ELS, psychopathology and mtDNAcn relationships with covariates age and sex.
    RESULTS: ELS+Psych individuals had significantly greater mtDNAcn compared to Control participants (p < .05), even after adjusting for relevant covariates. There was no difference between ELS-Psych individuals and Control participants.
    CONCLUSIONS: Increased rates of mtDNAcn among individuals with ELS+Psych, but not among those with ELS-Psych, compared to Controls indicates that observable effects of ELS may only occur in the presence of psychiatric symptomatology. Findings and future directions are discussed.
    Keywords:  Allostatic load; Childhood adversity; Early life stress; Mitochondria; Mitochondrial DNA copy number; MtDNAcn
    DOI:  https://doi.org/10.1016/j.psyneuen.2025.107504
  14. Nat Cell Biol. 2025 Jun;27(6): 890-901
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  15. Mol Genet Metab. 2025 Jun 04. pii: S1096-7192(25)00149-0. [Epub ahead of print]145(4): 109158
       OBJECTIVE: To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations.
    METHODS: This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS).
    RESULTS: Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3-60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, n = 18; SPI, n = 13; LP, n = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS < 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (p < 0.05). In terms of genetics, all patients were compound heterozygous variants in the ECHS1 gene, with 21 novel variants identified. The most common variant was the c.489G > A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes.
    CONCLUSIONS: This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G > A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.
    Keywords:  ECHS1 gene; Leigh syndrome; Prognosis; Synonymous variant; Urinary metabolite
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109158
  16. Orphanet J Rare Dis. 2025 Jun 13. 20(1): 306
      The mitochondrial m.3243 A > G variant is a prevalent mitochondrial disease mutation that causes multisystem maternal inheritance disorders. While clinical severity typically correlates with mutation load, symptom manifestation may be influenced by other variants and environmental factors. Notably, the m.3290T > C variant has been hypothesized as a potential protective variant for m.3243 A > G pathogenicity, though clinical evidence remains limited. Here we reported a six-generation Chinese pedigree carrying both m.3243 A > G and homoplasmic m.3290T > C variants. Clinical and genetic analyses revealed that carriers with extremely high m.3243 A > G heteroplasmy (> 95%) exhibited severe symptoms, whereas those with moderate or high levels showed limited or no clinical symptoms. Our findings provide novel evidence for the protective role of m.3290T > C in mitigating m.3243 A > G pathogenicity, highlighting its potential clinical significance.
    Keywords:  MELAS; Mitochondrial DNA; Mitochondrial disease; m.3243A > G; m.3290T > C
    DOI:  https://doi.org/10.1186/s13023-025-03774-5
  17. Transl Pediatr. 2025 May 30. 14(5): 1059-1064
       Background: Kearns-Sayre syndrome (KSS) is a mitochondrial genetic disorder characterized by progressive external ophthalmoplegia, short stature, atrioventricular block, and proximal renal tubular dysfunction. While Fanconi syndrome is a recognized renal manifestation of KSS, it is rare as the initial presenting feature. This report describes the clinical and genetic features of a child with KSS who initially presented with Fanconi syndrome.
    Case Description: A 10-year-old girl, initially diagnosed with Fanconi syndrome at 3 years of age, exhibited growth retardation by age 5 years and bilateral ptosis by age 8 years. In July 2022, her age of 10 years, she developed diabetes mellitus and third-degree atrioventricular block. The patient presented for medical evaluation. Upon examination, she was found to have sensorineural hearing loss, hyperlactatemia, elevated cerebrospinal fluid protein, decreased folate levels, and renal insufficiency. Muscle biopsy revealed ragged red fibers, and mitochondrial gene analysis confirmed the diagnosis of KSS. Whole-exome sequencing identified a heterozygous mutation in the DNA2 gene (c.865C>T, p.R286X) along with a 7,521-base pair mitochondrial DNA deletion. Symptoms improved with nutritional mitochondrial therapy.
    Conclusions: Mitochondrial mutations may contribute to the development of Fanconi syndrome. Fanconi syndrome may present as the initial manifestation of KSS. KSS should be considered in pediatric patients presenting with Fanconi syndrome and extrarenal manifestations, such as ptosis.
    Keywords:  Fanconi syndrome; Kearns-Sayre syndrome (KSS); case report; pediatric nephrology
    DOI:  https://doi.org/10.21037/tp-2025-138
  18. Neural Regen Res. 2025 Jun 19.
       ABSTRACT: The mechanisms leading to neurological and neurodegenerative diseases are not completely known, and new, more effective, therapeutic treatments are necessary for most neurological pathologies. The treatment of neurological and neurodegenerative diseases is complicated due to the blood-brain barrier, which makes it difficult for drugs to access the brain areas in which they must act to improve the pathology. A tool that can help to overcome this difficulty is the use of extracellular vesicles, which can easily cross the blood-brain barrier. The extracellular vesicles are considered a main way of communication between the brain and the rest of the body, with important implications for the physiopathology and therapy of neurological diseases. In recent years, the involvement of microbiota in many neurological pathologies, as well as its possible therapeutic role, has also become evident. A key mediator in the pathologic and beneficial effects of microbiota seems to be the bacterial extracellular vesicles. There is an important communication between the brain and the intestinal microbiota (the gut-brain axis), by which the microbiota influences brain function, impacts on mental health, and plays a role in different neurological and neurodegenerative diseases. The identification of the mechanisms involved in this gut-brain axis is essential to understanding the mechanisms of neurological pathologies and to developing more effective treatments for these diseases. Bacterial extracellular vesicles would play a relevant role in these processes. This review compiles the recent information and evidence on the role of bacterial extracellular vesicles in brain pathologies and on the therapeutic utility of bacterial extracellular vesicles in neurological and neurodegenerative diseases. One advantage of bacterial extracellular vesicles compared to extracellular vesicles derived from other cell types, such as stem cells, is that bacterial extracellular vesicles are generally easier to produce and modify. Bacterial extracellular vesicles may be easily modified to target a specific pathology and/ or to enhance its therapeutic efficacy. Although the studies are still scarce, they open a wide field of possibilities for future studies, which will lead to a deeper understanding of the role of microbiota and bacterial extracellular vesicles in neurological pathologies and the underlying mechanisms, as well as to the development of new treatments based on the use of bacterial extracellular vesicles in neurological diseases.
    Keywords:  bacteria; bacterial extracellular vesicles; gut-brain axis; inflammation; microbiota; neuroinflammation; neurological diseases; neurotransmission; pathogenic; probiotic; therapeutic treatment
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00236
  19. Aging Cell. 2025 Jun 16. e70135
      Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7-14 days of NAM depletion, despite NAD+ levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon-dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage-dependent anion channel 1 (VDAC1), which activated the cGAS-STING signaling pathway. Inhibition of VDAC oligomerization with VBIT-4, STING signaling with H-151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC-mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.
    DOI:  https://doi.org/10.1111/acel.70135
  20. Science. 2025 Jun 19. 388(6753): eadx0043
      The brain's response to injury includes the activation of intrinsic microglia and the influx of leukocytes, collectively constituting neuroinflammation, the "flame" of the brain. Although details differ and matter, neuroinflammation exacerbating neurodegeneration has similarities across multiple sclerosis and other neurological disorders, such as stroke and neurodegenerative diseases. Thus, lessons from successful disease-modifying therapies in multiple sclerosis may provide insights into strategies for modulating neuroinflammation and reducing neural injury in other neurological conditions. In this Review, we discuss these lessons and potential strategies for counteracting neuroinflammation, including taming the microglia-orchestrated brain immune responses that contribute to progressing neuropathology.
    DOI:  https://doi.org/10.1126/science.adx0043
  21. J Extracell Vesicles. 2025 Jun;14(6): e70097
      Extracellular vesicles (EV) have emerged as promising nanocarriers for drug delivery. However, the efficient loading of therapeutic molecules into EV and the subsequent purification of drug-loaded EV from unloaded drugs remain significant challenges. This review explores the most used methods for EV purification, meaning the separation of drug-loaded EV from unloaded drugs, including ultracentrifugation, density gradient centrifugation, ultrafiltration, size exclusion chromatography, dialysis and commercial exosome isolation kits. The principles, advantages and limitations of each method are discussed. Critical parameters such as molecular weight cutoff, membrane composition, and the nature of the loaded molecule are highlighted for their impact on the purification process. The review also addresses the technical aspects, including time, cost and equipment requirements, and emphasizes the need for standardized guidelines to improve reproducibility and comparability across studies. By providing a comprehensive overview of current purification strategies, this review aims to guide researchers in selecting the most appropriate methods for advancing EV-based drug delivery systems.
    DOI:  https://doi.org/10.1002/jev2.70097
  22. Front Endocrinol (Lausanne). 2025 ;16 1550068
      Extracellular vesicles (EVs) facilitate intercellular communication and the conveyance of bioactive substances, including proteins, lipids, and nucleic acids. They play a significant role in various reproductive biological processes, including gametogenesis, fertilization, early embryo development, and implantation. Dysfunctional EV activity is associated with various reproductive diseases, such as polycystic ovary syndrome (PCOS), endometriosis, male infertility, and recurrent pregnancy loss (RPL). This review systematically examines and categorizes current knowledge on EV functions in reproductive biology and disorders, and their potential as diagnostic and therapeutic tools. A systematic literature search from 2000 to 2024 identified studies showing EVs' influence on gamete maturation, fertilization, embryonic development, and implantation. They also play a role in reproductive disorders by affecting insulin resistance, androgen production, inflammation, angiogenesis, sperm quality, and maternal-fetal immune tolerance. The review concludes that EVs are integral to reproductive health, with further research needed to understand their mechanisms and clinical potential.
    Keywords:  embryo implantation; embryos; extracellular vesicles; fertility; oocyte; reproductive disorders; sperm
    DOI:  https://doi.org/10.3389/fendo.2025.1550068
  23. Chem Commun (Camb). 2025 Jun 20.
      A novel viscosity-sensitive, mitochondrial-targeted AIE fluorescent probe, TPE-4TPP, was developed to quantify dynamic changes in mitochondrial viscosity induced by an anticancer drug. Using fluorescence lifetime as a bridge, a quantitative relationship between drug duration and mitochondrial viscosity was established.
    DOI:  https://doi.org/10.1039/d5cc01021g
  24. Life Sci. 2025 Jun 15. pii: S0024-3205(25)00448-5. [Epub ahead of print] 123813
      The global burden of skin diseases has markedly increased in recent years, posing significant socioeconomic challenges. Although recent technological advances in dermatological care aim to address these issues, further research is needed to develop effective and innovative strategies. Intercellular communication plays a vital role in skin regeneration and repair. Extracellular vesicles (EVs), lipid bilayer-enclosed particles released by nearly all cell types, are categorized into exosomes, microvesicles, and apoptotic bodies based on their biogenesis and size. EVs carry diverse bioactive molecules, including proteins, lipids, and nucleic acids, enabling them to mediate critical cell-cell communication. Recent breakthroughs, particularly through spatially resolved multi-omics approaches, have underscored the essential roles of EVs in both physiological and pathological processes of the skin. In this review, we provide a comprehensive overview of EV biology, with a particular focus on their functions in skin homeostasis, aging, and diseases. We highlight emerging evidence of their therapeutic potential in preclinical models, with emphasis on EV interactions with various skin cell types, inflammatory and autoimmune skin conditions, skin aging, and tissue repair.
    Keywords:  Extracellular vesicles; Skin aging; Skin autoimmune diseases; Skin inflammatory diseases; Therapeutic applications
    DOI:  https://doi.org/10.1016/j.lfs.2025.123813
  25. Front Neurosci. 2025 ;19 1602149
      Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.
    Keywords:  ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2025.1602149