bims-polgdi Biomed News
on POLG disease
Issue of 2025–07–06
fifteen papers selected by
Luca Bolliger, lxBio



  1. Soc Sci Med. 2025 May 15. pii: S0277-9536(25)00507-6. [Epub ahead of print]382 118177
      'Mitochondrial disease' is an umbrella category for neurogenetic and metabolic diseases which are associated with mitochondrial dysfunction caused by genetic variations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). This article draws on interviews with four mitochondrial disease specialists in Germany in order to explore their perspectives on mitochondrial replacement techniques (MRTs), emerging 'IVF-based technologies' which could potentially prevent the transmission of mitochondrial DNA disease. MRTs aim to exchange (or replace) the cytoplasm of an intended parent's egg cell, which contains disease-causing mtDNA, with the cytoplasm from an egg cell of another individual (aka the mitochondrial donor). MRTs are legal and regulated by assisted reproduction legislation in the UK (since 2015) and Australia (since 2022) for the explicit purpose of reducing the risk of transmitting an mtDNA variant associated with a high risk of severe mitochondrial disease. MRTs are not available in Germany. In other countries, MRTs are offered by fertility clinics for a variety of indications, ranging from the prevention of mitochondrial disease to broader experiences of fertility difficulties. Mitochondrial disease specialists in Germany emphasized the predictability of mitochondrial unpredictability and a mitochondrial disease severity spectrum. Closely engaging with the use of two concepts by the specialists I interviewed-'predictability/unpredictability' and 'severity'-which also appeared in formal and public representations and discussions in the UK, I show how the invocation of these notions may paradoxically both enable and curtail support for the clinical implementation of MRTs.
    Keywords:  Assisted reproduction; Mitochondrial disease; Mitochondrial replacement techniques; Predictability; Rare disease; Severity spectrum; Unpredictability
    DOI:  https://doi.org/10.1016/j.socscimed.2025.118177
  2. Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14
      Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.
    Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity
    DOI:  https://doi.org/10.7554/eLife.104461
  3. Biochim Biophys Acta Mol Cell Res. 2025 Jun 30. pii: S0167-4889(25)00117-X. [Epub ahead of print]1872(7): 120012
      Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.
    Keywords:  15-HETE; Akt-FoxO1 signaling; Mitochondrial disease; m.3243A>G; mtDNA haplogroup
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120012
  4. Cell Death Dis. 2025 Jul 01. 16(1): 473
      Mitochondria, often referred to the powerhouse of the cell, are essential for cellular energy production, and their dysfunction can profoundly affect various organs. Transplantation of healthy mitochondria can restore the bioenergetics in diseased cells and address multiple conditions, but more potentials of this approach remain unclear. In this study, I demonstrated that the source of transplanted mitochondria is not limited by species, as exhibit no significant responses to mitochondria derived from different germlines. Moreover, I identified that metabolic compatibility between the recipient and exogenous mitochondria as a crucial factor in mitochondrial transplantation, which confers unique metabolic properties to recipient cells, enabling them to combat different diseases. Additionally, my findings indicated competitive interactions among mitochondria with varying functions, with more bioenergetic-active mitochondria yielded superior therapeutic benefits. Notably, no upper limit for the bioenhancement provided by exogenous mitochondria has been identified. Based on these insights, I proposes a novel therapeutic approach-adaptive bioenhancement through mitochondrial transplantation.
    DOI:  https://doi.org/10.1038/s41419-025-07643-8
  5. Eur J Med Res. 2025 Jul 01. 30(1): 524
      Vascular diseases (VD), such as cardiovascular diseases, cerebrovascular diseases, and diabetic diseases, originate from numerous pathophysiological changes and remain a serious public health concern. Extracellular vesicles (EVs) produced by cells contribute to regulating VD either dangerously or beneficially. The term EVs refers to the heterogeneous population of vesicles, such as exosomes and microvesicles that participate in cell communication during VD. EVs from different cells, especially those of stem cells, show great promise in the improvement of various VD. They can repair cellular damage, enhance and recover cell function, multiply cells, and prevent cell death and inflammation in specific tissues/cells. EVs have the potential to enhance conditions like cardiovascular disease, cerebrovascular disorders, and complications related to diabetes. Furthermore, an increasing amount of evidence indicates that EVs can be altered/loaded to create a drug delivery system for transporting therapeutic agents to cells, improving different VD. Different methods are used to engineer EVs to improve the efficacy of natural EVs. Despite the potential clinical application of EVs, this field facese many problems that need to be addressed. These limitations and challenges have unmasked the unexpected complexity of EVs regulatory mechanisms, and inspiring advances have been achieved.
    Keywords:  Cardiovascular disease; Cerebrovascular diseases; Exosomes; Extracellular vesicle; MiRNA
    DOI:  https://doi.org/10.1186/s40001-025-02822-x
  6. Nat Commun. 2025 Jul 01. 16(1): 5709
      Mitochondrial dysfunction contributes to aging and diseases like neurodegeneration and cardiovascular disorders. Mitochondria transfer and transplantation (MTT) represent promising therapeutic strategies aimed at restoring cellular function by introducing functional mitochondria into damaged cells. However, challenges like transfer efficiency, stability, and cellular integration limit clinical application. Recent biotechnological advances-such as liposomes, extracellular vesicles, and surface modifications-enhance mitochondrial protection, targeting, and biocompatibility. This Perspective highlights recent progress in MTT, its therapeutic potential, and current limitations. We also discuss the need for scalable, clinically translatable approaches and appropriate regulatory frameworks to realize the full potential of mitochondria-based nanotherapies in modern medicine.
    DOI:  https://doi.org/10.1038/s41467-025-61239-6
  7. Nat Rev Mol Cell Biol. 2025 Jul 03.
      Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.
    DOI:  https://doi.org/10.1038/s41580-025-00865-w
  8. Sci China Life Sci. 2025 Jul 02.
      Extracellular vesicles (EVs) are membrane-bound subcellular entities that perform crucial roles in cellular communication and the release of intracellular contents. Traditionally, EVs have been recognized for encapsulating a variety of biomolecules, including DNA, RNA, proteins, and metabolites. However, recent advancements in research have revealed that EVs can also encapsulate organelles, with mitochondria emerging as a significant cargo. This review delves into the burgeoning field of mitochondria-encapsulating EVs, such as mitophers, migrasomes, and exophers, along with other mitochondria-harboring EVs that are less characterized. We explore the discovery, distinctive features, and functional roles of these EVs in regulating mitochondrial quality and quantity, under both physiological and pathological conditions. The mechanisms underlying the generation of these vesicles are also examined. Additionally, we discuss the challenges and future directions in the study of mitochondria-containing EVs. Given their potential to serve as diagnostic biomarkers and therapeutic tools, these mitochondria-embedded vesicles represent a promising frontier in molecular and cell biology, with significant implications for understanding and treating a range of diseases.
    Keywords:  exopher; extracellular vesicles; migrasome; mitochondrial quality control; mitochondrial quantity control; mitocytosis; mitopher
    DOI:  https://doi.org/10.1007/s11427-024-2905-5
  9. Clin Genet. 2025 Jun 29.
      Mitochondrial diseases are a complex group of conditions exhibiting significant phenotypic and genetic heterogeneity. Genomic testing is increasingly used as the first step in the diagnostic pathway for mitochondrial diseases. We used next-generation sequencing followed by bioinformatic data analysis to identify potentially damaging variants in the POLRMT gene (NM_005035.4) in six new affected individuals. Structural protein analysis predicted the detrimental impact of variants on POLRMT protein structure. Patients show extended phenotypic abnormalities often presenting early in life with features including global developmental delay, cognitive impairment, short stature and muscular hypotonia. This study expands the genetic and phenotypic landscape of mitochondrial disease associated with POLRMT variants.
    Keywords:  POLRMT; mitochondrial disease; neurodevelopmental disorders; variant classification
    DOI:  https://doi.org/10.1111/cge.70011
  10. Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00170-2. [Epub ahead of print]145(4): 109179
      Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensive samples from MiSBIE participants with rare mitochondrial diseases (MitoD), we examined GDF15 biology in 290 plasma and 860 saliva aliquots from 40 subjects with the m.3243 A > G mutation (n = 25) or with single, large-scale mtDNA deletions (n = 15). Compared to healthy controls, both MitoD groups exhibited significantly elevated blood and saliva GDF15 (p < 0.0001). To examine the origin of GDF15 protein in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and identified high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones, saliva GDF15 is highest upon awakening and declines rapidly by 61.2 % within 45 min. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, saliva GDF15 correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked changes in GDF15 did not amplify noisy disease severity associations, but rather consistently increased the effects sizes for GDF15-symptoms connections, pointing to converging psychobiology underlying the responses to mitochondrial OxPhos defects and acute mental stress. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases and call for further studies examining the psychobiological processes linking mitochondria, mental stress, and GDF15 dynamics.
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109179
  11. Clin Epigenetics. 2025 Jul 02. 17(1): 112
       BACKGROUND/OBJECTIVES: Mitochondrial-nuclear crosstalk is critical for cell function, and nuclear DNA methylation (DNAm) may regulate this process. Mitochondria maintain an extranuclear genome, and mitochondrial DNA copy number (mtDNA-CN) has been previously associated with DNAm. However, there is little information on this relationship in children, whose brains are particularly vulnerable to energetic perturbations during development. Our objectives were to (1) characterize associations of mtDNA-CN with nuclear DNAm at birth; (2) determine their persistence into childhood; and (3) investigate associations in relation to neurodevelopment.
    METHODS: We quantified mtDNA-CN with qRT-PCR and DNAm with the MethylationEPIC BeadChip array in umbilical cord leukocytes (N = 422) in newborns from the PROGRESS birth cohort in Mexico City (2007-2011). At the 48-month visit, we measured DNAm in peripheral blood leukocytes (N = 177) and assessed the McCarthy Scales of Children's Abilities (N = 290). We performed an epigenome-wide association study (EWAS) with cord mtDNA-CN in mitochondrially relevant genes (23,261 CpG sites) and across the genome (745,691 sites). We determined if our results persisted until childhood and were associated with cognitive scales. The findings were replicated in a US-based cohort (N = 130).
    RESULTS: We observed 11 and 165 differentially methylated positions (DMPs) in mitochondria-related nuclear genes and across the genome, respectively, after correction for multiple comparisons. In mitochondrial genes, two significant DMPs mapped to PRELID3A and a DMP in the promoter region of SLC25A24 replicated in our external cohort. At 48 months of age, 17 of 165 DMPs remained associated with cord mtDNA-CN, 12 were associated with child memory scales, and associations with 17 replicated in our external cohort. Several positions mapped to genes in immune activation and development.
    CONCLUSIONS: In newborns, mtDNA-CN was associated with DNAm in mitochondria-related genes and throughout the genome, several of which remained associated in childhood, were associated with child memory scales, and were replicated in a US-based cohort. These findings open new avenues for future targets for children's health and disease.
    Keywords:  DNA methylation; Developmental origins of health and disease; Mitochondria; Neurodevelopment; mtDNA
    DOI:  https://doi.org/10.1186/s13148-025-01896-y
  12. Front Biosci (Landmark Ed). 2025 May 30. 30(6): 36405
      Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures that are secreted by nearly all cell types. EVs include small EVs (exosomes), large EVs (microvesicles), and apoptotic bodies, which are distinguished by their biogenesis and size. EV biogenesis involves endosomal pathways or direct budding from the plasma membrane, influenced by cellular states and external stimuli. The complex composition of EVs, proteins, lipids, RNA, DNA, and metabolites reflects their cell of origin, enabling EVs to mediate intercellular communication. EV uptake by recipient cells occurs via endocytosis, membrane fusion, or receptor-ligand interactions, influencing diverse physiological and pathological processes. Indeed, the biological roles of EVs range from immune modulation to tissue repair and contributions to cancer, neurodegeneration, musculoskeletal pathologies, and other disorders. Advances in isolation methods, including ultracentrifugation, size exclusion chromatography, and immunoaffinity techniques, have improved the purity and yield of EVs. Characterization technologies, such as nanoparticle tracking analysis, electron microscopy, and omics approaches, provide insights into their heterogeneity and functional cargo. Thus, EVs hold promise as non-invasive biomarkers for disease diagnosis and prognosis, offering high specificity and stability. Furthermore, the natural biocompatibility, ability to cross biological barriers, and capacity for functional cargo delivery of EVs position them as therapeutic tools and drug-delivery vehicles. Some of the most promising fields of application for EVs include cancer, neurodegeneration, and joint diseases; however, challenges remain in scaling production, achieving targeted delivery, and ensuring regulatory compliance. This review highlights recent advances in EV biology, isolation, and applications, emphasizing their crucial potential in precision medicine while identifying knowledge gaps and future research directions.
    Keywords:  biomarker; cancer; extracellular vesicles; intercellular communication; joint diseases; precision medicine; regenerative medicine
    DOI:  https://doi.org/10.31083/FBL36405
  13. J Cell Biochem. 2025 Jun;126(6): e70050
      Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
    Keywords:  autophagy; beta‐hydroxybutyrate; epigenetic; mitochondrial biogenesis; therapeutic strategies
    DOI:  https://doi.org/10.1002/jcb.70050
  14. Biochim Biophys Acta Mol Cell Res. 2025 Jun 28. pii: S0167-4889(25)00119-3. [Epub ahead of print]1872(7): 120014
      MEGDHEL syndrome is a severe mitochondrial disorder caused by mutations in the SERAC1 gene, characterized by sensorineural deafness, encephalopathy, hepatopathy, and Leigh-like syndrome. A hallmark feature is neonatal liver failure, often leading to high mortality. There is currently no effective treatment. In this study, we used AAV9-SERAC1 gene therapy to address liver dysfunction and mitochondrial impairments in the Serac1-/- mouse model. Treatment with 4 × 1011 viral genomes led to improvements in liver histology, including reduced fatty degeneration and cholesterol accumulation, as well as enhanced mitochondrial morphology and function. Transmission electron microscopy revealed restored mitochondrial cristae and an increased number of mitochondria in treated mice. Respiratory complex showed activity recovery and mitochondrial DNA content was increased. Behavioral assessments also demonstrated significant improvements in motor coordination, with treated mice showing enhanced grasping strength and balance compared to controls. These findings suggest that AAV9-SERAC1 gene therapy can improve liver function and locomotor abilities in Serac1-/- mice, offering a promising therapeutic strategy for MEGDHEL syndrome.
    Keywords:  MEGDHEL AAV9 gene therapy liver function
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120014
  15. Orphanet J Rare Dis. 2025 Jul 01. 20(1): 321
       BACKGROUND: Rare diseases affect small populations but present unique challenges in access to healthcare and social support. The needs of patients and their caregivers extend beyond medical treatments, impacting various aspects of their lives. This study provides a narrative overview of these diverse needs experienced by patients and caregivers.
    METHODS: A rapid literature review was conducted in PubMed and Embase, including studies assessing needs in rare diseases. Following Cochrane guidelines, two researchers screened 1.419 articles (74%) double-blinded, followed by a single researcher screening the remaining 509 articles (26%). Two researchers collaboratively extracted data into an extraction table. To validate and complement these findings, two stakeholder consultations were held with representatives from patient organisations, healthcare providers, the pharmaceutical industry, and policymakers.
    RESULTS: A total of 272 articles were included in the review, and respectively 25 and 33 participants participated in the consultations. The identified needs were categorized into two levels: (i) patient needs, and (ii) caregiver needs, along with one overarching transversal need: (iii) information needs. Patient needs spanned health, healthcare, and social dimensions. Psychological, mental, and emotional health were frequently highlighted, but also autonomy emerged as a significant need. Healthcare needs included gaps in timely and accurate diagnoses, underscoring the need for more awareness among healthcare providers and appropriate diagnostic tools. Coordinated multidisciplinary care and accessibility to care and treatments were also identified as essential, yet lacking. Socially, patients experienced unmet needs in support networks, workplace inclusion, education, and financial stability. Caregivers' needs were related to physical and mental health, social connection, and financial support. Information needs, affecting both levels and even extending to healthcare providers, underscored the demand for more comprehensive, accessible information on rare diseases, treatment options, healthcare services, and available social support.
    CONCLUSION: This study underscores the complex needs of persons living with rare diseases and their caregivers, advocating for a holistic approach in healthcare policy. Beyond medical interventions, addressing timely diagnosis, coordinated care, and psychological support are essential. Policymakers must consider these multifaceted needs to enhance patient outcomes and foster an inclusive, patient-centred healthcare framework.
    Keywords:  Patient-centred healthcare framework; Rare diseases; Unmet health-related needs
    DOI:  https://doi.org/10.1186/s13023-025-03838-6