bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–10–19
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
  2. POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
  3. From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
  4. NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
  5. Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature.
  6. Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation.
  7. Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
  8. Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
  9. Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
  10. MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
  11. Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
  12. Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
  13. Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
  14. Mitochondrial dysfunction alters early endosome trafficking via microtubule reorganization.
  15. SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
  16. Differential regulation of gene co-expression modules in muscles and liver of preterm newborns.
  17. Polycomb Repressive Complex 1 and USP16 localize to the mitochondrion and influence its function.
  18. Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.
  19. Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.
  20. In vivo mechano-tissue engineering by hydrogels capable of transmitting intercellular mechanical stress.
  21. Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.
  22. Extracellular vesicles for the delivery of gene therapy.
  1. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070
    Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
    Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.
      Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.
    Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
  2. Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):
    POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
    Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.
      POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.
    DOI:  https://doi.org/10.26508/lsa.202302563
  3. Mol Cell Biol. 2025 Oct 17. 1-27
    From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
    Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.
      Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.
    Keywords:  Mitochondria; mitochondrial disease; protein import; protein quality control
    DOI:  https://doi.org/10.1080/10985549.2025.2566671
  4. Nat Metab. 2025 Oct 13.
    NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
    Kasper T Vinten, Maria M Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E Janssens, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01387-7
  5. Mol Genet Metab. 2025 Oct 06. pii: S1096-7192(25)00251-3. [Epub ahead of print]146(3): 109259
    Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature.
    Alessia Catania, Silvia Marchet, Krisztina Einvag, Eleonora Lamantea, Ettore Salsano, Daniele Ghezzi, Costanza Lamperti.
       BACKGROUND: Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis. AARS2 and DARS2 biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood. Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS.
    METHODS: We recruited 6 adult patients affected by AARS2 (n = 2) and DARS2 (n = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses.
    RESULTS: Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable.
    CONCLUSIONS: Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with DARS2-related disorders.
    Keywords:  Amino acid; Clinical trial; Leukoencephalopathies; Mitochondrial aminoacyl tRNA synthetase
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109259
  6. Front Immunol. 2025 ;16 1640748
    Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation.
    Yangyang Zhao, Chunlei Wu, Xiaoxue Liang, Mengjiao Yang.
      Circulating cf-mtDNA has emerged as a dual-functional entity in human pathophysiology, serving not only as a disease biomarker but also as a potent innate immune activator through its molecular pattern recognition. Extracellular mtDNA engages PRRs, triggering dysregulated pro-inflammatory signaling in multiple cell lineages. Elevated mtDNA in circulation correlates with pathogenesis of autoimmune disorders, infectious diseases, critical illnesses, neurological disorders, and hematological abnormalities. Therapeutic strategies combining mtDNA monitoring with inhibitors targeting its release mechanisms and downstream pathways offer novel immunomodulatory strategies. This review systematically examines the therapeutic nexus of blood-derived mtDNA in immune activation and disease progression. Here we aim to elucidate the function of mtDNA in disease pathobiology while highlighting mitochondria's central position in human systemic homeostasis.
    Keywords:  blood circulation; cell-free DNA; extracellular vesicles; immunity; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fimmu.2025.1640748
  7. Am J Physiol Cell Physiol. 2025 Oct 16.
    Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
    Max Siragusa, Belem Yoval-Sánchez, Ivan Guerrero, Alexander Galkin.
      Although the content of mitochondrial enzymes in different tissues can vary greatly, understanding the regulation behind these differences has been hampered by a lack of quantitative knowledge in relation to postnatal development. Here we report a quantitative analysis of developing brain, heart, kidneys, and muscle tissue of C57BL/6J mice, focusing on the content of mitochondrial complex I, a key component of the respiratory chain: We found that in all tissues except kidneys, complex I content gradually increases after birth, reaching a plateau level at around 25 days. Complex I content in muscles does not change significantly until postnatal day 7-10, and then also increases. The greatest increment was found in kidneys, where a 16-fold increase in complex I level after birth was observed. We also found that content of complex I in all postnatal tissues, but muscle, is higher in males than in females. These baseline dynamics of this key mitochondrial flavoprotein serve as a reference for evaluating genetic influences on development and provide a standard for assessing mitochondrial complex I function during postnatal growth.
    Keywords:  MItochondria; Postnatal Development; mitochondrial complex I; mouse; tissue specificity
    DOI:  https://doi.org/10.1152/ajpcell.00692.2025
  8. Nat Metab. 2025 Oct 14.
    Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
    Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.
      Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress.
    DOI:  https://doi.org/10.1038/s42255-025-01388-6
  9. Adv Ophthalmol Pract Res. 2025 Nov-Dec;5(4):5(4): 278-284
    Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
    Shanshan Cao, Yong Liu, Mingming Sun, Yuan Zhang, Yonghua Sun, Quangang Xu, Shihui Wei, Huanfen Zhou.
       Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder primarily caused by mutations in MT-ND1, MT-ND4, and MT-ND6, leading to retinal ganglion cell degeneration and severe vision loss. While 90%-95% of cases involve three common mutations (m.11778G ​> ​A, m.3460G ​> ​A, m.14484T ​> ​C), the genetic and clinical profiles of rare mutations remain poorly characterized, contributing to diagnostic challenges.
    Methods: This cohort study analyzed 26 genetically confirmed LHON patients harboring rare mitochondrial DNA (mtDNA) mutations. Patients underwent best-corrected visual acuity (BCVA), optical coherence tomography (OCT) measurements (peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer [GCL] thickness), and neuroimaging findings. Prognostic outcomes were compared between pediatric (≤16 years) and adult (>16 years) subgroups.
    Results: The cohort (male:female ​= ​4.2:1) exhibited a median onset age of 17 years (range:4-42), with 30.77% unilateral involvement. Rare mutations were distributed in MT-ND4(34.62%,m.11696G ​> ​A), MT-ND1(34.62%,including m.3733G ​> ​A/m.3866T ​> ​C), and MT-ND6 (23.08%, m.14502T>C), with 26.92% harboring dual mutations. Younger patients showed significantly better visual recovery (59.09% vs. 22.73% achieving BCVA ≥ 0.3, P ​= ​0.014), despite comparable baseline vision and structural OCT parameters (pRNFL/GCL thickness, all P ​> ​0.05). T2 hyperintensity in the optic nerve magnetic resonance imaging (MRI) was present in 38.46% of cases.
    Conclusions: Our study probes into the clinical and genetic diversity of LHON with rare mtDNA mutations, revealing varied clinical presentations, such as more frequent unilateral involvement and enhanced optic nerve T2 MRI signals. Visual recovery was significantly better in the younger cohort. These results suggest the need for broader genetic testing in atypical LHON cases and offer insights into better prognostic strategies for new therapies.
    Keywords:  Leber's hereditary optic neuropathy; Maternal inheritance; Mitochondrial DNA; Rare mutation
    DOI:  https://doi.org/10.1016/j.aopr.2025.08.001
  10. Nat Cell Biol. 2025 Oct;27(10): 1708-1724
    MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
    Mai Nguyen, Jack J Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J Milnerwood, Sidong Huang, Michel Desjardins, Heidi M McBride.
      Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.
    DOI:  https://doi.org/10.1038/s41556-025-01774-y
  11. Mol Genet Metab. 2025 Oct 08. pii: S1096-7192(25)00252-5. [Epub ahead of print]146(3): 109260
    Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
    Xueyang Pan, Yue Wang, Ning Liu, Xi Luo, V Reid Sutton, William J Craigen, Qin Sun.
      Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging. To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions. These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.
    Keywords:  Chronic progressive external ophthalmoplegia (CPEO); ETC complex enzymatic assay; Heteroplasmy; Kearns-Sayre syndrome (KSS); Mitochondrial electron transport chain (ETC); Single large-scale mtDNA deletion syndrome (SLSMDS); mtDNA deletion; mtDNA next-generation sequencing (NGS)
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109260
  12. Front Cell Dev Biol. 2025 ;13 1650462
    Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
    Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.
      Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.
    Keywords:  NAD+; Parkinson’s disease; dopaminergic neurons; mitochondrial complex I; neurodegeneration; neurometabolism
    DOI:  https://doi.org/10.3389/fcell.2025.1650462
  13. Nature. 2025 Oct;646(8085): 530-532
    Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
    Gemma Conroy.
      
    Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Diseases; Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-03307-x
  14. Life Sci Alliance. 2026 Jan;pii: e202403020. [Epub ahead of print]9(1):
    Mitochondrial dysfunction alters early endosome trafficking via microtubule reorganization.
    Anjali Vishwakarma, Lilia Chihki, Kiran Todkar, Mathieu Ouellet, Marc Germain.
      Mitochondria are essential for bioenergetics and cellular processes including cell differentiation and immunity; alterations in these processes cause a wide range of muscular and neurological pathologies. Although these pathologies have traditionally been associated with ATP deficits, mitochondrial dysfunction also leads to reactive oxygen species (ROS) generation, inflammation, and alterations in the function of other organelles. Although the negative impact of mitochondrial dysfunction on lysosomal activity is established, the relationship between mitochondria and the rest of the endocytic compartment remains poorly understood. Here, we show that inhibiting mitochondrial activity through genetic and chemical approaches causes early endosome (EE) perinuclear aggregation and impairs cargo delivery to lysosomes. This impairment is due to ROS-mediated alterations in microtubule architecture and centrosome dynamics. Antioxidants can rescue these EE defects, underlying the pivotal role of mitochondria in maintaining cellular activities through ROS regulation of microtubule networks. Our findings highlight the significance of mitochondria beyond ATP production, emphasizing their critical involvement in endocytic trafficking and cellular homeostasis. These insights emphasize mitochondria's critical involvement in cellular activities and suggest novel targets for therapies to mitigate the effects of mitochondrial dysfunction.
    DOI:  https://doi.org/10.26508/lsa.202403020
  15. Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]
    SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
    Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.
      Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.
    Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
  16. Front Cell Dev Biol. 2025 ;13 1645959
    Differential regulation of gene co-expression modules in muscles and liver of preterm newborns.
    Petra Janovska, Tatyana Kobets, Lenka Steiner Mrazova, Michaela Svobodova, Marketa Tesarova, Pavel Kopecky, Petr Zouhar, Martin Rossmeisl, Viktor Stranecky, Stanislav Kmoch, Jan Kopecky.
       Background: Newborns undergo rapid metabolic and organ adaptations after birth, which are compromised in premature newborns, leading to adverse health outcomes. Molecular mechanisms underlying these transitions remain poorly understood due to limited tissue availability. To address this gap, we characterized tissue transcriptomes using autopsy samples from a unique newborn cohort.
    Methods: We analyzed liver (LI), heart (HM), and skeletal muscle (SM) transcriptomes using RNA sequencing in 41 predominantly premature newborns who died shortly after birth. Nearly 14,000 protein-coding gene transcripts per tissue were detected.
    Results: Tissues exhibited distinct expression profiles, with LI showed the highest number of tissue-specific genes. SM gene expression correlated strongly with gestational age at birth (i.e., the prenatal development), while LI was influenced by the duration of postnatal survival (i.e., the postnatal development). HM displayed minimal changes, suggesting stable myocardial metabolism during the perinatal transition. Weighted Gene Co-expression Network Analysis (WGCNA) identified tissue-specific gene co-expression modules linked to clinical traits such as gestational age, birth weight, survival duration, nutrition, and exposure to catecholamine treatment. The key functional annotations, validated by differential expression analysis, revealed that LI and SM modules were enriched for mitochondrial metabolism and oxidative phosphorylation genes, with more pronounced prenatal development in SM, and a postnatal increase in both tissues. Data suggests that energy metabolism in SM matures first, followed by the development of muscle functions. Hepatic modules were associated with a postnatal increase in the steroid hormone/xenobiotic metabolism, and a decline in hematopoietic activity. Robust annotations to ribosome activity suggested tissue-specific changes in protein synthesis, which declined prenatally in SM, postnatally in HM. Notably, the supply of exogenous glucose and nutrition type were strongly associated with hepatic gene expression, highlighting the central role of the liver in postnatal metabolic adaptation.
    Conclusion: Overall, our study highlights tissue-specific perinatal gene regulation, with mitochondrial maturation emerging as a crucial driver of postnatal adaptation, explaining vulnerabilities in preterm infants. We provide a unique resource for characterizing developmental changes in tissue transcriptomes during the fetal-to-neonatal transition in human newborns.
    Keywords:  WGCNA; human; mitochondria; premature newborn; tissue transcriptome
    DOI:  https://doi.org/10.3389/fcell.2025.1645959
  17. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2508812122
    Polycomb Repressive Complex 1 and USP16 localize to the mitochondrion and influence its function.
    Lei Shi, Chunxu Chen, Xiaokun Jian, Qiushi Wang, Yuan Shen, Asmaa Alajmi, Hao Zhang, Lisa S Shock, Louise T Chow, Hengbin Wang.
      Polycomb Repressive Complex 1 (PRC1) represses gene expression by ubiquitinating histone H2A or physically compacting chromatin. USP16, one of the histone H2A deubiquitinases, antagonizes PRC1-mediated H2A ubiquitination (H2Aub). Here, we report that both PRC1 and USP16 are also localized in mitochondria and influence mitochondrial function directly. Our findings are based on immunofluorescence and proximity ligation assays, cell fractionation, and biochemical analyses of isolated or affinity-purified mitochondria. We further showed that PRC1 and USP16 function with the ubiquitin pathway. Auxin-induced, mitochondria-specific depletion of the PRC1 subunit RING2 altered the ubiquitination status of mitochondrial proteins, including H2Aub. Disruption of PRC1, either through double knockout (KO) of RING1 and RING2 or through mitochondria-specific deletion of RING2 in the RING1 KO background, caused profound alterations in mitochondrial proteome and led to disturbances in mitochondrial integrity and impaired respiratory function. Thus, in addition to their canonical functions in the nucleus, PRC1 and USP16 also translocate into mitochondria and directly impact mitochondrial integrity and function.
    Keywords:  PRC1; USP16; mitochondria; respiratory function; ubiquitin
    DOI:  https://doi.org/10.1073/pnas.2508812122
  18. EMBO Mol Med. 2025 Oct 13.
    Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.
    Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard.
      Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.
    Keywords:  Barth Syndrome; Cardiac Tissue; Integrated Multi-omics; Mitochondrial Dysfunction
    DOI:  https://doi.org/10.1038/s44321-025-00320-5
  19. Methods Mol Biol. 2026 ;2976 119-134
    Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.
    Claudia Parra-Ruiz, Carlos Enrich, Silvana Zanlungo.
      Membrane contact sites (MCS) are dynamic nanoregions of close apposition between two different organelles, functioning as discrete lipid or ion transfer sites. This new concept in cell biology involves unique proteins at both membrane sites, named tethers, and emerges in early observations by transmission electron microscopy (TEM). Currently, this technique still constitutes a valuable tool for MCS visualization and quantification. In the last decade, Lysosomal Storage Diseases (LSD) have been instrumental in studying the MCS between lysosomes (Ly), or endolysosomes (EL), and other organelles in close proximity such as mitochondria or the endoplasmic reticulum (ER). At present, the analysis of composition, functioning, and alterations/rewiring of MCS in health and disease represents an innovative area of research for designing therapeutic strategies in a variety of pathologies. Here, we describe procedures for chemical fixation using the Flat Embedding technique to characterize and quantify the MCS between LE/Lys and mitochondria in human fibroblasts by thin-section TEM.
    Keywords:  Flat embedding; Image analysis; Lysosomal storage diseases; Lysosomes; Membrane contact sites; Mitochondria; Transmission electron microscopy-chemical fixation
    DOI:  https://doi.org/10.1007/978-1-0716-4844-5_10
  20. Nat Commun. 2025 Oct 15. 16(1): 8847
    In vivo mechano-tissue engineering by hydrogels capable of transmitting intercellular mechanical stress.
    Natsumi Ueda, Hayato Okazaki, Akihiro Mikuma, Ayane Kunieda, Soma Kawashima, Takeru Torii, Keiko Kawauchi, Masatake Matsuoka, Tomohiro Onodera, Norimasa Iwasaki, Koji Nagahama.
      Integrating the latest insights from mechanobiology into tissue engineering could lead to innovative technologies. Here we show a method to effectively elicit the regenerative response of transplanted cells by utilizing mechanical stress generated in vivo. The essential feature of our method is that it does not use specific ligands for the vital mechanosensor integrins to mechanically activate them. In our method, azide groups are introduced into the integrin, and the hydrogel is modified with cyclooctyne (DBCO) groups. Thus, bioorthogonal click reaction between the azide groups and the DBCO groups forms direct, stable, irreversible covalent bonds between the cellular integrin and the hydrogel. We demonstrate that the integrin-hydrogel linkage is in ON state regardless of the intensity of the stress, the cell cycle, or the extracellular environment, so that mechanical stress is rapidly and reliably transmitted to the nucleus through the linkage in vivo, resulting in regenerative response of the transplanted cells.
    DOI:  https://doi.org/10.1038/s41467-025-64656-9
  21. Cerebellum. 2025 Oct 16. 24(6): 166
    Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.
    Elena Conci, Thomas L Kelly, Ruth Armstrong, Pooja Harijan, Rita Horvath.
      
    Keywords:  Case report; Episodic ataxia; FGF14; Microdeletion; Spinocerebellar ataxia 27A
    DOI:  https://doi.org/10.1007/s12311-025-01919-7
  22. Nat Rev Bioeng. 2025 May;3(5): 360-373
    Extracellular vesicles for the delivery of gene therapy.
    Emilio Di Ianni, Wataru Obuchi, Koen Breyne, Xandra O Breakefield.
      Gene therapy has brought hope for the treatment of previously incurable diseases, such as genetic disorders, cancers and autoimmune diseases. However, gene therapy requires efficient delivery with cell and tissue specificity, which remains challenging owing to the limited targeting and cargo-loading capacity of viral delivery vehicles, as well as immunogenicity and toxicity concerns. Extracellular vesicles can be designed as non-viral carriers for gene therapy owing to their ability to deliver multiple cargo types, including transgenes, small encoding or non-coding RNA, DNA and functional proteins. Importantly, extracellular vesicles are immunologically neutral and can cross biological barriers. In this Review, we discuss the application of extracellular vesicles in gene therapy. We outline how the inherent content of extracellular vesicles can facilitate different gene-therapy approaches and examine the design of extracellular vesicles for the loading of gene-therapy tools, targeted delivery and cargo release. Finally, we survey clinical applications of extracellular vesicles and highlight important engineering and translational challenges.
    DOI:  https://doi.org/10.1038/s44222-025-00277-7
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