bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–11–09
39 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial Leigh syndrome: the state of the art.
  2. Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
  3. Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.
  4. Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.
  5. Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
  6. Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
  7. Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
  8. Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
  9. Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
  10. Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.
  11. Silencing of mitochondrial gene expression using polymorpholino chimeras.
  12. Severe Neurological Presentation in Siblings With COQ5-Related Primary Coenzyme Q10 Deficiency: Expanding Clinical and Molecular Spectrum.
  13. National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey.
  14. Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.
  15. An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
  16. The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
  17. Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
  18. Mitochondria beyond boundaries: from cellular powerhouses to intercellular messengers in health and disease.
  19. Imaging patterns of paediatric CNS mitochondrial disorders.
  20. Complex IV deficiency due toCOX4I1deep intronic and de novo variants results in progressive motor impairment andLeigh syndrome.
  21. Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).
  22. Size control: Tune the mitochondrial volume to time your cell division!
  23. Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release.
  24. Protocol for mitochondria lipid encapsulation using a dual-tube system for mitochondria transfer therapy.
  25. Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
  26. A new UCP1-independent thermogenic mechanism in peroxisomes.
  27. Mitochondrial cardiomyopathy with skeletal muscle myopathy caused by m.3260A > G mutation in MT-TL1 gene: a case report.
  28. Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
  29. Morphological alterations of peridroplet mitochondria in human liver biopsy.
  30. Galectin-3 directs mitophagy in response to Parkin-/proteasome-dependent rupture of mitochondrial outer membrane.
  31. Advancing epigenetic signatures as functional biomarkers in rare diseases.
  32. Functional dominance in the central dogma of tumor mitochondrial genetics.
  33. Mitochondrial ROS sources steer neuroinflammation.
  34. The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts.
  35. Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
  36. An atlas of mitochondrial ATP synthase activity across the lifespan.
  37. Barth syndrome: Natural history in infants and young children.
  38. Complex de novo structural variants are an underestimated cause of rare disorders.
  39. A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders.
  1. Arch Pediatr. 2025 Nov 05. pii: S0929-693X(25)00182-4. [Epub ahead of print]
    Mitochondrial Leigh syndrome: the state of the art.
    Gauthier Toutain, Célia Hoebeke, Marguerite Gastaldi, Mathieu Milh, Brigitte Chabrol.
       BACKGROUND: Leigh syndrome or subacute necrotizing encephalomyelopathy was first recognized as a neuropathological entity in 1951. It is a progressive neurological disease characterized by neuroradiological lesions, particularly in the brainstem and basal ganglia. Leigh's syndrome is a pan-ethnic disorder with onset usually in infancy or early childhood. Over the last six decades, this complex neurodegenerative disorder has been shown to comprise >100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This article reviews clinical, radiological, biochemical and genetic aspects of the disorder.
    OBJECTIVES: this overview provides a better understanding of this rare mitochondrial disease by identifying its clinical, radiological and genetic manifestations in order to improve early diagnosis, patient follow-up and genetic counseling.
    METHODOLOGY: systematic literature review RESULTS: Leigh syndromes present with childhood developmental regression, a loss of previously achieved developmental milestones. Numerous non-neurological manifestations of Leigh syndrome have been reported, many of which are related to the underlying genetic defects. These include cardiomyopathy, renal tubulopathy, gastrointestinal and endocrine dysfunction, and liver disease. Known genetic causes, including defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon CONCLUSION: Management of mitochondrial diseases must be multidisciplinary, and in collaboration with a center of reference (CRMR) or a center of competence (CCMR) with expertise in mitochondrial diseases.
    Keywords:  Central nervous system; Genetic; Itochondrial DNA; Leigh syndrome; Metabolic disease; Mitochondrial disease; Neurodegeneration; Neuroimaging; Nuclear DNA; OXPHOS; Treatment
    DOI:  https://doi.org/10.1016/j.arcped.2025.04.007
  2. Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):
    Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
    Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.
      The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.
    DOI:  https://doi.org/10.1093/nar/gkaf1140
  3. Wellcome Open Res. 2023 ;8 33
    Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.
    Jonathan Meyrick, Renae J Stefanetti, Linda Errington, Robert McFarland, Gráinne S Gorman, Nichola Z Lax.
       Introduction: Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma ( POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to employ systematic approaches, wherever possible, to investigate the cellular and animal models used in POLG-related research and assess how well they help us understand disease mechanisms in patients.
    Methods: Four databases were searched from inception to May 31 st, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model.
    Results: A total of 55 articles, including seven model organisms (Human, yeast [ Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Caenorhabditis elegans, and Zebrafish) with 258 distinct variants were included. Of these, 69% (N=38/55) of articles recapitulated mitochondrial DNA (mtDNA) depletion, 33% (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7/55) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders.
    Discussion: While some evidence is available to support the ability of POLG-related disease models to recapitulate molecular mechanisms and phenotypes, much is of limited quality, with inconsistencies evident across the literature. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease.
    PROSPERO registration: CRD42021234883.
    Keywords:  POLG; epilepsy; mitochondria; mtDNA; neurological manifestations; preclinical
    DOI:  https://doi.org/10.12688/wellcomeopenres.18637.2
  4. Biol Pharm Bull. 2025 ;48(11): 1652-1666
    Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.
    Itsumi Sato, Masahiro Shiraishi, Kaede Norota, Kaoru Shiraki, Yuma Yamada.
      Mitochondria are essential for cellular functions, including ATP production, calcium homeostasis, oxidative stress regulation, and apoptosis. Mitochondrial dysfunction is associated with a variety of diseases, including neurodegenerative disorders, skeletal muscle diseases, and mitochondrial diseases. This review explores the latest mitochondrial-targeted therapeutic approaches across the following key perspectives: (1) technological innovations in mitochondrial transplantation, focusing on tunnel nanotubes and extracellular vesicles; (2) the role of mitochondria in skeletal muscle diseases and therapeutic activation strategies; (3) advances in mitochondrial enhancement techniques within cell therapy, particularly in pediatric applications; and (4) the latest treatment modalities for mitochondrial diseases, such as gene and cell therapies. Taken together, these strategies demonstrate the transformative potential of mitochondrial targeting in cell- and organelle-specific medicine. Additionally, the MITO-Porter system is highlighted as an innovative drug delivery platform contributing to these advances.
    Keywords:  cell therapy; drug delivery system; mitochondria; mitochondrial disease; organelle medicine; skeletal muscle disease
    DOI:  https://doi.org/10.1248/bpb.b25-00218
  5. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]
    Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
    Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.
      Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.
    Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
  6. J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]
    Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
    Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.
      Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.
    Keywords:  Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone
    DOI:  https://doi.org/10.1093/jb/mvaf062
  7. Nat Genet. 2025 Nov 03.
    Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
    Sonia Boscenco, Jacqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Tricia Park, Flora McNulty, Sergio Lilla, Sara Zanivan, Alejandro Huerta-Uribe, Benan Nalbant, Mark Zucker, David Sumpton, Geoffray Monteuuis, Christopher B Jackson, Wei Wei, Patrick F Chinnery, Ronan Chaligne, Caleb A Lareau, Ed Reznik, Payam A Gammage.
      The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.
    DOI:  https://doi.org/10.1038/s41588-025-02374-0
  8. J Biol Chem. 2025 Nov 04. pii: S0021-9258(25)02735-8. [Epub ahead of print] 110883
    Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
    Mara Equisoain Redin, Veronica Bazzani, Eve Harding, Joshua McHale, Carlo Vascotto.
      Mitochondrial protein import is essential for organelle function and cellular homeostasis. While Cyclophilin D (CypD) is a well-characterized regulator of the mitochondrial permeability transition pore (MPTP) and resides in the matrix, the mechanisms underlying its import remain poorly defined. In this study, we identify CypD as a novel non-canonical substrate of the mitochondrial intermembrane space assembly (MIA) pathway mediated by the oxidoreductase Mia40. Structural analysis revealed conserved cysteine pairs in CypD that are compatible with disulfide bond formation. Using in vitro pull-down assays, we demonstrate a redox-sensitive interaction between CypD and Mia40, which was further confirmed by co-immunoprecipitation and proximity ligation assays. Expression of CypD cysteine mutants in cells revealed that residues Cys82 and Cys203 are critical for Mia40-dependent interaction and protein stability. Notably, expression of the Cys203Ala mutant significantly reduced cell viability, suggesting a key functional role for this residue. Functional experiments showed that depletion of Mia40 leads to a significant reduction in mitochondrial CypD levels, a result that was confirmed in a series of leukemia cell lines with variable Mia40 expression. Our results shed light on a previously unrecognized import mechanism for CypD and expand the known substrate repertoire of Mia40, demonstrating that the MIA pathway also contributes to the import of mitochondrial matrix proteins. This work highlights the functional versatility of the MIA pathway beyond the intermembrane space and reveals an additional regulatory level in mitochondrial proteostasis with implications for cell death signalling and mitochondrial pathophysiology.
    Keywords:  Cyclophilin D; Mia40; mitochondria; protein import; redox
    DOI:  https://doi.org/10.1016/j.jbc.2025.110883
  9. Nat Metab. 2025 Nov 04.
    Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
    Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T Chouchani, Anna G Orr, Adam L Orr.
      Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s42255-025-01390-y
  10. Mol Med. 2025 Nov 05. 31(1): 328
    Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.
    Andrea Salzinger, Esra Özkan, Vidya Ramesh, Jyoti Nanda, Karen Burr, David Story, Nhan T Pham, Siddharthan Chandran, Bhuvaneish T Selvaraj.
       BACKGROUND: The neuromuscular junction (NMJ) is the synapse between motor neurons and skeletal muscle and controlls movement. Impaired synaptic transmission and NMJ degeneration has been observed during healthy ageing and is also implicated in several neuromuscular diseases. On account of the high energy demands of being distally located and large sized, NMJs are enriched with mitochondria. This enrichment is dependent on transport of mitochondria across the axon to the NMJ.
    METHODS: We first established a human 3D neuromuscular assembloid model to study in-vitro NMJs, by fusing human stem cell derived spinal cord organoids and primary skeletal muscle organoids. To determine whether enhancing axonal mitochondrial transport modulates NMJ formation and maintenance, we generated a CRISPR-Cas9 meditated knock-out of syntaphilin in human stem cells.
    RESULTS: Firstly, we characterised the neuromuscular assembloid model which showed functional innervated NMJs as measured by juxtaposed neurofilament+ axons and α-bungarotoxin+ acetylcholine receptors. Secondly, we showed that spinal cord selective genetic ablation of syntaphilin - an axonally localised mitochondrial anchor protein - resulted in increased mitochondrial motility in motor neurons, and consequently increased axonal density and NMJ formation.
    CONCLUSION: This proof-of-concept study demonstrated that enhancing mitochondrial mobility could provide a therapeutic target to prevent NMJ degeneration.
    Keywords:  Assembloid; Axonal transport; Mitochondria; Neuromuscular diseases; Neuromuscular junction; Organoid; Stem cells
    DOI:  https://doi.org/10.1186/s10020-025-01319-x
  11. Nat Rev Mol Cell Biol. 2025 Nov 03.
    Silencing of mitochondrial gene expression using polymorpholino chimeras.
    Drishan Dahal.
      
    DOI:  https://doi.org/10.1038/s41580-025-00923-3
  12. JIMD Rep. 2025 Nov;66(6): e70038
    Severe Neurological Presentation in Siblings With COQ5-Related Primary Coenzyme Q10 Deficiency: Expanding Clinical and Molecular Spectrum.
    Parith Wongkittichote, Rachel M Guerra, Daniel J Wegner, Samantha Toy, Jacqueline A Hauer, David J Pagliarini, Jorge L Granadillo.
      Coenzyme Q10 (CoQ10) is a coenzyme and antioxidant involved in multiple bioenergetic and biosynthetic processes, particularly within mitochondria. The biosynthesis of CoQ10 is a tightly regulated process that involves multiple enzymes, including the methyltransferase COQ5. Genetic defects in COQ5 have recently been associated with autosomal recessive COQ5-related primary CoQ10 deficiency. The clinical manifestations of seven individuals previously reported were primarily neurological and ophthalmological. Here, we report two siblings with profound developmental delay and brain imaging consistent with multistage strokes. Clinical exome sequencing revealed compound heterozygous variants in COQ5, including one frameshift deletion and one missense variant. Our functional complementation studies demonstrate that a Saccharomyces cerevisiae COQ5 ortholog harboring the corresponding missense variant fails to fully rescue coq5∆ CoQ6 production, leading to the accumulation of CoQ biosynthetic intermediates. After the diagnosis, CoQ10 supplementation was started on the proband, leading to subjective clinical improvement. We describe new cases of COQ5-related primary CoQ10 deficiency and expand the phenotypic and molecular spectrum of the disease. We also establish a yeast system to evaluate the effects of the variants in COQ5 and support the use of CoQ10 supplementation for patients with COQ5-related primary CoQ10 deficiency.
    DOI:  https://doi.org/10.1002/jmd2.70038
  13. Acta Myol. 2025 Sep;44(3): 93-95
    National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey.
    Michelangelo Mancuso, Costanza Lamperti, Olimpia Musumeci.
       Objective: Thymidine kinase 2 (TK2) deficiency is a rare mitochondrial disease with variable phenotypes and emerging treatments. Prompt diagnosis is essential to optimize patient outcomes and management. To assess the current awareness, diagnostic approaches, and readiness to include TK2 screening in Italian neuromuscular clinical practice.
    Methods: A nationwide survey was distributed to AIM-affiliated clinicians. The questionnaire assessed TK2 awareness, diagnostic pathways, gene panel content, and attitudes towards screening in unresolved cases.
    Results: while awareness of TK2 deficiency was almost universal, inclusion of TK2 in genetic panels varied: 85% in metabolic myopathy panels, 56% in LGMD panels. Screening for TK2 in genetically unsolved SMA, FSHD, and OPMD phenotypes was inconsistent.
    Conclusions: Although awareness of TK2 deficiency is widespread, diagnostic strategies are inconsistent. Standardizing TK2 inclusion in NGS panels and promoting differential screening are key steps toward earlier diagnosis in the view of future treatment options.
    Keywords:  TK2; awareness; mitochondrial disease
    DOI:  https://doi.org/10.36185/2532-1900-1424
  14. FASEB J. 2025 Nov 15. 39(21): e71215
    Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.
    Adam C Richert, Yuxun Zhang, Sivakama S Bharathi, Abigail Hernandez, Tetyana Dodatko, Joanna Bons, Kayla E Roundtree, Brandon Stauffer, Chunli Yu, Birgit Schilling, Sander M Houten, Eric S Goetzman.
      Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC11) recreate the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC11 is chain-shortened in peroxisomes to glutaryl (DC5)-CoA, which then gives rise to the GA1-like pattern of DC5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC11 chain-shortening can enter mitochondria for reactivation by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT) and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is deficient in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.
    Keywords:  dicarboxylic acids; glutaric acidemia I; glutaryl‐coenzyme A; mitochondria; peroxisomes; succinyl‐coenzyme A
    DOI:  https://doi.org/10.1096/fj.202502381R
  15. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894
    An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
    Zachary L Sebo, Navdeep S Chandel.
      Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.017
  16. Sci Rep. 2025 Nov 07. 15(1): 39117
    The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
    Stefan Redl, Felix Von Zweydorf, Christian J Gloeckner, Inmaculada Posadas, Valentín Ceña, Michael W Hess, Giovanni Piccoli, María Dolores Pérez-Carrión.
      Parkinson's disease (PD) is a neurodegenerative pathology characterized by movement-associated symptoms due to the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Autophagy is an essential mechanism that restores homeostasis and promotes cell survival. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are among the most common in the familial cases. The LRRK2 E193K mutation falls in the Armadillo (ARM) domain and modifies LRRK2 interactome. The role of LRRK2 in autophagy has been widely explored, but the impact of E193K mutation on autophagy remains unknown. We found that the E193K variant increases autophagy in primary fibroblasts obtained from an E193K carrier. By cryo-based electron microscopy we observed that E193K fibroblasts present a higher amount of phagophores/autophagosomes. We showed that LRRK2 binds to the Dynein-1 complex, an essential regulator of retrograde transport of autophagosomes. Noteworthy, the E193K mutation jeopardizes this interaction and increases the cellular sensitivity to 1-methyl-4-phenylpyridinium (MPP+) toxin in fibroblasts as well as in a heterologous cell model. Our study reveals that the LRRK2 E193K variant influences the autophagic regulation and suggests that the dysregulation of the LRRK2-Dynein-1 complex causes autophagic defects and, eventually, cell death.
    Keywords:  Autophagy; Dynein-1 complex; LRRK2 protein; Organelle morphometry; Parkinson´s disease; Ultrastructure
    DOI:  https://doi.org/10.1038/s41598-025-26716-4
  17. Neurobiol Dis. 2025 Nov 03. pii: S0969-9961(25)00391-2. [Epub ahead of print] 107174
    Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
    Bavavarshini Tamilselvam, Gitika Thakur, Ruth Mathew, Eric Chai, Jose Lopez, Zhenyu Chen, Weihai Zhan, Craig Blackstone, Xue-Jun Li.
      Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurological diseases characterized by axonal degeneration of corticospinal motor neurons. SPG15, a common autosomal recessive form of HSP, is caused by mutations in the ZFYVE26 gene that encodes the spastizin protein. Spastizin partially localizes to mitochondria, suggesting a potential role in mitochondrial function. To investigate this possibility and explore treatments to mitigate neurodegeneration caused by spastizin deficiency, SPG15 patient-specific induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts and differentiated into cortical projection neurons. The SPG15 iPSC-derived neurons exhibited reduced ATP production compared to control neurons, indicating mitochondrial dysfunction in spastizin-deficient neurons. Also, given increased fragmentation of mitochondria in SPG15 neurons, we examined whether restoring mitochondrial morphology dynamics using P110, a peptide inhibitor of the mitochondrial fission protein DRP1, could protect SPG15 neurons. Indeed, treatment with P110 significantly suppressed the accumulated axonal swellings in SPG15 neurons. Further examination of the underlying mechanisms revealed that P110 restored mitochondrial morphology, ameliorated mitochondrial oxidative stress, and improved mitochondrial health, but it did not affect necrosis-related membrane integrity, suggesting specific targeting of mitochondrial deficits by P110. Furthermore, P110 significantly mitigated disease-related apoptosis in SPG15 neurons. Collectively, these findings reveal that restoring mitochondrial morphology and function using P110 lessens mitochondrial oxidative stress and mitigates degeneration of SPG15 neurons, offering a novel therapeutic approach for SPG15.
    Keywords:  Apoptosis; Axonal degeneration; Hereditary spastic paraplegias; Mitochondrial dysfunction; SPG15; iPSCs
    DOI:  https://doi.org/10.1016/j.nbd.2025.107174
  18. Sci China Life Sci. 2025 Nov 06.
    Mitochondria beyond boundaries: from cellular powerhouses to intercellular messengers in health and disease.
    Haixia Zhuang, Wenxin Mo, Jianming Xie, Tingting Zhang, Kailun Qiu, Weinan Wu, Wanyue Tan, Xiaoyi Jiang, Xiusheng Chen, Yongquan Hu, Huansen Huang, Hao Liu, Du Feng.
      Mitochondria, serving as the energy hub and death-immune hub of cells, play pivotal roles in maintaining normal cellular physiology and pathological functions. Under stress conditions, mitochondria can be released from cells into the extracellular environment and even the circulatory system through multiple pathways, and subsequently taken up by other cells. The process of mitochondrial release involves complex mechanisms, exerting multifaceted effects on the fate and functions of recipient cells and playing critical roles in both physiological and pathological processes. This review focuses on the stress-induced release of mitochondria, their uptake by recipient cells, and the changes brought about in the peripheral circulation, aiming to deepen the understanding of the molecular mechanisms and biological implications of this novel mode of intercellular communication and provide new therapeutic insights for related diseases.
    Keywords:  circulating mitochondria; intercellular crosstalk; mitochondrial quality control; mitochondrial transfer
    DOI:  https://doi.org/10.1007/s11427-025-3069-3
  19. Neuroradiology. 2025 Nov 05.
    Imaging patterns of paediatric CNS mitochondrial disorders.
    Pritika Gaur, Cesar Alves, Harun Yildiz, Kshitij Mankad, Sniya Sudhakar, Shamima Rahman, Asthik Biswas.
      This review seeks to provide neuroradiologists and clinicians with an imaging-based pattern recognition framework for primary mitochondrial disorders affecting the central nervous system (CNS). By utilising a comprehensive imaging phenotype approach to CNS mitochondrial disorders, it highlights the wide spectrum of neuroimaging patterns and the complexities they present in clinical settings. Using illustrative case examples, the review demonstrates how imaging acts as a vital bridge between clinical phenotypes and genotypes.
    Keywords:  Brain; Mitochondrial disorders; Paediatric; Spine
    DOI:  https://doi.org/10.1007/s00234-025-03805-9
  20. Mitochondrion. 2025 Nov 05. pii: S1567-7249(25)00092-3. [Epub ahead of print] 102095
    Complex IV deficiency due toCOX4I1deep intronic and de novo variants results in progressive motor impairment andLeigh syndrome.
    Olatz Ugarteburu, Laia Farré-Tarrats, Gerard Muñoz-Pujol, María Unceta, Javier De Las Heras, Ainhoa Garcia-Ribes, Arantza Arza-Ruesga, Belén de la Morena, Gianluca Arauz-Garofalo, Marina Gay, Gloria Garrabou, Javier Corral, Marta Vilaseca, Antonia Ribes, Judit García-Villoria, Laura Gort, Frederic Tort.
      COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient's tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV.Additionally, proteomic data in patient's fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.
    Keywords:  COX4I1; Leigh syndrome; Long read sequencing; Proteomics; complex IV
    DOI:  https://doi.org/10.1016/j.mito.2025.102095
  21. Ann Med Surg (Lond). 2025 Oct;87(10): 6904-6905
    Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).
    Amna Rahman, Muneeb Faiz, Maliha Khalid, Muhammad Talha, Aminath Waafira.
      Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial disorder primarily driven by mutations in mitochondrial DNA, particularly the m.8344A>G variant in MT-TK, and is characterized by epilepsy, myoclonus, ataxia, and other multisystemic features. With no curative therapy, recent attention has turned to the gut microbiome as a modifiable factor influencing neurologic symptoms in mitochondrial diseases. Dysbiosis-induced by antibiotics, diet, or preservatives-has been linked to altered microbial metabolites such as short-chain fatty acids and indoxyl sulfate, which may exacerbate neurological dysfunction. Preliminary clinical trials and preclinical studies suggest that probiotics and dietary interventions can modestly improve disease burden and symptoms such as constipation. However, significant challenges remain, including lack of standardization in analytical protocols, heterogeneous host-microbiota responses, and inadequate patient stratification. To fully realize the therapeutic potential of microbiome-based approaches in MERRF, coordinated multicenter trials, clear regulatory guidelines, and machine learning-enhanced stratification will be essential.
    Keywords:  MERRF syndrome; gut microbiome; mitochondrial disease; neurologic symptoms
    DOI:  https://doi.org/10.1097/MS9.0000000000003777
  22. Curr Biol. 2025 Nov 03. pii: S0960-9822(25)01254-0. [Epub ahead of print]35(21): R1053-R1055
    Size control: Tune the mitochondrial volume to time your cell division!
    Mikael Björklund.
      A new study links mitochondrial volume control with growth and cell division, suggesting that cells not only sense their mitochondrial content but also use this information to decide when to divide.
    DOI:  https://doi.org/10.1016/j.cub.2025.09.054
  23. J Clin Invest. 2025 Nov 03. pii: e181299. [Epub ahead of print]135(21):
    Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release.
    Chun-Yu Fu, Joshua B Kohl, Filip Liebsch, Davide D'Andrea, Tamás Ditrói, Seiryo Ogata, Franziska Neuser, Max Mai, Anna T Mellis, Emilia Kouroussis, Masanobu Morita, Titus Gehling, José Angel Santamaria-Araujo, Sin Yuin Yeo, Heike Endepols, Michaela Křížková, Viktor Kozich, Marcus Krueger, Julia B Hennermann, Uladzimir Barayeu, Takaaki Akaike, Peter Nagy, Milos Filipovic, Guenter Schwarz.
      Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.
    Keywords:  Amino acid metabolism; Clinical Research; Metabolism; Mitochondria; Neurodegeneration
    DOI:  https://doi.org/10.1172/JCI181299
  24. STAR Protoc. 2025 Oct 30. pii: S2666-1667(25)00580-5. [Epub ahead of print]6(4): 104174
    Protocol for mitochondria lipid encapsulation using a dual-tube system for mitochondria transfer therapy.
    Gen Hamanaka, Dong Bin Back, Ester Licastro, Shin Ishikane, Takafumi Nakano, Kazuhide Hayakawa.
      Mitochondria transplantation therapy is emerging as a novel therapeutic approach to promote neuroprotection in central nervous system (CNS) disorders. Here, we present a protocol for mitochondrial surface modification that enhances the restoration of intracellular adenosine triphosphate (ATP) levels under conditions of oxidative stress. We describe steps for isolating mitochondria, preparing the dual-tube system, and encapsulation with lipid coat. We then detail procedures for performing assays and analyses. For complete details on the use and execution of this protocol, please refer to Nakano et al.1.
    Keywords:  Metabolism; Neuroscience; cell Biology; tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2025.104174
  25. J Cell Sci. 2025 Nov 03. pii: jcs.263920. [Epub ahead of print]
    Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
    Sebabrata Maity, Anwesha Dutta Gupta, Izaz Monir Kamal, Rajdeep Das, Rupsha Mondal, Arpit Tyagi, Deepak Sharma, Joy Chakraborty, Saikat Chakrabarti, Oishee Chakrabarti.
      The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B or RETREG1, originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. While it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here we show that FAM134B can interact with the canonical fission-promoting protein, DRP1. Functional depletion of FAM134B leads to local Actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and patient-derived samples. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.
    Keywords:  DRP1; FAM134B; Fission; Mitochondrial hyperfusion
    DOI:  https://doi.org/10.1242/jcs.263920
  26. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00857-3. [Epub ahead of print]85(21): 3895-3897
    A new UCP1-independent thermogenic mechanism in peroxisomes.
    Anthony R P Verkerke, Shingo Kajimura.
      In a recent publication in Nature, Liu et al.1 report a UCP1-independent thermogenic mechanism in which peroxisomes generate heat in brown adipose tissue through active synthesis and oxidation of monomethyl branched-chain fatty acids (mmBCFAs) derived from branched-chain amino acids.
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.016
  27. J Med Case Rep. 2025 Nov 06. 19(1): 573
    Mitochondrial cardiomyopathy with skeletal muscle myopathy caused by m.3260A > G mutation in MT-TL1 gene: a case report.
    Anda Kadiša, Ritvars Vereskuns, Mihails Tarasovs, Ieva Mičule, Inna Inashkina.
       BACKGROUND: Mitochondrial myopathies are a group of rare hereditary disorders that primarily affect muscle tissue, and present with muscle weakness, fatigue, exercise intolerance, and muscle pain. A key aspect of mitochondrial myopathies is the involvement of different organ systems, such as the cardiovascular system. Various disease features, including clinical and genetic heterogeneity, pose serious difficulties in the diagnostic process. We report a case of a young adult male, who presented with findings that suggested myositis, and was diagnosed with skeletal muscle myopathy and mitochondrial cardiomyopathy, caused by a m.3260A > G variant in the MT-TL1 gene.
    CASE PRESENTATION: A 22-year-old Latvian Caucasian man presented with a half-year history of fatigue, weakness, heaviness in the chest, and loss of breath, as well as a swollen right lower leg for about a week. Laboratory findings revealed increased creatine phosphokinase, creatinine kinase MB, and troponin T levels. All performed autoantibody tests for autoimmune disorders were negative, and no evidence of paraneoplastic syndrome was found. During repeated stays in the hospital, the patient developed heart failure and experienced decreasing muscle strength and muscle pain throughout the whole body. Following an unsuccessful therapy with corticosteroids and later L-carnitine, addition of thiamine lead to an overall improvement in the patient's condition. Based on the family history, a genetic test was performed, which revealed a m.3260A > G variant in the MT-TL1 gene.
    CONCLUSION: Several factors cause the process of establishing the correct diagnosis of mitochondrial myopathies and cardiomyopathies to be challenging. The presented case aims to raise awareness of rare mitochondrial myopathies, to help clinicians speed up the diagnostic process.
    Keywords:  Case report; Heteroplasmy; Mitochondrial cardiomyopathy; Mitochondrial myopathy; m.3260A > G
    DOI:  https://doi.org/10.1186/s13256-025-05633-0
  28. Cell Death Differ. 2025 Nov 01.
    Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
    Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.
      The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.
    DOI:  https://doi.org/10.1038/s41418-025-01603-7
  29. Sci Rep. 2025 Nov 04. 15(1): 38650
    Morphological alterations of peridroplet mitochondria in human liver biopsy.
    Hanna Kawecka, Norihiro Imai, Yuki Ohsaki, Jinglei Cheng, Dongming Liu, Jingjing Zhang, Fumitaka Mizuno, Taku Tanaka, Shinya Yokoyama, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Michał Woźniak, Hiroaki Wake, Hiroki Kawashima.
      Mitochondrial dysfunction and the accumulation of lipid droplets (LD) contribute to the pathogenesis of liver diseases. Mitochondria bound to LD, termed peridroplet mitochondria (PDM), form a subpopulation with distinct functions compared to cytoplasmic mitochondria (CM). In this first in vivo human liver study, we aimed to investigate the morphological differences between PDM and CM and to assess their associations with clinical parameters. Our analysis of mitochondrial ultrastructure using transmission electron microscopy images of human liver biopsies showed that CM were significantly smaller, more spherical, and solid, whereas PDM were larger and more elongated. Overall, PDM exhibited more uniform morphology, while CM displayed disease-specific morphological alterations. CM were associated with serum liver enzyme levels and high-density lipoprotein cholesterol, suggesting sensitivity to liver stress and a potential role in liver cholesterol transport. In contrast, PDM were associated with serum triglyceride levels, indicating a role in lipid metabolism. Total PDM and LD counts showed a positive correlation, reinforcing their close functional relationship. These findings show that PDM and CM represent distinct mitochondrial subpopulations with unique morphologies and differing associations with hepatic pathophysiological pathways, which highlights the significance of LD interactions in contributing to mitochondrial heterogeneity.
    Keywords:  Deep learning model; Lipid droplets; Lipid metabolism; Mitochondrial contact sites; Mitochondrial dynamics; Transmission electron microscopy
    DOI:  https://doi.org/10.1038/s41598-025-22496-z
  30. Biol Direct. 2025 Nov 06. 20(1): 108
    Galectin-3 directs mitophagy in response to Parkin-/proteasome-dependent rupture of mitochondrial outer membrane.
    Pei-Han Liu, Yu-Shan Lin, Wei-Hua Chu, Wei-Tse Sun, Po-Yu Huang, Jie-Rong Huang, Wei-Chung Chiang.
      
    Keywords:  Biomolecular condensate; Galectin-3; Liquid-liquid phase separation (LLPS); Mitochondrial outer membrane (OMM) rupture ; PINK1/Parkin-dependent mitophagy
    DOI:  https://doi.org/10.1186/s13062-025-00692-1
  31. Epigenomics. 2025 Nov 05. 1-11
    Advancing epigenetic signatures as functional biomarkers in rare diseases.
    Andrea Ciolfi, Marco Ferilli, Camilla Cappelletti, Marco Tartaglia.
      Alterations of the DNA methylation (DNAm) status of the genome underlie an increasing number of rare diseases. Recently, DNAm has also emerged as a highly informative biomarker for diagnosing rare disorders, which can be associated with distinctive genome-wide DNAm patterns (i.e., episignatures). Indeed, episignature testing has proven to represent an effective orthogonal omics technology, providing independent functional evidence to support or prioritize specific diagnostic hypotheses for hundreds of rare diseases, and reclassify variants of uncertain significance (VUS) emerging from genomic sequencing. Furthermore, the stability and plasticity inherent in DNAm make it a promising tool for personalized medicine, including patient stratification and therapeutic monitoring. This review outlines current technologies and analytical methodologies for genome-wide DNAm profiling and explores potential avenues of research, emphasizing artificial intelligence and multiomics integration to effectively manage patients with rare and complex phenotypes. We critically assess the current limitations and future directions of genome-wide DNAm profiling to expand the implementation of DNAm signatures as functional biomarkers, highlighting their importance as supplementary tools to genomic sequencing in clinical and research settings.
    Keywords:  DNA methylation; DNAm signature; animal models; biomarker; diagnosis; epigenomics; episignature; patient stratification; rare diseases; therapy
    DOI:  https://doi.org/10.1080/17501911.2025.2583891
  32. Nat Genet. 2025 Nov 03.
    Functional dominance in the central dogma of tumor mitochondrial genetics.
      
    DOI:  https://doi.org/10.1038/s41588-025-02375-z
  33. Nat Metab. 2025 Nov 04.
    Mitochondrial ROS sources steer neuroinflammation.
    Huajun Pan, Fei Yin.
      
    DOI:  https://doi.org/10.1038/s42255-025-01391-x
  34. Cell Rep. 2025 Oct 30. pii: S2211-1247(25)01257-4. [Epub ahead of print]44(11): 116486
    The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts.
    Junsheng Chen, Megan C Yap, Arthur Bassot, Danielle M Pascual, Tadashi Makio, Jannik Zimmermann, Heather Mast, Rakesh Bhat, Samuel G Fleury, Yuxiang Fan, Adriana Zardini Buzatto, Jack Moore, Klaus Ballanyi, Liang Li, Michael Overduin, M Joanne Lemieux, Hélène Lemieux, Grazia M S Mancini, Bruce Morgan, Paul C Marcogliese, Thomas Simmen.
      Thioredoxin-related transmembrane proteins (TMXs) of the endoplasmic reticulum (ER) determine not only redox conditions within the ER lumen but also the formation and function of ER-mitochondria membrane contact sites (ERMCS). The presence of cytosolic, reactive oxygen species (ROS)-derived redox nanodomains at ERMCS suggests TMXs could also control these. The prime candidate for such a function is TMX2, the sole TMX family protein with a cytosolic thioredoxin domain. Indeed, TMX2 controls the extent of ERMCS through interaction with outer mitochondrial membrane proteins, including TOM70. Assisted by cytosolic peroxiredoxins, TMX2 moderates the sulfenylation of the TOM70 C206 residue. Thereby, TMX2 reduces mitochondrial Ca2+ uptake and metabolism. Accordingly, mutation of the TMX2 gene in cells from a patient with a neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) results in hyperactive mitochondria. In a fly in vivo NEDMCMS model, TMX2 knockdown manifests predominantly in glial cells, where it prevents seizure-like behavior.
    Keywords:  CP: Molecular biology; Ca(2+); ER; MCS; PRDX; TMX2; TOM70; endoplasmic reticulum; membrane contact sites; mitochondria; peroxiredoxin; redox
    DOI:  https://doi.org/10.1016/j.celrep.2025.116486
  35. Structure. 2025 Nov 05. pii: S0969-2126(25)00396-X. [Epub ahead of print]
    Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
    Huifang Yan, Fengyun Ni, Qinghua Wang, Jianpeng Ma.
      Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC's catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.
    Keywords:  C-VOMIT; biotin-dependent carboxylase; catabolism; catalysis; propionic acidemia; propionyl-coenzyme A carboxylase
    DOI:  https://doi.org/10.1016/j.str.2025.10.009
  36. Mol Metab. 2025 Oct 31. pii: S2212-8778(25)00185-1. [Epub ahead of print] 102278
    An atlas of mitochondrial ATP synthase activity across the lifespan.
    Muzna Saqib, Dylan C Sarver, Christy M Nguyen, Fangluo Chen, Marcus M Seldin, G William Wong.
      Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102278
  37. Mol Genet Metab. 2025 Oct 30. pii: S1096-7192(25)00262-8. [Epub ahead of print]146(4): 109270
    Barth syndrome: Natural history in infants and young children.
    Sharada Vishwanath, Anne Brockmeyer, Brittany Hornby, W Reid Thompson, Hilary J Vernon.
      Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by pathogenic variants in TAFAZZIN. It is characterized by cardiomyopathy, neutropenia, growth delay, skeletal myopathy, and developmental concerns. Advances in genetic testing have enabled earlier diagnoses, creating opportunities to better define the natural history of disease in infancy and early childhood. We conducted a longitudinal, observational study of 21 male patients (ages 0-48 months) with genetically confirmed BTHS evaluated at the Barth Syndrome Interdisciplinary Clinic at Kennedy Krieger Institute. Data collected included perinatal history, growth, feeding, cardiac function, hematologic findings, gross motor development, quality of life, and pain assessment. Gross motor skills were assessed via milestone acquisition and the Peabody Developmental Motor Scales (PDMS-2/3). Quality of life was evaluated using the PedsQL™ parent-proxy questionnaire. The most common presenting features were cardiomyopathy (n = 10) and failure to thrive (n = 6), with an average age at diagnosis of 5.5 months, which was significantly earlier than historical cohorts. Eighteen patients developed cardiac dysfunction, 25 % required heart transplantation, and one death occurred due to cardiopulmonary arrest. Feeding difficulties were frequent, with 16 patients affected and 7 requiring gastrostomy tubes. Growth delay was common, though height/weight ratios were often preserved. Neutropenia was present in 19 patients, with variable severity and infection risk. Gross motor development was delayed, particularly for standing and walking, with progressive deficits on PDMS subtests. Quality of life scores indicated substantial impairment, especially in fatigue and general functioning domains. Pain was rarely reported. We conclude that infants and toddlers with BTHS present with significant cardiac, growth, and developmental abnormalities. Earlier diagnosis facilitated by genetic testing allows for earlier intervention and monitoring. These findings highlight the need for proactive cardiac surveillance, nutritional support, and early therapeutic interventions to optimize outcomes, and they provide critical endpoints for future clinical trials in this young age group.
    Keywords:  Barth syndrome; Cardiomyopathy; Natural history; Neutropenia
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109270
  38. Nat Commun. 2025 Nov 03. 16(1): 9528
    Complex de novo structural variants are an underestimated cause of rare disorders.
    Hyunchul Jung, Tsun-Po Yang, Susan Walker, Petr Danecek, O Isaac Garcia-Salinas, Matthew D C Neville, Joseph Christopher, Isidro Cortés-Ciriano, Helen Firth, Aylwyn Scally, Matthew Hurles, Peter Campbell, Raheleh Rahbari.
      Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conduct a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, obtained as part of the UK 100,000 Genomes Project. We identify 1,870 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n = 158; 8.4%) emerge as the third most common type of SV, following simple deletions and duplications. We classify 65% of these complex dnSVs into 11 subtypes. Among probands with dnSVs (n = 1,696), 9% exhibit exon-disrupting pathogenic dnSVs associated with the probands' phenotype. Notably, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or whole-exome sequencing methods are found to be complex dnSVs. We also find distinct genomic properties of de novo deletions depending on the parent of origin. This study highlights the importance of complex dnSVs in the cause of rare disorders and demonstrates the necessity of specific genomic analysis to avoid overlooking these variants.
    DOI:  https://doi.org/10.1038/s41467-025-64722-2
  39. Cell Stem Cell. 2025 Nov 03. pii: S1934-5909(25)00374-1. [Epub ahead of print]
    A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders.
    Lu Wang, Yuji Nakamura, Junhao Li, David Sievert, Yang Liu, Toan Nguyen, Prudhvi Sai Jetti, Ethan Thai, Rachel Yibei Zhou, Jiaming Weng, Naomi Meave, Manya Yadavilli, Robyn Howarth, Kevin Camey, Niyati Banka, Charlotte Owusu-Hammond, Chelsea Barrows, Stephen F Kingsmore, Maha S Zaki, Eran Mukamel, Joseph G Gleeson.
      Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.
    Keywords:  brain organoids; epilepsy; intellectual disability; microcephaly; neurodevelopmental disease; polymicrogyria; single-cell sequencing
    DOI:  https://doi.org/10.1016/j.stem.2025.10.006
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