bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–08–10
48 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Updates on Mitochondrial Myopathies.
  2. Single large-scale mitochondrial DNA deletion syndromes: scientific and family conference optimizes the collection of rare disease research outcomes.
  3. Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations.
  4. Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
  5. Multiplexed quantum sensing reveals coordinated thermomagnetic regulation of mitochondria.
  6. The cytochrome oxidase defect in ISC-depleted yeast is caused by impaired iron-sulfur cluster maturation of the mitoribosome assembly factor Rsm22.
  7. Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.
  8. Reframing primary mitochondrial disease as a sterile interferonopathy.
  9. A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
  10. Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
  11. Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
  12. A novel m.14677 T > C variant in mitochondrial tRNAGlu gene causes chronic progressive external ophthalmoplegia.
  13. Crystal structure of Fis1 and Bap31 provides information on protein-protein interactions at mitochondria-associated ER membranes.
  14. ATP Synthase Abundance in Neuronal Extracellular Vesicles Reflects Changes in the Mitochondria of Parent Neurons.
  15. Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
  16. Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.
  17. Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
  18. Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.
  19. Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.
  20. Mitochondrial disease management through phytochemical interventions.
  21. Dopaminergic Neuron-Specific Tfam Knockout Links Inter-Organelle Miscommunication to Early-Onset Parkinsonism.
  22. Deuterium trafficking, mitochondrial dysfunction, copper homeostasis, and neurodegenerative disease.
  23. A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
  24. Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.
  25. Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
  26. Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
  27. Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer.
  28. Extracellular vesicle-mediated delivery of mitochondrial circRNA MTCO2 protects against cerebral ischemia by modulating mPTP-dependent ferroptosis.
  29. Granulopoietic Dysregulation in a Patient-Tailored Mouse Model of Barth Syndrome.
  30. Cryogenic electron tomography and elemental analysis of mitochondrial granules in human retinal ganglion cells.
  31. EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework.
  32. 'Adrift From the World': Exploring the Lived Experiences of Individuals Affected by an Inherited Optic Neuropathy in the United Kingdom - A Qualitative Study.
  33. Protocol for measuring mitochondrial respiratory capacity from buccal cell swabs.
  34. Decompartmentalization of the yeast mitochondrial metabolism to improve chemical production in Issatchenkia orientalis.
  35. Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
  36. Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
  37. Conserved function, divergent evolution: mitochondrial outer membrane insertases across eukaryotes.
  38. Calcium signaling in postsynaptic mitochondria: mechanisms, dynamics, and role in ATP production.
  39. An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial protein import.
  40. Mechanistic insights into ubiquinone Q10 in Parkinson's disease: mitochondrial protection, ferroptosis inhibition, and antioxidant recycling.
  41. Generation and characterisation of four human NAD(P)HX epimerase (NAXE) knockout iPSC lines.
  42. Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
  43. The Undiagnosed Diseases Network (UDN) Solves Ocular Syndromic Diagnostic Dilemmas.
  44. Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
  45. G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies.
  46. The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
  47. Precise mapping of single-stranded DNA breaks by sequence-templated erroneous DNA polymerase end-labelling.
  48. The complex web of membrane contact sites in brain aging and neurodegeneration.
  1. Curr Neurol Neurosci Rep. 2025 Aug 04. 25(1): 55
    Updates on Mitochondrial Myopathies.
    Emanuele Barca, Valentina Emmanuele.
       PURPOSE OF REVIEW: Mitochondrial myopathies (MM) are a genetically and clinically heterogeneous group of disorders that remain underrecognized in adult and pediatric neurology. This review aims to provide a clinically useful tool for guiding diagnosis and management of MM. We also highlight the rapidly evolving diagnostic and therapeutic landscape, including novel diagnostic approaches and disease-modifying interventions.
    RECENT FINDINGS: Large cohort data highlight key clinical subtypes - fixed myopathies, syndromic forms, and metabolic myopathies- with distinct diagnostic implications. Novel tools such as GDF-15, long-read mtDNA sequencing, and multi-omic approaches are enhancing diagnostic sensitivity. Emerging therapies for TK2 deficiency and precision mitochondrial gene editing are progressing rapidly, with several nearing regulatory decisions. Numerous preclinical therapeutic strategies are currently under development, offering promise for improving outcomes in these otherwise devastating disorders. Recognizing MM in clinical settings is essential for timely diagnosis, to guide prognosis and family planning as well as provide access to emerging treatment. A tiered diagnostic approach and integration of new genomic technologies can improve outcomes.
    HUMAN AND ANIMAL RIGHTS: This article does not contain any studies with human or animal subjects performed by any of the authors.
    Keywords:  Exercise intolerance; Mitochondrial myopathy; Muscle biopsy; Next-generation sequencing; Rhabdomyolysis; TK2 deficiency
    DOI:  https://doi.org/10.1007/s11910-025-01444-4
  2. Orphanet J Rare Dis. 2025 Aug 04. 20(1): 399
    Single large-scale mitochondrial DNA deletion syndromes: scientific and family conference optimizes the collection of rare disease research outcomes.
    Laura E MacMullen, Elizabeth Reynolds, Marissa Weis, Ibrahim George-Sankoh, Sara Nguyen, Katelynn D Stanley, Mariya Redko, Maria Poblete, Amy C Goldstein, Rebecca D Ganetzky.
       BACKGROUND: The SLSMDS Research Network is a collaborative network comprising patient advocates, researchers, clinicians, and affected families seeking to improve outcomes for individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Building off of jointly developed research infrastructures, including a patient registry and natural history study, advocates and clinicians cohosted the SLSMDS Family and Scientific Conference, enabling the collection of patient data from an ultra-rare and geographically dispersed patient population. Here we describe the data collection procedures for single-time point laboratory assessments and patient reported outcomes for a subset of individuals with SLSMDS.
    RESULTS: Utilizing a reproducible model of rare disease data collection, we expand our understanding of the common psychiatric manifestations, describe variability in terms of self-care and quality of life, and emphasize potential biomarkers for individuals with SLSMDS.
    CONCLUSION: Our study describes how efficient patient-researcher partnerships can develop and sustain novel mechanisms to collect rare disease data, improve our understanding of the natural history of these disorders, and support development of future treatments.
    Keywords:  Chronic progressive external ophthalmoplegia; Conference; Kearns Sayre syndrome; Patient-reported outcomes; Pearson syndrome; Rare disease; Single large‐scale mitochondrial deletion syndromes; mtDNA
    DOI:  https://doi.org/10.1186/s13023-025-03632-4
  3. Nat Commun. 2025 Aug 07. 16(1): 7267
    Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations.
    Undiagnosed Diseases Network
      Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform in-depth analyses on individual patients with ultra-rare diseases. The increasing sizes of ultra-rare disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale case-based diagnostic analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We further release a software package, RaMeDiES, enabling automated cross-analysis of deidentified sequenced cohorts for new diagnostic and research discoveries. Gene-level findings and variant-level information across the cohort are available in a public-facing browser ( https://dbmi-bgm.github.io/udn-browser/ ). These results show that case-level diagnostic efforts should be supplemented by a joint genomic analysis across cohorts.
    DOI:  https://doi.org/10.1038/s41467-025-61712-2
  4. Res Sq. 2025 Jul 31. pii: rs.3.rs-7093535. [Epub ahead of print]
    Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
    Johan Auwerx, Xiaoxu Li, Weisha Li, Arwen Gao, YunYun Zhu, Elena Katsyuba, Katherine Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt Houtkooper, Joshua Coon.
      The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.
    DOI:  https://doi.org/10.21203/rs.3.rs-7093535/v1
  5. bioRxiv. 2025 Aug 01. pii: 2025.07.30.666664. [Epub ahead of print]
    Multiplexed quantum sensing reveals coordinated thermomagnetic regulation of mitochondria.
    Md Shakil Bin Kashem, Stella Varnum, Olivia Lazorik, Rocky Giwa, Shiva Iyer, Changyu Yao, David W Piston, Chong Zu, Jonathan R Brestoff, Shankar Mukherji.
      Mitochondria are multifunctional organelles that convert the potential energy stored in nutrients and intermediary metabolites into both heat and an electrochemical proton-motive force. However, how these outputs are synchronized in cells remains an enduring question. In this work, leveraging multiplexed nanodiamond quantum sensors to monitor both changes in temperature and magnetic field fluctuations in single primary cells obtained from diverse tissues in adult mice, we identified thermomagnetic correlation profiles uncovering a regulatory feedback loop in which the cell draws upon available intracellular iron to maintain the mitochondrial electrochemical gradient. These profiles reverse in cells derived from a mouse model of Leigh syndrome and raise the intriguing possibility that primary mitochondrial diseases can be understood as disorders of thermomagnetic homeostasis.
    DOI:  https://doi.org/10.1101/2025.07.30.666664
  6. FEBS Lett. 2025 Aug 06.
    The cytochrome oxidase defect in ISC-depleted yeast is caused by impaired iron-sulfur cluster maturation of the mitoribosome assembly factor Rsm22.
    Ulrich Mühlenhoff, Dominik Trauth, Weronika Śliwińska, Linda Boss, Roland Lill.
      Mitochondria contain the bacteria-inherited iron-sulfur cluster assembly (ISC) machinery to generate cellular iron-sulfur (Fe/S) proteins. Mutations in human ISC genes cause severe disorders with a broad clinical spectrum and are associated with strong defects in mitochondrial Fe/S proteins, including respiratory complexes I-III. For unknown reasons, complex IV (aka cytochrome c oxidase), a non-Fe/S, heme-containing enzyme, is severely affected. Using yeast as a model, we show that depletion of Rsm22, the counterpart of the human mitoribosome assembly factor METTL17, phenocopies the defects observed upon impairing late-acting ISC proteins, that is, diminished activities of mitoribosomal translation and respiratory complexes III and IV. Rsm22 binds Fe/S clusters in vivo, thereby satisfactorily explaining the defect of respiratory complex IV in ISC-deficient cells, because this complex contains three mitochondrial DNA-encoded subunits. Impact statement Defects in mitochondrial Fe/S protein biogenesis also impact respiratory complex IV (COX), even though it lacks Fe/S clusters. Here, we show that the mitoribosome assembly factor Rsm22 binds Fe/S clusters in vivo. Rsm22 maturation defects impair mitoribosomal protein translation including COX subunits, explaining the COX defects in Fe/S cluster-deficient cells.
    Keywords:  biogenesis; cytochromes; iron–sulfur protein; mitochondrial DNA; mitochondrial ribosomes; respiratory chain complexes; translation
    DOI:  https://doi.org/10.1002/1873-3468.70129
  7. Pediatr Radiol. 2025 Aug 07.
    Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.
    Suzanne O'Hagan, Surita Meldau, Penelope Rose, Magriet Van Niekerk, Christelle Ackermann, Gillian Riordan, Ronald Van Toorn.
       BACKGROUND: MPV17-related mitochondrial deoxyribonucleic acid (DNA) maintenance defects present in most affected individuals as an early-onset encephalohepatopathic disease. Diagnosis requires comprehensive molecular genetic testing, which is often not available in resource-limited settings. Therefore, the role of imaging as a diagnostic tool necessitates further exploration. Herein, we present the largest known cohort of patients with genetically confirmed MPV17-related mitochondrial DNA depletion syndrome, highlighting in detail the neuroimaging findings.
    OBJECTIVE: To establish novel features on magnetic resonance imaging (MRI) that characterise MPV17-related mitochondrial DNA depletion syndrome, in order to provide a non-invasive, accessible, and reproducible biomarker inquiry.
    MATERIALS AND METHODS: Retrospective, descriptive study based at a large tertiary level hospital. Eight patients with MPV17-related mitochondrial DNA depletion syndrome who had undergone brain MRI were identified between 2015 and 2023. Neuroimaging findings were captured and described in detail. Two board-certified radiologists with experience in paediatric neuroradiology reviewed all images by consensus.
    RESULTS: All patients were homozygous for the MPV17: c.106C>T variant. Age at brain MRI ranged from 11 days to 8 months. Seven out of the eight patients showed signal abnormalities in the reticulospinal tracts and/or reticular formation. Other neuroimaging findings included leukoencephalopathy, injury to extra-reticular white matter tracts and frequent basal ganglia involvement. Newly identified areas of involvement include the perirolandic cortices, hippocampi, optic pathways and olfactory nerves.
    CONCLUSION: Lesions in the reticular formation and reticulospinal tracts on brain MRI in a neonate or infant with hepatic dysfunction may represent a distinctive, albeit not specific, feature of MPV17-related mitochondrial DNA depletion syndrome.
    Keywords:  MPV17 mitochondrial DNA depletion syndrome; Mitochondrial DNA; Mitochondrial disease; Neuroimaging; Pediatric; Resource-limited settings; Reticular formation
    DOI:  https://doi.org/10.1007/s00247-025-06341-z
  8. Mol Genet Metab. 2025 Jul 30. pii: S1096-7192(25)00208-2. [Epub ahead of print]146(1-2): 109217
    Reframing primary mitochondrial disease as a sterile interferonopathy.
    Eva Morava, Ibrahim Elsharkawi, Tamas Kozicz.
      
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109217
  9. BMJ Case Rep. 2025 Aug 08. pii: bcr0720080504. [Epub ahead of print]2009
    A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    An I Jonckheere, Marije Hogeveen, Leo Nijtmans, Mariel van den Brand, Antoon Janssen, Heleen Diepstra, Frans van den Brandt, Bert van den Heuvel, Frans Hol, Tom Hofste, Livia Kapusta, U Dillmann, M Shamdeen, J Smeitink, J Smeitink, Richard Rodenburg.
      To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G→A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.
    DOI:  https://doi.org/10.1136/bcr.07.2008.0504
  10. bioRxiv. 2025 Jul 29. pii: 2025.07.28.667051. [Epub ahead of print]
    Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
    Casadora Boone, Sophie Judge, Ahmad Shami, Bezawit Danna, Andrea B Ball, Tejashree Pradip Waingankar, Hera Saqub, Ajit S Divakaruni, Samantha C Lewis.
      Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools available to cells is critical, as monounsaturated fatty acid supplementation rescued both ER proteostasis and mtDNA synthesis, even in the presence of excess saturated fat. We propose that shutoff of mtDNA synthesis conserves mtDNA-to-mitochondrial network scaling until cells can regain ER homeostasis.
    Summary: Overnutrition of cultured human cells causes endoplasmic reticulum dysfunction, which downregulates mitobiogenesis in turn by constraining mtDNA synthesis.
    DOI:  https://doi.org/10.1101/2025.07.28.667051
  11. Cell Calcium. 2025 Jul 19. pii: S0143-4160(25)00065-X. [Epub ahead of print]131 103056
    Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
    Sara A Garcia, Anne M Neumaier, Michael Kohlhaas, Anton Xu, Alexander Nickel, Katharina J Ermer, Luzia Enzner, Christoph Maack, Vasco Sequeira, Christopher N Johnson.
      Mitochondrial calcium (Ca2+) uptake and factors that regulate this process have been an area of immense interest given the roles in cellular energetics. Here, we have investigated the ability of the Ca2+ sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca2+ Uniporter (MCU). Our data leveraged recombinantly produced CaM and mitochondria isolated from healthy and MCU impaired/diseased mice (Barth syndrome model). We found CaM enhanced Ca2+ uptake in both the absence and presence of CaMKII inhibition (KN93 as well as AIP). Mitochondria lacking function MCU (Barth syndrome model) validated that MCU was responsible for Ca2+ uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca2+ buffering. Fitting the Ca2+fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca2+ uptake. This CaM enhancement effect persisted in the presence of PTP impairment (cyclosporin), and subtle modification to the CaM protein sequence (D131E) revealed that an intact CaM-C domain Ca2+ binding was required for enhancement of MCU function.
    Keywords:  Calcium; Calmodulin; Calmodulin dependent kinase II (CaMKII); Mitochondrial calcium uniporter (MCU); Permeability transition pore (PTP)
    DOI:  https://doi.org/10.1016/j.ceca.2025.103056
  12. J Hum Genet. 2025 Aug 06.
    A novel m.14677 T > C variant in mitochondrial tRNAGlu gene causes chronic progressive external ophthalmoplegia.
    Nahoko Katayama Ueda, Masakazu Mimaki, Shota Ito, Ayuka Murakami, Satoshi Yokoi, Ichizo Nishino, Masahisa Katsuno, Yu-Ichi Goto.
      Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by progressive ptosis and ophthalmoplegia, caused by single deletions, point mutations, or multiple deletions in mitochondrial DNA (mtDNA). Most point mutations occur in tRNA genes. Here, we report a novel variant of the tRNAGlu gene associated with CPEO. A 45-year-old male presented with ptosis and external ophthalmoplegia; however, blood test results, including lactate levels and autoantibodies, were normal. CPEO was suspended, prompting additional myopathological examination, mtDNA sequencing analysis, long polymerase chain reaction (PCR) analysis, and single-fiber analysis to compare mutation loads between ragged-red fibers (RRFs) and non-RRFs. Histopathological examination revealed scattered COX-negative RRFs. No deletions were found in the mtDNA. MtDNA sequencing analysis revealed a novel variant, m.14677 T > C, in the tRNAGlu gene, with Sanger sequencing indicating 45% heteroplasmy in the muscle tissue. Single-fiber analysis showed a significantly higher mutation load of m.14677 T > C in RRFs (range: 25.3-92.8%; median: 88.1%; n = 6) compared with non-RRFs (range: 3.5-85.9%; median: 17.1%; n = 5) (P = 0.03). Based on the significantly higher mutation load in RRFs than in non-RRFs, pathological evidence of mitochondrial disease, and the mutation's occurrence at an evolutionarily conserved site, we concluded that m.14677 T > C, a novel variant of the tRNAGlu gene, is the cause of CPEO. Biochemical and histopathological examinations of muscle tissue, combined with single-fiber analysis, are valuable tools for evaluating mtDNA variants, particularly those within tRNA genes.
    DOI:  https://doi.org/10.1038/s10038-025-01381-7
  13. Commun Biol. 2025 Aug 06. 8(1): 1161
    Crystal structure of Fis1 and Bap31 provides information on protein-protein interactions at mitochondria-associated ER membranes.
    Minh Duc Nguyen, Yonghyeok Kim, Seung-Hyun Bae, Soeun Kim, Hyun Ku Yeo, Nam-Chul Ha, Ginam Cho, Sunghyun Moon, Kwang-Hwi Cho, Hyonchol Jang, Seoung Min Bong, Byung Il Lee.
      In eukaryotic cells, mitochondria and the endoplasmic reticulum (ER) form close contacts at mitochondria-associated ER membranes (MAMs), which are involved in diverse cellular processes. The outer mitochondrial membrane protein Fis1, known for its role in mitochondrial fission, has been reported to interact with the ER-resident protein Bap31. Here, we present crystal structures of the cytosolic domain of human Fis1 in two distinct conformations, along with a co-crystal structure of Fis1 bound to the C-terminal region of the Bap31_vDED domain. One Fis1 structure resembles monomeric yeast Fis1 and features a characteristic N-terminal "Fis1 arm" conformation, which may indicate an autoinhibitory function. In the co-complex, the Bap31_vDED region engages the convex surface of Fis1's tetratricopeptide repeat (TPR) domain. These findings provide structural insight into the interaction between Fis1 and Bap31 at ER-mitochondria contact sites.
    DOI:  https://doi.org/10.1038/s42003-025-08625-4
  14. J Extracell Vesicles. 2025 Aug;14(8): e70140
    ATP Synthase Abundance in Neuronal Extracellular Vesicles Reflects Changes in the Mitochondria of Parent Neurons.
    Pamela J Yao, Carlos Nogueras-Ortiz, Krishna Ananthu Pucha, Dimitrios Kapogiannis.
      Mitochondrial proteins are found in extracellular vesicles (EVs) such as neuron-derived EVs (NEVs). Yet whether and how NEV-borne mitochondrial proteins relate to the state of mitochondria in the parent neurons is unclear. Studying the mitochondrial ATP synthase in primary hippocampal neurons and their released EVs, we discovered that the abundance of ATP synthase in NEVs echoes the catalytic activity level of ATP synthase in neurons. We also observed, unexpectedly, that within the neuron, the quantity of ATP synthase remains constant irrespective of the level of its activity. Using non-canonical amino acid tagging coupled with proximity ligation assay, we found that the amount of nascent ATP synthase is linearly correlated to its activity, which may contribute to maintaining the overall quantity of ATP synthase in the neuron stable. Furthermore, we identified a sub-population of mitochondria-derived vesicles (MDVs) that carry ATP synthase and are not targeted to lysosomal degradation. Our findings suggest a strategy used by neurons in regulating and fine-tuning mitochondrial ATP synthase through MDV and NEV generation. Further studies are needed to elucidate the relationship between ATP synthase-containing-NEVs and -MDVs.
    Keywords:  ATP synthase; extracellular vesicles; mitochondria; mitochondrial‐derived vesicles; mitovesicles; neurons
    DOI:  https://doi.org/10.1002/jev2.70140
  15. Nat Commun. 2025 Aug 04. 16(1): 7174
    Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
    Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.
      The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.
    DOI:  https://doi.org/10.1038/s41467-025-62484-5
  16. Nat Commun. 2025 Aug 02. 16(1): 7121
    Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.
    Guohua Lv, Nicole M Sayles, Yun Huang, Chiara Mancinelli, Kevin McAvoy, Neil A Shneider, Giovanni Manfredi, Hibiki Kawamata, David Eliezer.
      Mitochondrial proteins CHCHD10 and CHCHD2 are mutated in rare cases of heritable FTD, ALS and PD and aggregate in tissues affected by these diseases. Here, we show that both proteins form amyloid fibrils and report cryo-EM structures of fibrils formed from their disordered N-terminal domains. The ordered cores of these fibrils are comprised of a region highly conserved between the two proteins, and a subset of the CHCHD10 and CHCHD2 fibril structures share structural similarities and appear compatible with sequence variations in this region. In contrast, disease-associated mutations p.S59L in CHCHD10 and p.T61I in CHCHD2, situated within the ordered cores of these fibrils, cannot be accommodated by the wildtype structures and promote different protofilament folds and fibril structures. These results link CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration and further suggest that fibril formation by the WT proteins could also be involved in disease etiology.
    DOI:  https://doi.org/10.1038/s41467-025-62149-3
  17. Nat Neurosci. 2025 Aug 06.
    Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
    Eizo Marutani, Maria Miranda, Timothy J Durham, Sharon H Kim, Dreson L Russell, Presli P Wiesenthal, Paul Lichtenegger, Marissa A Menard, Charlotte F Brzozowski, Haobo Li, Gary Ruvkun, Joshua D Meisel, Laura Volpicelli-Daley, Vamsi K Mootha, Fumito Ichinose.
      Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.
    DOI:  https://doi.org/10.1038/s41593-025-02010-4
  18. EMBO Mol Med. 2025 Aug 05.
    Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.
    Curran Landry, James P Costanzo, Miguel Mitne-Neto, Mayana Zatz, Ashleigh E Schaffer, Maria Hatzoglou, Alysson R Muotri, Helen C Miranda.
      Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.
    Keywords:  ALS (Amyotrophic Lateral Sclerosis); ER-MAM (Endoplasmic Reticulum Mitochondria Associated Membrane); ISR (Integrated Stress Response); Neurodegeneration; VAPB ((Vesicle Associated Membrane Protein Associated Protein B)
    DOI:  https://doi.org/10.1038/s44321-025-00279-3
  19. bioRxiv. 2025 Jul 24. pii: 2025.07.24.666629. [Epub ahead of print]
    Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.
    Subrata Pradhan, Sagar Gaikwad, Chi-Lin Tsai, Charlene Smith, Nan Zhang, Keegan Bush, Anirban Chakraborty, Subo Yuan, Sanjeev Choudhary, C Dirk Keene, Lisa M Ellerby, Tapas K Hazra, Albert R La Spada, Yogesh P Wairkar, Tatsuo Ashizawa, John A Tainer, Tej K Pandita, Leslie M Thompson, Partha S Sarkar.
      Huntingtin (HTT) function is enigmatic, as the native protein plays critical roles in neuronal health, while mutant HTT (mHTT), carrying an expanded polyglutamine stretch, triggers neurotoxicity and contributes to the pathogenesis of Huntington's disease (HD). We recently found that HTT is part of a nuclear transcription-coupled DNA repair (TCR) complex with DNA repair enzymes including polynucleotide-kinase-3'-phosphatase (PNKP). This complex resolves DNA lesions during transcription to maintain genome integrity, while in HD, mHTT impairs the activity of this complex, resulting in accumulation of DNA lesions. Using molecular, cellular biology and computational methods, we find that HTT has a role in assembling a functional DNA repair complex in mitochondria. Together with mitochondrial RNA polymerase and transcription factors, HTT resolves mitochondrial DNA lesions to preserve mitochondrial genome integrity and function. Pathogenic mHTT impairs this activity, resulting in persistent DNA lesions and reduced mitochondrial function in HD. Importantly, restoring activity of this complex in a Drosophila HD model through ectopic HTT or PNKP expression significantly improves mitochondrial genome integrity and ameliorates motor deficits.
    HIGHLIGHTS: HTT organizes a functional, multifactorial mitochondrial DNA repair complexMutant HTT impairs the mitochondrial DNA repair complex causing DNA damage accumulationHTT-associated repair complex resolves mitochondrial DNA lesions and DNA integrityRestoring repair activity in HD flies rescues mitochondrial DNA integrity and motor defects.
    DOI:  https://doi.org/10.1101/2025.07.24.666629
  20. Mol Cell Biochem. 2025 Aug 03.
    Mitochondrial disease management through phytochemical interventions.
    R Prabhu Ramya, K B Megha, S Reshma, M J Ajai Krishnan, S Amir, Rashmi Sharma, P V Mohanan.
      Mitochondrial diseases are a diverse group of disorders caused by dysfunction in mitochondria, the energy-generating organelles of cells. These disorders result from mutations in either nuclear or mitochondrial DNA and can be classified as primary (genetic origin) or secondary (environmentally induced). Due to their systemic impact, mitochondrial dysfunction leads to a wide range of clinical symptoms varying from tissue type and patient age. This review aims to provide a comprehensive overview of mitochondrial diseases, focusing on their classification, pathophysiology, diagnostic challenges and emerging therapeutic strategies. Current diagnostic approaches face limitations due to the complexity and heterogeneity of mitochondrial disorders. Recent evidence highlights the potential of phytochemicals such as polyphenols, flavonoids, alkaloids and terpenoids in modulating mitochondrial function. These natural compounds can enhance mitochondrial biogenesis, reduce oxidative stress and improve cellular energy metabolism. Phytochemicals represent a promising therapeutic avenue for mitigating mitochondrial dysfunction. However, further research is needed to validate their efficacy and develop standardized treatment protocols. An improved understanding of the molecular mechanisms involved in mitochondrial pathology will aid in developing more targeted diagnostic and therapeutic strategies.
    Keywords:  Mitochondrial biogenesis; Mitochondrial diseases; Oxidative stress; Phytochemicals; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s11010-025-05360-6
  21. FASEB J. 2025 Aug 15. 39(15): e70900
    Dopaminergic Neuron-Specific Tfam Knockout Links Inter-Organelle Miscommunication to Early-Onset Parkinsonism.
    Weiyan Shen, Mengling Zheng, Yanlin Zhao, Feitao Ni, Xudong Zhu.
      Parkinson's disease (PD) is characterized by mitochondrial dysfunction and dopaminergic neuron loss, with multiple subtypes existing due to various clinical manifestations. Compared to sporadic PD, early-onset PD is underrepresented due to its idiopathic or familial nature. How mitochondrial instability drives early-onset PD-associated neurodegeneration requires further clarification. Here, we used a dopaminergic neuron-specific Tfam conditional knockout (cKO) mouse model to investigate how mitochondrial transcription factor A (TFAM) deficiency impacts early-onset PD pathogenesis. As early as 2 months old, Tfam cKO mice exhibited progressive motor deficits, α-synuclein accumulation, and TH+ neuronal loss in the substantia nigra pars compacta (SNpc), culminating in significantly reduced body weight and shortened lifespan. Several hallmarks of mitochondrial dysfunction were observed in Tfam cKO neurons, including mtDNA depletion and impaired respiration, lowered NAD+/NADH ratio and membrane potential, accompanied by elevated pSer65 ubiquitin and ER stress activation. Transcriptomic profiling revealed dysregulated inter-organelle communication, with downregulated nicotinic acetylcholine receptor (nAChR) subunits and compensatory nuclear ribosomal gene upregulation in Tfam cKO neurons. Pharmacological mitophagy inhibition worsened dopaminergic neuron loss in Tfam cKO mice, partially due to cytosolic mtDNA leakage activating the cGAS-cGAMP-TBK1 inflammatory axis, exacerbating neuroinflammation and neuronal death. Genetic cGAS ablation attenuated neuroinflammation and delayed behavioral decline but failed to rescue mitochondrial defects or survival. In conclusion, our findings suggest Tfam cKO mice as a model linking inter-organelle miscommunication to early-onset PD pathogenesis. Targeted knockout of cGAS attenuates neuroinflammation in Tfam cKO mice, but not the overall PD symptoms and lifespan.
    DOI:  https://doi.org/10.1096/fj.202501454RR
  22. Front Mol Biosci. 2025 ;12 1639327
    Deuterium trafficking, mitochondrial dysfunction, copper homeostasis, and neurodegenerative disease.
    Stephanie Seneff, Anthony M Kyriakopoulos.
      Deuterium is a natural heavy isotope of hydrogen, containing an extra neutron. Eukaryotic organisms have devised complex metabolic policies that restrict the amount of deuterium reaching the mitochondria, because it damages the ATPase pumps, leading to release of excessive reactive oxygen species and inefficiencies in ATP production. Human metabolism relies heavily on the gut microbiome to assure an abundant supply of deuterium depleted (deupleted) nutrients to the host. Mitochondrial dysfunction is a hallmark of many chronic diseases, and deuterium overload, often due to gut dysbiosis, may be a major factor contributing to this issue. In this paper, we explore the potential role of certain amyloidogenic proteins, including amylin, amyloid beta, the prion protein, huntingtin, and α-synuclein, in disease processes that result in the accumulation of deposits of protein fibrils, along with lipid membrane components of damaged mitochondria, which we argue may be a mechanism to sequester deuterium in order to reduce the deuterium burden in the tissues. We show how cardiolipin, an anionic lipid synthesized in mitochondria and localized to the mitochondrial membrane, may play a central role both in trapping deuterium in the mitochondrial membrane and in inducing protein misfolding to facilitate the formation of deuterium-rich deposits. We focus on the potential role of the amino acid histidine and its interaction with the mineral copper, both to catalyze certain essential reactions and to facilitate the misfolding of amyloidogenic proteins triggered by contact with anionic phospholipids, particularly cardiolipin, and especially in the outer mitochondrial membrane of deuterium-damaged mitochondria.
    Keywords:  amyloidogenic proteins; cardiolipin; copper; deuterium; histidine; mitochondrial dysfunction; neurodegeneration
    DOI:  https://doi.org/10.3389/fmolb.2025.1639327
  23. bioRxiv. 2025 Aug 01. pii: 2025.07.29.667405. [Epub ahead of print]
    A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
    Emir Maldosevic, Radoslaw Gora, Liangguang Leo Lin, Linyao Elina Zhou, Zexin Jason Li, Yelena Peskova, Ling Qi, Shu-Ou Shan, Ahmad Jomaa.
      The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to the signal recognition particle (SRP) to ensure the fidelity of protein targeting to the endoplasmic reticulum (ER). However, the mechanism by which NAC prevents the mistargeting of nascent mitochondrial proteins remains unclear. Here, we identified a molecular switch in NAC that allows its central barrel domain to adopt a stabilized conformation on ribosomes exposing a mitochondrial targeting sequence (MTS). Mutations of the MTS on the nascent chain or in the NAC switch region increases NAC barrel dynamics and reduces its binding to the ribosome. This leads to an impaired ability of NAC to prevent mistargeting by SRP and causes ER stress in human cells. Our work reveals how NAC detects nascent mitochondrial proteins early in translation and prevents their promiscuous access to SRP, elucidating the structural basis that underlies this role and providing novel insights into protein targeting fidelity with broader implications for cellular proteostasis.
    DOI:  https://doi.org/10.1101/2025.07.29.667405
  24. bioRxiv. 2025 Jul 31. pii: 2025.07.28.667250. [Epub ahead of print]
    Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.
    Simon Couly, Yuko Yasui, Ioannis Grammatikakis, Yuriko Kimura, Josh Hinkle, Juan Gomez, Hsiang-En Wu, Ghosh Paritosh, Ashish Lal, Michael Michaelides, Brandon Harvey, Tsung-Ping Su.
      Sigma-1 receptor (S1R) is a Ca 2+ sensitive, ligand-operated receptor chaperone protein present on the endoplasmic reticulum (ER) membrane and more specifically at the mitochondria-associated ER membrane (MAM). Upon activation by ER calcium depletion or ligand binding, S1R can increase calcium efflux from the ER into the mitochondria by chaperoning IP3 receptor type3 (Ip3R3). Mitochondrial metabolism has an intricate relationship with glycolysis. Despite S1R affecting mitochondria, the relevance of S1R to glycolysis and its impact on the overall cellular energy metabolism is not known. This study utilizes wild-type (Wt) and S1R knockout (S1R KO) Neuro2a (N2a) cells and Wt and S1R KO mice for primary culture of cortical neurons studies and longitudinal in-vivo imaging. In this manuscript we describe the fundamental functions of S1R on glycolysis, mitochondrial activity and NAD + /NADH metabolism, keystone coenzymes essential for glycolysis and for mitochondrial activity. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 but no change in mitochondrial oxygen consumption. Furthermore, we observed an increased NAD + /NADH ratio in S1R KO condition. Positron emission tomography revealed decreased [ 18 F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking down GRIM19 in S1R KO condition rescued the glycolysis deficit. Altogether, these data show for the first time that S1R modulates glycolysis and NAD metabolism in various neuronal systems. This new insight on the S1R function may lead to new therapeutic applications of S1R ligands where compromised glycolysis and cellular NAD+/NADH ratios occur such as aging and neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.07.28.667250
  25. bioRxiv. 2025 Aug 02. pii: 2025.08.01.668168. [Epub ahead of print]
    Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
    Sherry X Zhou, Benjamin Madden, Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis J Maher.
       BACKGROUND: The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells.
    METHODS: We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition.
    RESULTS: SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.
    CONCLUSIONS: SDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. These findings reveal cell type-specific adaptations to SDH loss. The plasticity of the response of imCCs may underlie the tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.
    DOI:  https://doi.org/10.1101/2025.08.01.668168
  26. Sci Adv. 2025 Aug 08. 11(32): eadw4954
    Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
    Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.
      Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.
    DOI:  https://doi.org/10.1126/sciadv.adw4954
  27. Ageing Res Rev. 2025 Aug 05. pii: S1568-1637(25)00202-8. [Epub ahead of print]112 102856
    Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer.
    Junhan Liang, Zhaoqin Su, Gongmeiyue Su, Madiha Rasheed, Shiyi Tang, Hafsa Sunniya, Mohamed Maazouzi, Yaoyuan Cui, Junxiao Wang, Xuezhe Wang, Jing Yang, Mingchao Ding, Zhao Li, Yulin Deng.
      Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuronal degeneration and pathological α-synuclein accumulation. Mitochondrial dysfunction is a central feature in PD pathogenesis, contributing to impaired bioenergetics, oxidative stress, neuroinflammation, and defective organelle communication. This review synthesizes the current understanding of mitochondrial quality control mechanisms, including fission, fusion, mitophagy, and biogenesis, and their disruption in PD. Particular emphasis is placed on the role of intercellular mitochondrial transfer as a compensatory mechanism. Emerging evidence suggests that mitochondria can be transferred between neurons and glial cells through tunneling nanotubes, extracellular vesicles, and gap junctions, offering protective effects by restoring metabolic function and attenuating cellular stress. We examine the molecular mediators of these transfer pathways, the influence of PD-associated mutations, and the bidirectional dynamics between donor and recipient cells. Additionally, we explore translational strategies, including mitochondrial transplantation, bioengineered mitochondria, and stem cell-based delivery systems. While preclinical models demonstrate promising therapeutic outcomes, clinical translation faces challenges, including targeting specificity, mitochondrial viability, and immune compatibility. By integrating mechanistic insights with therapeutic developments, this review highlights mitochondrial transfer as a novel and promising approach in the future treatment of PD, potentially addressing longstanding limitations in conventional neuroprotective strategies.
    Keywords:  Future therapies; Mitochondria transfer; Mitochondrial dysfunction; Parkinson’s disease; Quality control
    DOI:  https://doi.org/10.1016/j.arr.2025.102856
  28. Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00319-2. [Epub ahead of print]86 103806
    Extracellular vesicle-mediated delivery of mitochondrial circRNA MTCO2 protects against cerebral ischemia by modulating mPTP-dependent ferroptosis.
    Jialei Yang, Shipo Wu, Miao He.
      Ischemic stroke remains a major cause of mortality and long-term disability, with few effective neuroprotective treatments currently available. Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, is increasingly recognized as a driver of neuronal damage. However, the mitochondrial mechanisms linking ischemia to ferroptosis remain poorly defined. Here, we identify circMTCO2, a mitochondria-encoded circular RNA, as a novel endogenous modulator of neuronal ferroptosis. CircMTCO2 expression is dynamically downregulated following cerebral ischemia/reperfusion both in vitro and in vivo. Mechanistically, circMTCO2 binds directly to adenine nucleotide translocase 1 (ANT1), a key component of the mitochondrial permeability transition pore (mPTP), thereby inhibiting mPTP opening and suppressing mitochondrial ROS (mtROS) release. Disruption of the binding site abolishes the circMTCO2-ANT1 interaction and eliminates the protective effects of circMTCO2. To restore and enhance this intrinsic defense mechanism, we developed a dual-targeting extracellular vesicle system (RVG-EVmt-RNA) capable of delivering circMTCO2 specifically to brain neuronal mitochondria. Systemic administration of RVG-EVmt-RNA attenuated mtROS production, reduced neuronal ferroptosis, decreased infarct volume, and improved neurological function in a mouse model of ischemic stroke, without inducing systemic toxicity. These findings establish circMTCO2 as a previously unrecognized mitochondrial circRNA that regulates ferroptosis by modulating mPTP activity, and provide proof of concept that organ-to-organelle circRNA delivery can be leveraged as a precision neuroprotective strategy for ischemic stroke.
    Keywords:  Extracellular vesicles; Ferroptosis; Ischemic stroke; Mitochondrial circRNA; Targeted delivery; circMTCO2
    DOI:  https://doi.org/10.1016/j.redox.2025.103806
  29. Stem Cell Rev Rep. 2025 Aug 05.
    Granulopoietic Dysregulation in a Patient-Tailored Mouse Model of Barth Syndrome.
    Elizabeth A Sierra Potchanant, Maegan L Capitano, Donna M Edwards, Baskar Ramdas, Scott Cooper, James Ropa, S Louise Pay, Aditya Sheth, Paige L Snider, Hilary J Vernon, Ngoc-Tung Tran, Reuben Kapur, Simon J Conway.
      Barth syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy, skeletal muscle myopathy and fatigue, growth restriction, and neutropenia. Neutropenia increases the risk of life-threatening bacterial infections, a major cause of death in individuals with BTHS. Currently, there is no curative treatment for BTHS or associated neutropenia. The development of therapeutic strategies to correct BTHS-associated neutropenia has been hindered by a limited understanding of the underlying molecular mechanisms involved. BTHS is caused by a mutation in the Tafazzin gene encoding a transacylase required for the maturation of cardiolipin, an inner mitochondrial membrane phospholipid crucial for mitochondrial structure and function. We introduced a BTHS patient's point mutation (TAZD75H) into the mouse Tafazzin enzyme's critical acyltransferase site using CRISPR/Cas9-mediated genome editing, resulting in a patient-tailored point mutant knock-in BTHS model (TazD75H) that expresses a stable mutant TazD75H protein lacking transacylase activity. TazD75H mice were then used to investigate how loss of Tafazzin enzymatic activity impacts hematopoiesis. Male TazD75H mice exhibited impaired granulopoiesis and neutropenia secondary to impaired function of hematopoietic progenitors. Furthermore, they demonstrated age-dependent neutrophil maturation impairment reflecting the variable neutropenia observed in BTHS patients. Additionally, male TazD75H mice exhibit chronic lymphopenia that persists post TazD75H bone marrow transplantation. Mechanistically, the TAZD75H point mutation caused hematopoietic cell mitochondrial dysfunction in patient-derived immortalized TAZD75H lymphoblasts, increasing reactive oxygen species production and mitochondrial membrane depolarization. Likewise, Cyclosporine A treatment rescued these mitochondrial phenotypes in vitro, confirming TAZD75H mitochondrial dysfunction. Overall, our findings demonstrate that mitochondrial dysfunction secondary to TAFAZZIN loss of enzymatic function underlies BTHS-associated neutropenia and lymphopenia.
    Keywords:  Barth syndrome; Hematopoietic stem cells; Neutropenia; Patient-tailored mouse model; Tafazzin
    DOI:  https://doi.org/10.1007/s12015-025-10945-1
  30. Structure. 2025 Jul 25. pii: S0969-2126(25)00258-8. [Epub ahead of print]
    Cryogenic electron tomography and elemental analysis of mitochondrial granules in human retinal ganglion cells.
    Gong-Her Wu, Cathy Hou, Andrew Thron, Hirenkumar Rajendra Patel, Liam Spillane, Sanket Rajan Gupte, Serena Yeung-Levy, Sahil Gulati, Christopher Booth, Yaping Joyce Liao, Wah Chiu.
      Combining three-dimensional (3D) visualization with elemental analysis of vitrified cells can provide crucial insights into subcellular structures and elemental compositions in their native environments. We present a coordinated approach using cryogenic electron energy loss spectroscopy (cryoEELS) and cryogenic electron tomography (cryoET) to characterize the elemental distribution and ultrastructure of vitrified cells. We applied this method to examine calcium disposition in the mitochondria of cultured human retinal ganglion cells (RGCs) exposed to pro-calcifying conditions relevant to optic disc drusen pathology. Our cryoEELS analysis revealed mitochondrial granules with elevated calcium signals, offering direct evidence of mitochondrial calcification. Additionally, cryoET coupled with artificial intelligence-based analysis enabled quantification of the volume and spatial distribution of these calcium granules. This integrated workflow can be broadly applied to various cell types, facilitating the study of ultrastructure and elemental distribution in subcellular structures under diverse physiological and pathological conditions, as well as in response to therapeutic interventions.
    Keywords:  calcium; cryogenic electron energy loss spectroscopy; cryogenic electron tomography; elemental analysis; human retinal ganglion cell; mitochondrial granules
    DOI:  https://doi.org/10.1016/j.str.2025.07.010
  31. Geroscience. 2025 Aug 06.
    EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework.
    Amin Haghani, Ake T Lu, Qi Yan, Juan Carlos Izpisua Belmonte, Pradeep Reddy, Victor Cheng, X William Yang, Nan Wang, Khyobeni Mozhui, Kevin Murach, Alejandro Ocampo, Robert W Williams, Mathias Jucker, Carina Bergmann, Jesse R Poganik, Bohan Zhang, Vadim N Gladyshev, Steve Horvath.
      Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
    Keywords:  Aging biomarkers; Biological age; DNA methylation; EnsembleAge; Epigenetic clocks; Healthspan; Lifespan interventions; MethylGauge dataset; Mouse models; Rejuvenation; Stress response
    DOI:  https://doi.org/10.1007/s11357-025-01808-1
  32. Value Health. 2025 Aug 05. pii: S1098-3015(25)02490-8. [Epub ahead of print]
    'Adrift From the World': Exploring the Lived Experiences of Individuals Affected by an Inherited Optic Neuropathy in the United Kingdom - A Qualitative Study.
    Benson S Chen, Chloe Seikus, James Ferguson, Valerija Tadić, Mike Horton, Patrick Yu-Wai-Man, Stephanie Archer.
       OBJECTIVES: Little is understood about the lived experiences of individuals affected by inherited optic neuropathies (IONs) in the United Kingdom. The aim of this study was to understand how autosomal dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON), the two more commonly encountered IONs, impact affected individuals and the factors contributing to their vision-related quality of life (VRQoL).
    METHODS: Semi-structured qualitative interviews were conducted with 20 individuals with a genetic diagnosis of DOA (10 participants) or LHON (10 participants) and affected by vision loss. Eligible participants were purposively sampled to achieve variation in participant age, sex, duration of visual impairment, and location in the UK. Using inductive thematic analysis, a range of themes and sub-themes were developed.
    RESULTS: Participants' experiences could be broadly summarised across four overarching themes: [1] IONs impacted all aspects of life, most notably psychosocial and emotional wellbeing; [2] participants learned to cope by adapting and adjusting to visual impairment, often on their own, with little external support or resources; [3] participants' identities as visually-impaired people were determined by how they viewed themselves and others' reactions to their disability; and [4] good VRQoL was defined as having independence with the support of others.
    CONCLUSIONS: Visual impairment due to an ION threatens the independence of affected individuals, leading to psychosocial losses and reduced emotional wellbeing. Despite the challenges they face, people living with an ION describe a "relatively" good VRQoL, often due to the positive impact of social support, enabling them to lead fulfilling lives.
    Keywords:  lived experience; mitochondrial disease; optic atrophy; quality of life
    DOI:  https://doi.org/10.1016/j.jval.2025.07.023
  33. STAR Protoc. 2025 Aug 02. pii: S2666-1667(25)00410-1. [Epub ahead of print]6(3): 104004
    Protocol for measuring mitochondrial respiratory capacity from buccal cell swabs.
    Tina R Ram, Chunlong Mu, Jaclyn C Campbell, Sarah J MacEachern, Jane Shearer.
      Mitochondrial respirometry provides a detailed assessment of oxygen consumption within the electron transport system, yet methods detailing respiration from non-invasive samples remain limited. Here, we present a protocol for measuring mitochondrial respiration in cultured buccal cells. We outline procedures for buccal cell collection, primary cell culture, and respirometry calibration, followed by oxygen consumption measurements and cell count for data normalization. This protocol allows reliable evaluation of mitochondrial function from non-invasive buccal cell samples, offering a valuable tool for metabolic investigation.
    Keywords:  Cell Biology; Cell culture; Cell-based Assays; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2025.104004
  34. Nat Commun. 2025 Aug 02. 16(1): 7110
    Decompartmentalization of the yeast mitochondrial metabolism to improve chemical production in Issatchenkia orientalis.
    Vinh G Tran, Shih-I Tan, Hao Xu, Daniel R Weilandt, Xi Li, Sarang S Bhagwat, Zhixin Zhu, Jeremy S Guest, Joshua D Rabinowitz, Huimin Zhao.
      Microbial production of chemicals may suffer from inadequate cofactor provision, a challenge further exacerbated in yeasts due to compartmentalized cofactor metabolism. Here, we perform cofactor engineering through the decompartmentalization of mitochondrial metabolism to improve succinic acid (SA) production in Issatchenkia orientalis. We localize the reducing equivalents of mitochondrial NADH to the cytosol through cytosolic expression of its pyruvate dehydrogenase (PDH) complex and couple a reductive tricarboxylic acid pathway with a glyoxylate shunt, partially bypassing an NADH-dependent malate dehydrogenase to conserve NADH. Cytosolic SA production reaches a titer of 104 g/L and a yield of 0.85 g/g glucose, surpassing the yield of 0.66 g/g glucose constrained by cytosolic NADH availability. Additionally, expressing cytosolic PDH, we expand our I. orientalis platform to enhance acetyl-CoA-derived citramalic acid and triacetic acid lactone production by 1.22- and 4.35-fold, respectively. Our work establishes I. orientalis as a versatile platform to produce markedly reduced and acetyl-CoA-derived chemicals.
    DOI:  https://doi.org/10.1038/s41467-025-62304-w
  35. Nat Commun. 2025 Aug 07. 16(1): 7304
    Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
    Shengnan Li, Zhaoliang Shan, Guochun Zhao, Yuwei Li, Minghui Du, Xiuxiu Ti, Yuxue Gao, Wenting Li, Hui Zuo, Yan Wang, Qing Zhang.
      Mitochondria coordinate with lysosomes to maintain cellular homeomstasis. However, in mitochondrial defect condition, how they communicate is less clear. Here, utilizing dMterf4 RNAi fly model, we find that expression of lysosomal alpha-mannosidase VI (LManVI) is significantly downregulated. Mechanistically, we show that dMterf4 RNAi-triggered mitochondrial defect mediates downregulation of lysosomal LManVI through Med8/Tfb4-E(z)/pho axis, causing impairment of lysosomal function. Reciprocally, downregulation of lysosomal LManVI further decreases many mitochondrial genes expression through downregulation of transcriptional coactivator PGC-1, leading to aggravating the dMterf4 RNAi-mediated mitochondrial defect, suggesting that mitochondrial defect can crosstalk with lysosomes to make mitochondrial status worse in a positive feedback way. Finally, we demarcate that this interaction between mitochondria and lysosomes may be conserved in mammalian cells. Therefore, our findings unveil a communication mechanism between mitochondria and lysosomes in mitochondrial defect case, which provides insights about the treatments of related mitochondrial and lysosomal diseases through modulation of the mitochondria-lysosomes axis.
    DOI:  https://doi.org/10.1038/s41467-025-62147-5
  36. Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00321-0. [Epub ahead of print]86 103808
    Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
    Jose Adan Arevalo, Dianna Xing, Roberto Garcia Leija, Max A Thorwald, Diana Daniela Moreno-Santillán, Kaitlin N Allen, Giovanna Selleghin-Veiga, Heidi C Avalos, Eva Utke, Justin L Conner, George A Brooks, José Pablo Vázquez-Medina.
      An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A2 activities. Here, we show decreased mitochondrial Prdx6 levels, increased mitochondrial lipid peroxidation, and dysregulated muscle bioenergetics in aged mice and muscle cells derived from older humans. Mechanistically, we found that Prdx6 supports optimal mitochondrial function and prevents mitochondrial fragmentation by limiting mitochondrial lipid peroxidation via its membrane remodeling activities. Our results suggest that age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics, thereby opening the door to therapeutic modulation of Prdx6 to counteract diminished mitochondrial function in aging.
    DOI:  https://doi.org/10.1016/j.redox.2025.103808
  37. Biol Chem. 2025 Aug 11.
    Conserved function, divergent evolution: mitochondrial outer membrane insertases across eukaryotes.
    Anna Roza Dimogkioka, Doron Rapaport.
      Mitochondrial function relies heavily on the proper targeting and insertion of nuclear-encoded proteins into the outer mitochondrial membrane (OMM), a process mediated by specialised biogenesis factors known as insertases. These insertases are essential for the membrane integration of α-helical OMM proteins, which contain one or multiple hydrophobic transmembrane segments. While the general mechanisms of mitochondrial protein import are well established, recent research has shed light on the diversity and evolutionary conservation of OMM insertases across eukaryotic lineages. In Saccharomyces cerevisiae, the mitochondrial import (MIM) complex, composed of Mim1 and Mim2, facilitates the integration of various α-helical OMM proteins, often in cooperation with import receptors such as Tom20 and Tom70. In Trypanosoma brucei, the functional MIM counterpart pATOM36 performs a similar role despite lacking sequence and structural homology, reflecting a case of convergent evolution. In mammals, MTCH2 has emerged as the principal OMM insertase, with MTCH1 playing a secondary, partially redundant role. This review provides a comparative analysis of these insertases, emphasising their conserved functionality, species-specific adaptations, and mechanistic nuances.
    Keywords:  MIM complex; MTCH2; insertases; mitochondrial outer membrane; pATOM36
    DOI:  https://doi.org/10.1515/hsz-2025-0169
  38. Front Mol Neurosci. 2025 ;18 1621070
    Calcium signaling in postsynaptic mitochondria: mechanisms, dynamics, and role in ATP production.
    Tatiana Feofilaktova, Liliia Kushnireva, Menahem Segal, Eduard Korkotian.
      While the overall ATP level in neurons remains relatively stable, local fluctuations in synaptic compartments - driven by synaptic potentials - necessitate rapid ATP adjustments. The energy supply for synaptic activity in neurons must be under precise homeostatic control: increased ATP consumption in active synapses requires continuous replenishment, whereas in periods of inactivity, excess ATP production may occur. Overproduction of ATP in thousands of individual synapses is metabolically wasteful, while underproduction threatens to disrupt molecular cascades associated with ongoing synaptic bursts, ion homeostasis, protein synthesis, and neural plasticity. Fine-tuned regulation of ATP synthesis must therefore be controlled locally and dynamically, ensuring metabolic efficiency while preventing disruptions in synaptic bursts, ion homeostasis, and neuronal plasticity. This review summarizes the intricate molecular mechanisms through which mitochondria (MT) interact with their postsynaptic environment to maintain energy balance. We examined the fundamental features of mitochondria in conjunction with their unique properties and roles in nervous tissue, highlighting their ability to dynamically adjust energy production based on local demand rather than maintaining a strictly uniform ATP output. The regulation of ATP synthesis may involve mitochondrial transport, fusion, and fission, as well as changes in mitochondrial shape and molecular structure. This review describes the activity of ATP synthase, the mitochondrial calcium uniporter and other signaling cascades in the context of their uneven distribution within mitochondria. Furthermore, we discuss rapid calcium influxes from postsynaptic membranes and the endoplasmic reticulum into mitochondria-associated membranes (MAMs), their buffering mechanisms, and the generation of dynamic responses. We focus on the role of calcium ion (Ca2+) as a precise regulator of ATP production, particularly in mitochondria located near synaptic regions, where it ensures an adequate energy supply for local activity. Overall, we propose potential pathways of interaction between mitochondria and their postsynaptic microdomains. Given that some of the mechanisms discussed remain hypothetical, we emphasize the urgent need for experimental validation to refine understanding of mitochondrial function in synaptic transmission.
    Keywords:  ATP synthase; Ca2+ signaling; MAM; MCU; dendritic spine; endoplasmic reticulum; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fnmol.2025.1621070
  39. bioRxiv. 2025 Jul 23. pii: 2025.07.19.665690. [Epub ahead of print]
    An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial protein import.
    Max J Bachochin, Kelly L McGuire, Brian D Cook, Qiaozhen Ye, Steve Silletti, Kevin D Corbett, Elizabeth A Komives, Mark A Herzik.
      Tom70 mediates mitochondrial protein import by coordinating the transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 ( Hs Tom70c) is entirely α -helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding domain (NTD) and a C-terminal preprotein-binding domain (CTD). However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 Å crystal structure of unliganded Hs Tom70c, revealing two distinct conformations - open and closed - within the asymmetric unit. These states are stabilized in part by interdomain crystal contacts and are supported in solution by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and dynamical network analyses reveal a continuum of motion linking the NTD and CTD via key structural elements, notably residues in helices α 7, α 8, and α 25. Engagement of the CTD by the viral protein Orf9b interrupts this network, stabilizing a partially-closed intermediate conformation and dampening dynamics at distal NTD sites. Collectively, our findings lay the groundwork for understanding Tom70 allostery and provide a framework for dissecting its mechanistic roles in chaperone engagement, mitochondrial import, and viral subversion.
    DOI:  https://doi.org/10.1101/2025.07.19.665690
  40. Arch Physiol Biochem. 2025 Aug 05. 1-17
    Mechanistic insights into ubiquinone Q10 in Parkinson's disease: mitochondrial protection, ferroptosis inhibition, and antioxidant recycling.
    Mohamed J Saadh, Tamara Nazar Saeed, Ali Fawzi Al-Hussainy, Ashishkumar Kyada, Suhas Ballal, Mayank Kundlas, A Sabarivani, Jasur Rizaev, Sada Ghalib Taher, Mariem Alwan, Mahmood Jawad, Hiba Mushtaq.
       BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Although the exact cause of Parkinson's disease is still unknown, neuroinflammation and mitochondrial dysfunction have been identified as essential factors in the disease's pathophysiology.
    METHODS: Coenzyme Q10 has gathered considerable attention as a potential therapeutic agent due to its dual function in antioxidant defense and mitochondrial bioenergetics. It is an essential electron carrier in the mitochondrial electron transport chain and plays a crucial role in reducing oxidative stress, a primary cause of neuronal degeneration in Parkinson's disease.
    RESULTS: Coenzyme Q10 supplements can enhance mitochondrial activity, reduce oxidative stress, and protect dopaminergic neurons from degeneration. To improve Coenzyme Q10 formulations and ascertain its effectiveness in slowing the progression of Parkinson's disease, more study is required.
    CONCLUSION: This review examines the neuroprotective mechanisms of Coenzyme Q10 and its potential as a therapeutic option for Parkinson's disease.
    Keywords:  CoQ10; Parkinson’s disease; coenzyme Q10; mitochondrial dysfunction; neuroprotective therapies
    DOI:  https://doi.org/10.1080/13813455.2025.2541698
  41. Stem Cell Res. 2025 Jul 25. pii: S1873-5061(25)00132-1. [Epub ahead of print]87 103782
    Generation and characterisation of four human NAD(P)HX epimerase (NAXE) knockout iPSC lines.
    Tim Sikora, Myrto Patraskaki, Sara Howden, Alison Graham, John Christodoulou, Carole L Linster, Nicole J Van Bergen.
      Pathogenic variants in NAD(P)HX epimerase (NAXE) cause early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1), an ultra-rare severe neurometabolic disorder resulting in death in infancy. The absence of functional NAD(P)HX epimerase leads to accumulation of S- and R-forms of NAD(P)HX, inhibiting key metabolic pathways. We have generated four NAXE-deficient cell lines via simultaneous CRISPR/Cas9-mediated gene knockout (KO) of NAXE and episomal reprogramming of control human fibroblasts into induced pluripotent stem cells (iPSCs). We have demonstrated loss of NAXE gene expression, characterized iPSC pluripotency and differentiation potential into three germ layers. This provides a suitable model for investigating disease mechanisms and therapies.
    DOI:  https://doi.org/10.1016/j.scr.2025.103782
  42. Mol Med. 2025 Aug 04. 31(1): 273
    Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
    Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple.
       BACKGROUND: The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.
    METHODS: Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2R707W/R707W fibroblasts, and in Mfn2R707W/R707W mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.
    RESULTS: Forcing galactose metabolism in human MFN2R707W/R707W dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2R707W/R707W brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2R707W/R707W mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2R707W/R707W preadipocytes. In male Mfn2R707W/R707W mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2R707W/R707W preadipocytes.
    CONCLUSIONS: Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.
    Keywords:  Alcohol; Lipodystrophy; MFN2; Mitofusin; Multiple symmetrical lipomatosis; Rapamycin; Sirolimus
    DOI:  https://doi.org/10.1186/s10020-025-01314-2
  43. Am J Ophthalmol. 2025 Aug 06. pii: S0002-9394(25)00387-3. [Epub ahead of print]
    The Undiagnosed Diseases Network (UDN) Solves Ocular Syndromic Diagnostic Dilemmas.
    Undiagnosed Diseases Network
       PURPOSE: The multicenter NIH-funded Undiagnosed Diseases Network (UDN) exists to diagnose puzzling and newly discovered conditions. We report the UDN's assistance in diagnosing perplexing ocular disorders along with six case illustrations.
    DESIGN: Retrospective Interventional Case Series SUBJECTS: Participants with ocular phenotypes who had applied and were accepted into the UDN with detailed supporting letters written by ophthalmologists or other clinicians when clinically indicated genetic and laboratory testing results were not diagnostic.
    METHODS: Human Phenotype Ontology Codes were used to identify and categorize subjects with ocular phenotypes. Advanced genomic technologies (exome, genome, mitochondrial and RNA sequencing, X-inactivation analysis, immunoblot analysis) were available for diagnoses.
    MAIN OUTCOME MEASURE: Proportion of cases solved by the UDN in subjects manifesting an ophthalmic component of their undiagnosed disorder.
    RESULTS: The national UDN diagnostic rate for subjects with an eye phenotype was 40.2% (452 of 1123); the diagnostic rate for the other subjects (without an eye) phenotype was 27.8% (276 of 992). In univariate analysis, having an eye phenotype was significantly associated with receiving a diagnosis (odds ratio [OR] = 1.75; confidence intervals [CI] = 1.45 - 2.10; p=2.28e-09). Of 58 eye diagnosed cases/104 total diagnosed cases at the Vanderbilt UDN site, six will be discussed more fully. Vanderbilt UDN cases include an autosomal dominant glaucoma with a variant in TEK/TIE2; a de novo heterozygous variant in PRPS1 causing microcornea and glaucoma with skewed X-inactivation affecting a female; a homozygous variant in NADK2 causing optic nerve atrophy, autosomal recessive variants in EPG5 resulting in optic nerve atrophy and cone-rod dystrophy; and a rare de novo variant in COG4 causing a cataract/ retinitis pigmentosa/ nystagmus phenotype. EPG5 and COG4 are not present on inherited retinal disease panels.
    CONCLUSIONS: The UDN is a national resource available to increase solving undiagnosed diseases including those with ocular phenotypes, facilitate research on undiagnosed diseases, and create a collaboration to improve care options for patients with undiagnosed diseases. Clinicians including ophthalmologists can collaborate with the UDN to solve challenging ocular mysteries using genomic technologies.
    Keywords:  Undiagnosed Diseases Network; ophthalmic diseases; ophthalmic genetics; rare diseases
    DOI:  https://doi.org/10.1016/j.ajo.2025.07.028
  44. bioRxiv. 2025 Jul 24. pii: 2025.07.23.666395. [Epub ahead of print]
    Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
    Mariella Quispe-Carbajal, Lauren Todd, Steven E Glynn.
      Yme1 is a conserved ATP-dependent protease that maintains mitochondrial function by degrading proteins in the intermembrane space. However, how Yme1 selects substrates within the crowded mitochondrial environment is poorly understood. An established substrate of Yme1 in yeast is the Tim10 subunit of the small Tim9-Tim10 protein chaperone complex, which is degraded following disruption of the subunit's internal disulfide bonds. Here, we use biochemical and biophysical approaches to examine initial substrate binding and degradation of small Tim proteins by Yme1 and shed light on the molecular mechanism of substrate selection. We show that Yme1 preferentially binds Tim10 over other small Tim proteins by forming a high-affinity interaction with the subunit irrespective of the presence of its disulfide bonds. This interaction is primarily mediated by Tim10's flexible N-terminal 'tentacle', though substrate unfolding exposes additional contact sites that enhance engagement. Notably, the human ortholog TIMM13 is also recognized by yeast Yme1, suggesting conservation of recognition strategy across species. Yme1 also binds to the assembled Tim9-Tim10 chaperone but independently of the Tim10 N-terminal tentacle. These findings suggest that Yme1 surveils the folding state of Tim10 throughout its functional lifecycle - both as a folded monomer and as a subunit of the functional chaperone complex - but only commits to degradation after disruption of its disulfide bonds.
    DOI:  https://doi.org/10.1101/2025.07.23.666395
  45. BMJ Case Rep. 2025 Aug 08. pii: bcr0820080632. [Epub ahead of print]2009
    G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies.
    Carles Gaig, María José Martí, Mario Ezquerra, Adriana Cardozo, Maria Jesus Rey, Eduardo Tolosa.
      The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson's disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without α-synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy.
    DOI:  https://doi.org/10.1136/bcr.08.2008.0632
  46. Annu Rev Cell Dev Biol. 2025 Aug 06.
    The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
    Nazma Malik, Reuben J Shaw.
      Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120420-094431
  47. Nat Commun. 2025 Aug 04. 16(1): 7130
    Precise mapping of single-stranded DNA breaks by sequence-templated erroneous DNA polymerase end-labelling.
    Leonie Wenson, Johan Heldin, Marcel Martin, Yücel Erbilgin, Barış Salman, Anders Sundqvist, Wesley Schaal, Friederike A Sandbaumhüter, Erik T Jansson, Xingqi Chen, Anton Davidsson, Bo Stenerlöw, Jaime A Espinoza, Mikael Lindström, Johan Lennartsson, Ola Spjuth, Ola Söderberg.
      The ability to analyze whether DNA contains lesions is essential in identifying mutagenic substances. Currently, the detection of single-stranded DNA breaks (SSBs) lacks precision. To address this limitation, we develop a method for sequence-templated erroneous end-labelling sequencing (STEEL-seq), which enables the mapping of SSBs. The method requires a highly error-prone DNA polymerase, so we engineer a chimeric DNA polymerase, Sloppymerase, capable of replicating DNA in the absence of one nucleotide. Following the omission of a specific nucleotide (e.g., dATP) from the reaction mixture, Sloppymerase introduces mismatches directly downstream of SSBs at positions where deoxyadenosine should occur. This mismatch pattern, coupled with the retention of sequence information flanking these sites, ensures that the identified hits are bona fide SSBs. STEEL-seq is compatible with a variety of sequencing technologies, as demonstrated using Sanger, Illumina, PacBio, and Nanopore systems. Using STEEL-seq, we determine the SSB/base pair frequency in the human genome to range between 0.7 and 3.8 × 10-6 with an enrichment in active promoter regions.
    DOI:  https://doi.org/10.1038/s41467-025-62512-4
  48. Cell Mol Life Sci. 2025 Aug 08. 82(1): 301
    The complex web of membrane contact sites in brain aging and neurodegeneration.
    Domenico Azarnia Tehran, Paola Pizzo.
      To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.
    Keywords:  Inter-organelle crosstalk; Neuronal homeostasis; Organelle contacts; Synaptic dysfunction; Therapeutic targets
    DOI:  https://doi.org/10.1007/s00018-025-05830-6
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