bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–06–22
sixty-nine papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Dysfunctional mitochondria trap proteins in the intermembrane space.
  2. Transcription arrest induces formation of RNA granules in mitochondria.
  3. Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
  4. Role of mitochondria in physiological activities, diseases, and therapy.
  5. Machine learning to predict mitochondrial diseases by phenotypes.
  6. Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency.
  7. Modelling mitochondrial diseases in neurons In Vitro: A systematic review.
  8. Lipid nanoparticle delivery of the CRISPR/Cas9 system directly into the mitochondria of cells carrying m.7778G>T mutation in MtDNA (mt-Atp8).
  9. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  10. Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
  11. ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.
  12. Autosomal dominant myopathy caused by a novel ISCU variant.
  13. Shaping the composition of the mitochondrial outer membrane.
  14. Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction.
  15. Mitochondrial Preparation from Microglia for Glycan Analysis.
  16. Fumarate hits the brakes on mitophagy.
  17. Medication targeting to subcellular organelles: Emphasizing mitochondria as a therapeutic marvel-Current situation and future prospects.
  18. Few shot learning for phenotype-driven diagnosis of patients with rare genetic diseases.
  19. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.
  20. Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
  21. Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.
  22. Early-Onset Hearing Loss in Leber's Hereditary Optic Neuropathy: A Case Report.
  23. The Mitochondrial Foundations of Parkinson's Disease: Therapeutic Implications.
  24. Mitochondrial deoxyguanosine kinase depletion induced ROS causes melanocyte stem cell exhaustion and hair greying.
  25. Guidelines for the measurement of oxygen consumption rate in Caenorhabditiselegans.
  26. pDCs drive immunopathology by sensing oxidized mitochondrial DNA.
  27. Expanding the Genetic and Phenotypic Spectrum of Kearns-Sayre Syndrome: A Case Report.
  28. Local and global control on mitochondrial ageing.
  29. A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases.
  30. Update of the sideroflexin (SLC56) gene family.
  31. NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
  32. Synaptic mitochondria in aging and neurodegenerative diseases: unraveling their functional decline and vulnerability.
  33. Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.
  34. 'Killswitch' protein lets scientists study immobilized cellular droplets.
  35. Neuroglobin: A promising candidate to treat neurological diseases.
  36. Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
  37. Reduced expression of Pss gene in Drosophila cortex glia causes dopaminergic cell death.
  38. Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease.
  39. Mice with human cells developed using 'game-changing' technique.
  40. Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China.
  41. Antioxidant therapy in inborn metabolic diseases.
  42. The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
  43. We need to show AI what didn't work as well as what did.
  44. LSMEM2, Localized at the Neuromuscular Junction, Modulates Mitochondrial Integration in Skeletal Muscles.
  45. Multiple roles for a mitochondrial enzyme.
  46. Identification of technically challenging variants - whole genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases.
  47. An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.
  48. Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
  49. Rewriting cancer's code: A micropeptide's mitochondrial mission.
  50. Protocol to implement saturation mutagenesis-reinforced functional assays to resolve small-sized variants in disease-related genes.
  51. 'Super-healing' animals inspire human treatments.
  52. Kearns-Sayre syndrome presenting with fanconi syndrome: a case report.
  53. Enzymatic approaches to nicotinic acid synthesis: recent advances and future prospects.
  54. Friedreich's ataxia-a rare multisystem disease.
  55. Mutant zebrafish lacking slc25a22a show spontaneous seizures and respond to the anti-seizure medication valproic acid.
  56. Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
  57. Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise.
  58. Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
  59. Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.
  60. The m.3290T > C variant might be a protective factor against the pathogenic m.3243 A > G variant: a case study.
  61. Resting Ca2+ fluxes protect cells from fast mitochondrial fragmentation, cell stress responses, and immediate transcriptional reprogramming.
  62. Human mitochondrial pyrophosphatase hPPA2: In vitro and in silico study of the factors affecting its function.
  63. Short-term dietary methionine restriction with high fat diet counteracts metabolic dysfunction in male mice.
  64. Perturb-Multimodal: A platform for pooled genetic screens with imaging and sequencing in intact mammalian tissue.
  65. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
  66. Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
  67. AI slashes time to produce gold-standard medical reviews - but sceptics urge caution.
  68. Structural biology of Parkinson's Disease-associated Leucine-Rich Repeat Kinase 2 (LRRK2).
  69. Toward streamline variant classification: discrepancies in variant nomenclature and syntax for ClinVar pathogenic variants across annotation tools.
  1. EMBO J. 2025 Jun 16.
    Dysfunctional mitochondria trap proteins in the intermembrane space.
    Tamara Flohr, Markus Räschle, Johannes M Herrmann.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
  2. Life Sci Alliance. 2025 Sep;pii: e202403082. [Epub ahead of print]8(9):
    Transcription arrest induces formation of RNA granules in mitochondria.
    Katja G Hansen, Autum Baxter-Koenigs, Caroline Am Weiss, Erik McShane, L Stirling Churchman.
      Mitochondrial gene expression regulation is required for the biogenesis of oxidative phosphorylation (OXPHOS) complexes, yet the spatial organization of mitochondrial RNAs (mt-RNAs) remains unknown. Here, we investigated the spatial distribution of mt-RNAs during various cellular stresses using single-molecule RNA-FISH. We discovered that transcription inhibition leads to the formation of distinct RNA granules within mitochondria, which we term inhibition granules. These structures differ from canonical mitochondrial RNA granules and form in response to multiple transcription arrest conditions, including ethidium bromide treatment, specific inhibition or stalling of the mitochondrial RNA polymerase, and depletion of the SUV3 helicase. Inhibition granules appear to stabilize certain mt-mRNAs during prolonged transcription inhibition. This phenomenon coincides with an imbalance in OXPHOS complex expression, where mitochondrial-encoded transcripts decrease while nuclear-encoded subunits remain stable. We found that cells recover from transcription inhibition via resolving the granules, restarting transcription, and repopulating the mitochondrial network with mt-mRNAs within hours. We suggest that inhibition granules may act as a reservoir to help overcome OXPHOS imbalance during recovery from transcription arrest.
    DOI:  https://doi.org/10.26508/lsa.202403082
  3. Nat Commun. 2025 Jun 17. 16(1): 5328
    Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
    Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.
      Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-60857-4
  4. Mol Biomed. 2025 Jun 19. 6(1): 42
    Role of mitochondria in physiological activities, diseases, and therapy.
    Lilin Wang, Xiaoting Zhou, Tianqi Lu.
      Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.
    Keywords:  Cancer; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Therapy
    DOI:  https://doi.org/10.1186/s43556-025-00284-5
  5. Mitochondrion. 2025 Jun 18. pii: S1567-7249(25)00058-3. [Epub ahead of print] 102061
    Machine learning to predict mitochondrial diseases by phenotypes.
    Chieh-Wen Kuo, Hui-An Chen, Rai-Hseng Hsu, Chaoszu Wu, Ching Hsu, Ming-Jen Lee, Yin-Hsiu Chien, Hsueh-Wen Hsueh, Feng-Jung Yang, Pi-Chuan Fan, Wen-Chin Weng, Ru-Jen Lin, Ta-Ching Chen, Chih-Chao Yang, Wang-Tso Lee, Wuh-Liang Hwu, Ni-Chung Lee.
      Diagnosing mitochondrial diseases remains challenging because of the heterogeneous symptoms. This study aims to use machine learning to predict mitochondrial diseases from phenotypes to reduce genetic testing costs. This study included patients who underwent whole exome or mitochondrial genome sequencing for suspected mitochondrial diseases. Clinical phenotypes were coded, and machine learning models (support vector machine, random forest, multilayer perceptron, and XGBoost) were developed to classify patients. Of 103 patients, 43 (41.7%) had mitochondrial diseases. Myopathy and respiratory failure differed significantly between the two groups. XGBoost achieved the highest accuracy (67.5%). In conclusion, machine learning improves patient prioritization and diagnostic yield.
    Keywords:  Machine learning; Mitochondrial diseases; Phenotype
    DOI:  https://doi.org/10.1016/j.mito.2025.102061
  6. Mol Genet Metab. 2025 Jun 03. pii: S1096-7192(25)00150-7. [Epub ahead of print]145(4): 109159
    Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency.
    Elsbeth Chow, Lindsey Miller, Anna Clearman, Patricia Arnold, Mary Kay Koenig, S Nicholas Russo.
      Thymidine kinase 2 (TK2) deficiency is an ultrarare mitochondrial depletion and deletion syndrome characterized by mutations in the nuclear TK2 gene responsible for encoding the mitochondrial thymidine kinase 2 enzyme. TK2's role is to phosphorylate the nucleosides deoxycytidine (dC) and deoxythymidine (dT) required for mitochondrial DNA (mtDNA) replication; therefore, deficient TK2 enzymes result in dysfunctional replication of mtDNA. TK2 deficiency presents in children as progressive muscle weakness, respiratory difficulty, and mtDNA depletion. Fewer than 120 patients have been described in medical literature, and there are currently no FDA-approved treatments for TK2 deficiency. Provision of exogenous deoxynucleosides (dC/dT) allow for replication of mtDNA via cytosolic enzymes thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK), as well as any residual TK2 activity. Here we describe a 26-year-old female with childhood-onset TK2 deficiency characterized by progressive myopathy, fatigue, weight loss, atrophy, bone fractures, dysphagia, neuropathy, and respiratory failure. With initiation of deoxynucleoside therapy and multiple therapy modalities (physical, occupational, and speech), her rate of decline slowed and she has shown steady improvement.
    Keywords:  Deoxynucleoside therapy; Mitochondria; Mitochondrial depletion; Thymidine kinase deficiency
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109159
  7. J Neuromuscul Dis. 2025 Jun 19. 22143602241307198
    Modelling mitochondrial diseases in neurons In Vitro: A systematic review.
    Mariana Zarate-Mendez, Nihal A Basha, Oliver Podmanicky, Natalia Malig, Denisa Hathazi, Rita Horvath.
      Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases.In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.
    Keywords:  induced pluripotent stem cells; neuronal models; primary mitochondrial diseases
    DOI:  https://doi.org/10.1177/22143602241307198
  8. Sci Rep. 2025 Jun 19. 15(1): 18717
    Lipid nanoparticle delivery of the CRISPR/Cas9 system directly into the mitochondria of cells carrying m.7778G>T mutation in MtDNA (mt-Atp8).
    Kaede Norota, Sen Ishizuka, Misa Hirose, Yusuke Sato, Masatoshi Maeki, Manabu Tokeshi, Saleh M Ibrahim, Hideyoshi Harashima, Yuma Yamada.
      Mitochondrial genome mutations are associated with various diseases and gene therapy targeted to mitochondria has the potential to effectively treat such diseases. Here, we targeted a point mutation in mitochondrial DNA (mtDNA) that can cause mitochondrial diseases via delivery of the clustered, regularly interspaced, short palindromic repeats/Cas9 (CRISPR/Cas9) system to mitochondria using an innovative lipid nanoparticle (LNP) delivery system. To overcome the major barrier of the mitochondrial membrane structure, we investigated a strategy to deliver ribonucleoprotein (RNP) directly to mitochondria via membrane fusion using MITO-Porter, a mitochondria-targeting lipid nanoparticle. First, we constructed RNP-MITO-Porter, in which an RNP was loaded into MITO-Porter using a microfluidic device. Sequence-specific double-strand breaks were confirmed when the constructed RNP-MITO-Porter was applied to isolated mitochondria. Next, the RNP-MITO-Porter was applied to HeLa cells, and a portion of the RNP-MITO-Porter was colocalized with mitochondria and caused sequence-specific double-strand breaks in mtDNA. Finally, RNP-MITO-Porter was successfully delivered to mitochondria of cells derived from a mouse carrying a point mutation (m.7778G > T) in mtDNA (mt-Atp8) (LMSF-N-MTFVB cells), and created double-strand breaks at the target sequence. RNP-MITO-Porter is expected to contribute significantly to the clinical application of mitochondrion-targeted gene therapy.
    Keywords:  CRISPR/Cas9 ribonucleoprotein (RNP); Lipid nanoparticle (LNP); MITO-Porter; Mitochondrial genome editing; Mitochondrial-targeted delivery
    DOI:  https://doi.org/10.1038/s41598-025-03671-8
  9. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00659-X. [Epub ahead of print]44(7): 115888
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs over glucose. Here, we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FAs under cold conditions.
    Keywords:  CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115888
  10. Commun Biol. 2025 Jun 17. 8(1): 936
    Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
    Elodie Lafargue, Jean-Pierre Duneau, Nicolas Buzhinsky, Pamela Ornelas, Alexandre Ortega, Varun Ravishankar, James Sturgis, Ignacio Casuso, Lucie Bergdoll.
      VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
    DOI:  https://doi.org/10.1038/s42003-025-08311-5
  11. Nat Struct Mol Biol. 2025 Jun 19.
    ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.
    Edrees H Rashan, Abigail K Bartlett, Daven B Khana, Jingying Zhang, Raghav Jain, Gina Wade, Luciano A Abriata, Andrew J Smith, Zakery N Baker, Taylor Cook, Alana Caldwell, Autumn R Chevalier, Patrick Forny, Brian F Pfleger, Matteo Dal Peraro, Peng Yuan, Daniel Amador-Noguez, Judith A Simcox, David J Pagliarini.
      Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism.
    DOI:  https://doi.org/10.1038/s41594-025-01596-4
  12. Front Genet. 2025 ;16 1605440
    Autosomal dominant myopathy caused by a novel ISCU variant.
    Joanna M Rusecka, Camilla Ceccatelli Berti, Dominika Szczęśniak, Małgorzata Bednarska-Makaruk, Magdalena Mroczek, Magdalena M Kacprzak, Agnieszka Sobczyńska-Tomaszewska, Paola Goffrini.
      Hereditary myopathy with lactic acidosis due to Iron-Sulfur Cluster Assembly Enzyme (ISCU) deficiency is a rare disorder of energy metabolism characterized clinically by myopathy with exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes. ISCU protein plays an important role in iron-sulphur clusters (Fe-S) assembly and is therefore essential for the activity of mitochondrial Fe-S proteins such as succinate dehydrogenase and aconitase. Recessive hypomorphic ISCU alleles have been associated with hereditary myopathy with lactic acidosis, also known as Swedish-type myopathy. To date, only one heterozygous dominant variant (c.287G>T, p.Gly96Val) in the ISCU gene has been reported as pathogenic. Functional studies have shown that this variant has a detrimental, dominant effect on activity of Fe-S-dependent enzymes. Whole exome sequencing performed in an adult female patient with progressive muscle weakness led to the identification of a novel heterozygous variant c.399del (p.Val134Ter) in the ISCU gene. This variant is localized in the functional IscU_like domain of the ISCU protein, with bioinformatics prediction of damaging effects on protein function. Moreover, the same variant was also found in a few family members, who present signs of myopathy. This novel variant segregates with the disease and results in a phenotype reminiscent of the recessive disease previously reported. Yeast Saccharomyces cerevisiae is a widely used tool able to assess the impact of the VUS in a quick and efficient way, therefore functional studies were performed on this model system. The results obtained not only confirm the pathogenetic effect of the variant, but also support its dominant inheritance.
    Keywords:  ISCU; WES; mitochondria; mitochondrial myopathy; yeast model
    DOI:  https://doi.org/10.3389/fgene.2025.1605440
  13. Nat Cell Biol. 2025 Jun;27(6): 890-901
    Shaping the composition of the mitochondrial outer membrane.
    Gayathri Muthukumar, Jonathan S Weissman.
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  14. Acta Physiol (Oxf). 2025 Jul;241(7): e70073
    Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction.
    Huijie Zhang, Fengzhi Yu, Zhenjun Tian, Dandan Jia.
       AIM: Mitochondrial dysfunction is pivotal in both the development and progression of cardiovascular diseases (CVDs), though its exact mechanisms remain unclear. Cardiolipin (CL), a key mitochondrial phospholipid, is involved in various mitochondrial functions, including dynamics, membrane integrity, oxidative phosphorylation, mitochondrial DNA maintenance, and mitophagy. Due to enzyme limitations in the CL biosynthesis pathway, premature CL undergoes remodeling to acquire the proper acyl content for its function. Disruption in CL composition leads to mitochondrial dysfunction, contributing significantly to CVDs. The purpose of this review is to explore the role of CL remodeling in the mechanism of mitochondrial dysfunction that occurs in CVDs.
    METHODS: This review examines CL's critical role in mitochondrial function, the consequences of CL deficiencies in CVDs, and the impact of mutations or deficiencies in CL remodeling enzymes-tafazzin (TAZ), Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1), and Monolysocardiolipin acyltransferase (MLCLAT1)-on CL homeostasis, mitochondrial function, and CVDs pathogenesis. Emerging CL-targeted therapies are also reviewed.
    RESULTS: Proper CL function is crucial for mitochondrial health and cardioprotection. Pathological CL remodeling due to mutations or deficiencies in TAZ, ALCAT1, or MLCLAT1, drives mitochondrial dysfunction and accelerates CVDs progression. Based on these insights, current CL-based therapeutic strategies are also summarized, including precision medicine/gene therapy, targeted pharmacotherapy, and dietary interventions.
    CONCLUSION: Targeting CL may represent a promising clinical therapeutic strategy for CVDs.
    Keywords:  ALCAT1; cardiolipin remodeling; cardiovascular diseases; mitochondrial dysfunction; tafazzin
    DOI:  https://doi.org/10.1111/apha.70073
  15. J Vis Exp. 2025 May 30.
    Mitochondrial Preparation from Microglia for Glycan Analysis.
    Meghana Madabhushi, Tana V Palomino, Mallikarjun H Patil, David C Muddiman, Daniel J Tyrrell, Juhi Samal.
      Understanding the glycosylation patterns of mitochondrial proteins in microglia is critical for determining their role in neurodegenerative diseases. Here, we present a novel and high-throughput methodology for glycomic analysis of mitochondrial proteins isolated from cultured microglia. This method involves the isolation of mitochondria from microglial cultures, quality assessment of mitochondrial samples, followed by an optimized protein extraction to maximize glycan detection, and infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) high-resolution accurate mass (HRAM) mass spectrometry to provide detailed profiles of mitochondrial glycosylation. This protocol emphasizes the importance of maintaining mitochondrial integrity during isolation and employs stringent quality control to ensure reproducibility, including measuring mitochondrial purity after extraction. This approach allows for the comprehensive profiling of glycosylation changes in microglial mitochondria under various experimental conditions in vitro, which offers insight into mitochondrial changes associated with neurodegenerative diseases. This approach could be adapted to other in vitro treatments, other cultured cell types, or primary cells. Through this standardized approach, we aim to advance the understanding of microglial mitochondrial glycans, contributing to the broader field of neurodegenerative research.
    DOI:  https://doi.org/10.3791/68179
  16. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263
    Fumarate hits the brakes on mitophagy.
    Ana Paula Magalhães Rebelo, Christian Frezza.
      In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.032
  17. Exp Cell Res. 2025 Jun 13. pii: S0014-4827(25)00247-2. [Epub ahead of print]450(2): 114647
    Medication targeting to subcellular organelles: Emphasizing mitochondria as a therapeutic marvel-Current situation and future prospects.
    Riyad F Alzhrani, Adel Ali Alhowyan, Ehab I Taha, Sabry M Attia, Samir A Salama, Gamaleldin I Harisa.
      Subcellular disorders are linked with several diseases, specifically mitochondrial dysfunction linked to age, metabolic disorders, cancer, cardiovascular disease, and other mitochondrial diseases (MDs). Intracellular medication delivery is a promising option for effective therapy. This study aims to highlight subcellular delivery with focus on mitochondrial pharmacology, gene therapy, transplantation, and drug targeting. PubMed, Google Scholar, Scopus, and other scholarly sources were leveraged to prepare this narrative review. According to current studies, intermittent fasting, consistent exercise, well-balanced diets, and proper sleep can all help to increase mitochondrial quality. Molecular therapies improve mitochondrial bioenergetics, redox status, biogenesis, dynamics, mitophagy, bioenergetic, and sirtuins. The antioxidant supplementation restores endogenous antioxidants such as alpha-lipoic acid, tocopherols, L-carnitine, and coenzyme Q10 to prevent mitochondrial damage. Mdivi-1, melatonin, resveratrol, PGC-1α agonists, metformin, and Opa1 activators modify the dynamics and biogenesis of mitochondria. Bioactive phytochemicals, including curcumin, berberine, quercetin, and capsaicin, affect OXPHOS and mitochondrial sirtuins. These agents affect gene expression, antioxidant defenses, inflammation, and mitochondrion functions. Therefore, bioactive phytochemicals limit oxidative damage, increase insulin sensitivity, and improve extended cell longevity. Mitochondrial transplantation and gene therapy using mRNA and gene editing technologies are promising treatment options for MDs. Mitoquidone, triphenylphosphine, mitochondrial-targeting peptides, and nanocarriers localize medicines within mitochondrial compartments. In conclusion, a good lifestyle and bioactive materials, alongside mitochondrial medications, gene therapy, transplantation, and drug targeting, could restore overall cellular health.
    Keywords:  Bioactive compounds; Gene therapy; MDT; Mitochondrial biogenesis; Sirtuins; Uncouplers
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114647
  18. NPJ Digit Med. 2025 Jun 20. 8(1): 380
    Few shot learning for phenotype-driven diagnosis of patients with rare genetic diseases.
    Undiagnosed Diseases Network
      There are over 7000 rare diseases, some affecting 3500 or fewer patients in the United States. Due to clinicians' limited experience with such diseases and the heterogeneity of clinical presentations, ~70% of individuals seeking a diagnosis remain undiagnosed. Deep learning has demonstrated success in aiding the diagnosis of common diseases. However, existing approaches require labeled datasets with thousands of diagnosed patients per disease. We present SHEPHERD, a few-shot learning approach for multi-faceted rare disease diagnosis. SHEPHERD performs deep learning over a knowledge graph enriched with rare disease information and is trained on a dataset of simulated rare disease patients. We demonstrate SHEPHERD's effectiveness across diverse diagnostic tasks, performing causal gene discovery, retrieving "patients-like-me", and characterizing novel disease presentations, using real-world cohorts from the Undiagnosed Diseases Network (N = 465), MyGene2 (N = 146), and the Deciphering Developmental Disorders study (N = 1431). SHEPHERD demonstrates the potential of knowledge-grounded deep learning to accelerate rare disease diagnosis.
    DOI:  https://doi.org/10.1038/s41746-025-01749-1
  19. Genet Med. 2025 Jun 11. pii: S1098-3600(25)00131-5. [Epub ahead of print] 101484
    Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.
    Sarah C Grünert, Matthias R Baumgartner, Juliette Bouchereau, Alberto Burlina, Peter T Clayton, Javier de Las Heras, Carlo Dionisi-Vici, Corinne Gemperle-Britschgi, Claudia Haase, Stanley H Korman, Johannes Krämer, Eva Kühlwein, Esther M Maier, Arianna Maiorana, Manuel Schiff, Carl Ulrich Schmid, Trine Tangeraas, Raina Yamamoto, Johannes Zschocke, Jörn Oliver Sass.
       PURPOSE: Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far.
    PATIENTS AND METHODS: We performed a comprehensive literature search to identify all published cases of HMGCS2D (n=59). Additionally, data of 16 yet undescribed patients with this disorder were collected. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided.
    RESULTS: Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life, but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only one variant was identified to be common, (HMGCS2) NM_005518.4: c.634G>A, p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established.
    DISCUSSION: This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D including a list of HMGCS2 variants identified in affected individuals.
    Keywords:  HMGCS2; fatty acid catabolism; ketogenesis; ketone body metabolism; ketone body synthesis; mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency
    DOI:  https://doi.org/10.1016/j.gim.2025.101484
  20. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809
    Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
    Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.
      Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.
    Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2025.115809
  21. Aging Cell. 2025 Jun 16. e70135
    Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.
    Claudia C S Chini, Laura Colman, Eduardo Palmieri, Jessica L Strange, Sonu Kashyap, Bing Han, Andres Benitez-Rosendo, Gina L Ciccio Lopez, Sara Peixoto Rabelo, Shreyartha Mukherjee, Gustavo H de Souza, John Varga, Ralph G Meyer, Mirella L Meyer-Ficca, Eduardo N Chini.
      Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7-14 days of NAM depletion, despite NAD+ levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon-dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage-dependent anion channel 1 (VDAC1), which activated the cGAS-STING signaling pathway. Inhibition of VDAC oligomerization with VBIT-4, STING signaling with H-151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC-mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.
    DOI:  https://doi.org/10.1111/acel.70135
  22. Ear Nose Throat J. 2025 Jun 19. 1455613251347923
    Early-Onset Hearing Loss in Leber's Hereditary Optic Neuropathy: A Case Report.
    Maria Al Bandari, Enas Nasr, Sharon L Cushing, Michal Inbar-Fiegenberg.
      Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders that is characterized in young adults and teenagers as bilateral, painless, subacute visual failure. Extraocular manifestations include neurological and cardiac features. Sensorineural hearing loss (SNHL) has not been reported as a clinical feature of this disorder. We report a patient diagnosed with LHON having the common m.11778G>A; p. Arg340 pathogenic variant who was also diagnosed with bilateral mild-to-moderate high-frequency SNHL as a neonate through our provincial newborn screening program. Genetic workup, including a next-generation sequencing "Comprehensive Hereditary Hearing Loss Panel" for common and non-syndromic hearing loss and sequencing of the mitochondrial genome, was negative for a second pathogenic variant. The infectious workup was negative. Non-enhanced magnetic resonance imaging of the brain and internal auditory canal was normal. To our knowledge, SNHL has not been reported before as a clinical feature of patients diagnosed with LHON, and hence this rare and unusual presentation merits reporting.
    Keywords:  LHON; Leber’s hereditary optic neuropathy; SNHL; mitochondrial DNA; mitochondrial disorder; mtDNA; sensorineural hearing loss
    DOI:  https://doi.org/10.1177/01455613251347923
  23. Aging Dis. 2025 Jun 18.
    The Mitochondrial Foundations of Parkinson's Disease: Therapeutic Implications.
    Smijin K Soman, Micah R J Woodruff, Ruben K Dagda.
      Mitochondria are dynamic organelles vital for neuronal function due to their ability to generate ATP, sequester cytosolic calcium (Ca2+), regulate lipid metabolism, and modulate apoptosis signaling. In order to maintain these essential functions in healthy neurons, mitochondria must be continuously replenished through mitochondrial turnover and biogenesis. Conversely, the dysregulation of mitochondrial homeostasis can lead to oxidative stress and contribute to the neuropathology of Parkinson's disease (PD). This review will provide an updated in-depth review of mitochondrial processes such as mitophagy, biogenesis, trafficking, oxidative phosphorylation, Ca2+ sequestration, mitochondrial transfer, and their relevance to PD pathophysiology. We provide an extensive overview of the neuroprotective molecular signaling pathways regulated by PD-associated proteins that converge at the mitochondrion. Importantly, in this review we highlight aspects of mitochondrial pathology that converge across multiple models including iPSCs, patient-derived fibroblasts, cell culture models, rodent models and chemical and genetic models of PD. Finally, we provide a comprehensive update on the molecular toolbox used to interrogate these signaling pathways using in vitro and in vivo models of PD and provide insight into the downstream protein targets that can be leveraged to develop novel therapies against PD.
    DOI:  https://doi.org/10.14336/AD.2025.0440
  24. Cell Regen. 2025 Jun 16. 14(1): 25
    Mitochondrial deoxyguanosine kinase depletion induced ROS causes melanocyte stem cell exhaustion and hair greying.
    Kaiyao Zhou, Gangyun Wu, Rui Dong, Changhao Kan, Lin Xie, Lijuan Gao, Hua Li, Jianwei Sun, Wenxiu Ning.
      Hair pigmentation is regulated by melanocyte stem cells (MeSCs) within the hair follicle. Mitochondrial dysfunction is associated with hair depigmentation, primarily due to defects in melanogenesis. However, the mechanisms by which mitochondria support MeSCs during hair pigmentation remain obscure. In this study, we investigated the role of mitochondrial deoxyguanosine kinase (DGUOK), which provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, in hair pigmentation and MeSCs maintenance. Dguok depleted and conditional knockout mice exhibit premature hair greying. This phenotype was not due to impaired melanin production by melanocytes but was associated with a significant loss of MeSCs and mature melanocytes. Notably, Dguok deficiency decreased the expression of 13 mtDNA-encoded genes, increased the levels of reactive oxygen species (ROS) and apoptosis in MeSCs. Treatment with N-acetylcysteine (NAC), an ROS inhibitor, effectively mitigated the depigmentation and rejuvenated the MeSCs population. These findings underscore the critical role of DGUOK in regulating mtDNA integrity, which is vital for sustaining MeSCs and ensuring hair pigmentation, providing valuable insights that may inform therapeutic strategies for combating hair greying.
    Keywords:  DGUOK; Hair pigmentation; MeSCs; Mitochondrial DNA; ROS
    DOI:  https://doi.org/10.1186/s13619-025-00242-0
  25. Redox Biol. 2025 Jun 11. pii: S2213-2317(25)00236-8. [Epub ahead of print]85 103723
    Guidelines for the measurement of oxygen consumption rate in Caenorhabditiselegans.
    Anna Gioran, Niki Chondrogianni.
      Mitochondria are known as the powerhouse of the cell as through oxidative phosphorylation, they produce energy in the form of ATP. Nevertheless, mitochondria are also considered as the main producers of free radicals. Several mitochondrial parameters are needed to be examined to fully characterize mitochondria and the outcomes of their positive (i.e. energy production) or negative (i.e. production of free radicals/oxidative stress) function. Oxygen consumption rate (OCR) measurement is an excellent readout for mitochondrial respiratory capacity and it is the most frequently used assessment to examine mitochondrial function or as part of a broader bioenergetic profiling. Given the link between mitochondrial dysfunction, and increased oxidative stress and damage, and the fact that mitochondrial dysfunction is often reflected in OCR, its measurement is important for the complete characterization of the cellular redox status. Although much of this work is being done in cells or isolated mitochondria, there is an increasing need for the measurement of OCR in whole organismal models such as the nematode Caenorhabditis elegans. As a free-living organism with simple maintenance and conserved mitochondrial biology, C. elegans attracts interest as a model for ageing and age-related diseases, among others, in which bioenergetics but also various mitochondria-related redox aspects need to be evaluated. Therefore, the need for platforms suitable for OCR measurements in this model is evident. In this work, we have employed a newly developed system (Resipher) for the measurement of OCR in C. elegans and we outline basic protocols as well as the pharmacological interventions that can be used to assess the function of the respiratory chain. More specifically, we demonstrate the importance of the number of animals used in measurements that include mitochondrial complex inhibitors, how the presence of bacteria when used as a food source for the nematodes should be carefully considered and/or eliminated and how to avoid artefacts when measuring differently sized nematodes. The present work is not only intended to be used as a protocol for a specific measurement system but it can also be used as a guideline when setting up OCR experiments with any device, as it reveals parameters that may be overlooked and should be carefully considered.
    Keywords:  C. elegans; Experimental protocol; Mitochondria; Oxygen consumption rate
    DOI:  https://doi.org/10.1016/j.redox.2025.103723
  26. Nat Immunol. 2025 Jun 17.
    pDCs drive immunopathology by sensing oxidized mitochondrial DNA.
    Moshe Arditi, Timothy R Crother.
      
    DOI:  https://doi.org/10.1038/s41590-025-02193-9
  27. Cureus. 2025 May;17(5): e84293
    Expanding the Genetic and Phenotypic Spectrum of Kearns-Sayre Syndrome: A Case Report.
    Christian Messina.
      Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disorder characterized by progressive bilateral ptosis and symmetric ophthalmoparesis. When CPEO is associated with pigmentary retinopathy, cardiac conduction defects, endocrine abnormalities, muscle weakness, and other neurological impairments, it defines Kearns-Sayre syndrome (KSS), most commonly caused by a single large-scale mitochondrial DNA (mtDNA) deletion. We report a case of a 34-year-old man with a three-year history of progressive bilateral ptosis. A muscle biopsy from the left vastus lateralis revealed cytochrome c oxidase-deficient fibers (COX-negative). mtDNA analysis revealed a novel single large-scale deletion detected in muscle tissue. This deletion has not been previously reported in the scientific literature and led to a diagnosis of KSS. Additionally, cerebrospinal fluid analysis revealed the presence of oligoclonal bands, a finding not previously described in KSS. The deleted mtDNA region includes ND4, ND5, and ND6 genes, which encode subunits of NADH dehydrogenase. These genes are implicated in various biological functions, including mitochondrial energy production, seizure susceptibility, and inflammatory processes.
    Keywords:  chronic progressive external ophthalmoplegia; cpeo; kearns-sayre syndrome; mitochondrial disorders; neuromuscular diseases; oligoclonal band (ocb)
    DOI:  https://doi.org/10.7759/cureus.84293
  28. J Physiol. 2025 Jun 15.
    Local and global control on mitochondrial ageing.
    Luigi Ferrucci, Natalia Bobba-Alves, David J Marcinek.
      
    Keywords:  circadian rhythm; energy; mitochondria
    DOI:  https://doi.org/10.1113/JP289058
  29. ACS Pharmacol Transl Sci. 2025 Jun 13. 8(6): 1473-1497
    A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases.
    Jianing Wu, Xin Zhou, Xin Xu, Jing Xie.
      Cartilage-related osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are typical degenerative diseases that cause a heavy socioeconomic burden for lack of disease-modifying treatments. Due to the avascular and hypoxic microenvironment of cartilage, chondrocytes primarily achieve energy supply through cytoplasmic anaerobic glycolysis; thus, mitochondria, energy producers through aerobic phosphorylation, have received little attention until recently. Mitochondria carry out a crucial role in the regulation of cellular bioenergetics, metabolism, and signaling while also serving as a central platform where diverse biological processes converge, thereby contributing significantly to cellular homeostasis and cartilage physiology. Mitochondrial functionality is intertwined with mitochondrial morphology, which is determined by a dynamic balance between mitochondrial fusion and fission. Disruption of the equilibrium leads to mitochondrial dysfunction and the onset of diseases. Although the potential role of mitochondria in the pathogenesis of cartilage-related diseases has been proposed and sporadic studies have begun to focus on the underlying molecular mechanisms of mitochondrial fusion/fission, the importance of the physiological and pathological functions of mitochondrial fusion-fission dynamics in cartilage biological processes is little discussed. This review aims to bridge the gap by characterizing its interplay with mitochondrial quality control, energy metabolism, redox homeostasis regulation, cellular senescence, and apoptosis, which are all closely associated with cartilage physiology and pathology. Moreover, its role in cartilage-related diseases, especially OA and IVDD, is further discussed. This review emphasizes the emerging field of mitochondrial fusion-fission dynamics in skeletal systems and possibly provides new cues for disease control and clinical intervention.
    Keywords:  Cartilage; Chondrocytes; Intervertebral disc degeneration; Mitochondrial fission; Mitochondrial fusion; Osteoarthritis
    DOI:  https://doi.org/10.1021/acsptsci.4c00706
  30. Hum Genomics. 2025 Jun 20. 19(1): 69
    Update of the sideroflexin (SLC56) gene family.
    Angeliki I Katsafadou, Daniel W Nebert, Sergey A Krupenko, David C Thompson, Vasilis Vasiliou.
      The human sideroflexin (SFXN) gene family, also classified as solute carrier family 56 (SLC56), encodes a group of five mitochondrial transmembrane proteins (SFXN1-SFXN5) involved in key aspects of mitochondrial metabolism, cellular homeostasis, and development. SFXNs are highly conserved across eukaryotic species, with evolutionary the origin traced back to the earliest metazoans. Functionally, each of the five family members exhibits distinct functional specialization. Particularly, SFXN1 and SFXN3 facilitate mitochondrial serine transport, supporting one-carbon metabolism. SFXN2 and SFXN4 are implicated in mitochondrial iron regulation, heme biosynthesis, and iron-sulfur cluster assembly. SFXN5, predominantly expressed in the brain, is proposed to regulate citrate metabolism and immune cell functions. Mutations or dysregulation of SFXN genes have been linked to certain human diseases, including congenital sideroblastic anemia, oxidative phosphorylation disorders, neurodegenerative conditions, and cancers. Structurally, SFXNs share conserved transmembrane domains and key motifs critical for substrate transport, mitochondrial iron homeostasis, and overall mitochondrial function. The evolutionary trajectory of the SFXN family-from amino acid transport to functionally specialized roles in higher organisms-highlights their biological and clinical significance. Comparative studies across model organisms reveal both conserved and divergent functions, emphasizing their importance in health and disease. A comprehensive understanding of the SFXN family not only advances fundamental mitochondrial research but also opens avenues for novel therapeutic interventions.
    Keywords:  Biomarkers; Classification; Gene families; Nomenclature; SFXN; SLC56; Sideroflexins
    DOI:  https://doi.org/10.1186/s40246-025-00779-w
  31. Metabolism. 2025 Jun 13. pii: S0026-0495(25)00193-3. [Epub ahead of print]170 156324
    NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
    Jian Lv, Junmei Wang, Qin Chen, Qianhua Zhong, Hongchao Zhan, Qiuxiao Guo, Jiajie Li, Ningning Guo, Yu Fang, Jingjing Tong, Zhihua Wang.
      Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.
    Keywords:  Aging; Cardiac aging; Metabolic disorder; Mitochondrial dysfunction; NIPSNAP1/2
    DOI:  https://doi.org/10.1016/j.metabol.2025.156324
  32. Neural Regen Res. 2025 Jun 19.
    Synaptic mitochondria in aging and neurodegenerative diseases: unraveling their functional decline and vulnerability.
    Karina A Cicali, Angie K Torres, Cheril Tapia-Rojas.
       ABSTRACT: Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and nonsynaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.
    Keywords:  aging; hippocampus; memory; mitochondria; synaptic mitochondria
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01571
  33. Redox Biol. 2025 Jun 09. pii: S2213-2317(25)00228-9. [Epub ahead of print]85 103715
    Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.
    Rehna Paula Ginting, Hoang-Anh Pham-Bui, Choijamts Munkhzul, Siti Aisyah Fuad, Ahyeon Son, Jong-Seok Moon, Jaeseok Han, Mihye Lee, Min-Woo Lee.
      Maintaining redox balance is crucial for mitochondrial homeostasis. During browning of white adipocytes, both the quality and quantity of mitochondria undergo dramatic changes. However, the mechanisms controlling the redox balance in the mitochondria during this process remain unclear. In this study, we demonstrate that thermogenic activation occurs before mitochondrial biogenesis during cold-induced browning of inguinal white adipose tissue (iWAT) and is accompanied by increased mitochondrial stress and integrated stress response (ISR) signaling. Specifically, cold exposure enhances the expression of ATF4, an ISR effector. Adipocyte-specific deletion of ATF4 results in increased energy expenditure, but paradoxically leads to a lower core body temperature, and heightened pro-inflammation in iWAT after cold exposure, which is restored by the antioxidant, MitoQ. Mechanistically, ATF4 regulates the redox balance through MTHFD2, an enzyme involved in mitochondrial redox homeostasis by NADPH generation. Cold exposure upregulates MTHFD2 expression in an ATF4-dependent manner, and its inhibition by DS18561882 in vivo leads to impaired cold-induced mitochondrial respiration similar to the effects of ATF4 loss. These findings suggest that ATF4 is essential for redox balance via MTHFD2, thereby affecting tissue homeostasis during iWAT browning.
    DOI:  https://doi.org/10.1016/j.redox.2025.103715
  34. Nature. 2025 Jun 17.
    'Killswitch' protein lets scientists study immobilized cellular droplets.
    Elie Dolgin.
      
    Keywords:  Biochemistry; Biophysics; Cell biology; Drug discovery; Technology
    DOI:  https://doi.org/10.1038/d41586-025-01840-3
  35. Neural Regen Res. 2025 Jun 19.
    Neuroglobin: A promising candidate to treat neurological diseases.
    Ivan Millan Yañez, Isabel Torres-Cuevas, Marisol Corral-Debrinski.
       ABSTRACT: Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide. Altogether, the burden of neurological disorders has increased considerably over the past 30 years because of population aging. Overall, neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow. Autism spectrum disorder, motor neuron disease, encephalopathy, epilepsy, stroke, ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease represent a non-exhaustive list of neurological illnesses. These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system. Among the common features of neurological handicaps, we find protein aggregation, oxidative stress, neuroinflammation, and mitochondrial impairment in the target tissues, e.g., the brain, cerebellum, and spinal cord. The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis, are responsible for their dependence on functional mitochondria for their integrity. Reactive oxygen species, produced along with the respiration process within mitochondria, can lead to oxidative stress, which compromises neuronal survival. Besides having an essential role in energy production and oxidative stress, mitochondria are indispensable for an array of cellular processes, such as amino acid metabolism, iron-sulfur cluster biosynthesis, calcium homeostasis, intrinsic programmed cell death (apoptosis), and intraorganellar signaling. Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases, therapies that are effective to diminish or halt neuronal dysfunction/death are rare. Given the genetic complexity responsible for neurological disorders, the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life. A promising candidate is the neuroglobin, a globin superfamily member of 151 amino acids, which is found at high levels in the brain, the eye, and the cerebellum. The protein, which localizes to mitochondria, is involved in electron transfer, oxygen storage and defence against oxidative stress; hence, possessing neuroprotective properties. This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions, which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.
    Keywords:  ataxia; brain; cerebellum; gene therapy; mitochondria; neuroglobin; neurological disease; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01503
  36. Cell Commun Signal. 2025 Jun 19. 23(1): 290
    Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
    Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni.
      Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
    Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-025-02308-7
  37. J Parkinsons Dis. 2025 Jun 16. 1877718X251349407
    Reduced expression of Pss gene in Drosophila cortex glia causes dopaminergic cell death.
    Banya Pak, Chaeeun Kim, Seung-Hae Kwon, Joon-Kyu Lee, Sang-Hak Jeon.
      BackgroundParkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. While abnormal protein aggregation has been classically implicated in PD, increasing evidence suggests that lipid dysregulation may also contribute to neuronal vulnerability. Recent studies have begun to link abnormal phosphatidylserine (PS) metabolism to mitochondrial impairment and dopaminergic neuron loss in PD, yet the underlying cellular mechanisms remain poorly defined.ObjectiveThis study aimed to determine how impaired PS synthesis in cortex glia affects mitochondrial function, oxidative stress, and dopaminergic neuron survival, using a Drosophila model of glia-specific Phosphatidylserine synthase (Pss) knockdown.MethodsTo dissect the glial contribution to PS-related neurodegeneration, we employed a Drosophila model in which the Pss gene was selectively knocked down in cortex glia using the GAL4-UAS system. We evaluated PD-like phenotypes by assessing the number of dopaminergic neurons in the PPL1 and PPL2 clusters, as well as locomotor activity and lifespan, following glia-specific knockdown of Pss gene.ResultsCortex glia-specific knockdown of Pss impaired locomotion and reduced lifespan in flies, indicating a systemic decline in neuronal and mitochondrial function. Pss knockdown reduced mitochondrial transcription factor A (Tfam) expression, disrupted mitochondrial gene expression, and elevated ROS levels. Western blot analysis also revealed reduced AKT phosphorylation without changes in total AKT. These results ultimately lead to loss of dopaminergic neurons.ConclusionsThese findings establish a mechanistic link among abnormal PS metabolism, impaired AKT signaling, mitochondrial dysfunction, and dopaminergic neuron loss. Our study provides novel evidence that glia-driven abnormalities in PS metabolism may cause PD-like neurodegeneration, offering mechanistic insights and potential therapeutic targets.
    Keywords:  Parkinson's disease; cortex glia; dopaminergic cells; mitochondrial dysfunction; phosphatidylserine
    DOI:  https://doi.org/10.1177/1877718X251349407
  38. Front Comput Neurosci. 2025 ;19 1594330
    Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease.
    Xi Luo, Diana C El Assal, Yanjun Liu, Samira Ranjbar, Ronan M T Fleming.
       Introduction: Emerging evidence suggests that different metabolic characteristics, particularly bioenergetic differences, between the synaptic terminal and soma may contribute to the selective vulnerability of dopaminergic neurons in patients with Parkinson's disease (PD).
    Method: To investigate the metabolic differences, we generated four thermodynamically flux-consistent metabolic models representing the synaptic and non-synaptic (somatic) components under both control and PD conditions. Differences in bioenergetic features and metabolite exchanges were analyzed between these models to explore potential mechanisms underlying the selective vulnerability of dopaminergic neurons. Bioenergetic rescue analyses were performed to identify potential therapeutic targets for mitigating observed energy failure and metabolic dysfunction in PD models.
    Results: All models predicted that oxidative phosphorylation plays a significant role under lower energy demand, while glycolysis predominates when energy demand exceeds mitochondrial constraints. The synaptic PD model predicted a lower mitochondrial energy contribution and higher sensitivity to Complex I inhibition compared to the non-synaptic PD model. Both PD models predicted reduced uptake of lysine and lactate, indicating coordinated metabolic processes between these components. In contrast, decreased methionine and urea uptake was exclusively predicted in the synaptic PD model, while decreased histidine and glyceric acid uptake was exclusive to the non-synaptic PD model. Furthermore, increased flux of the mitochondrial ornithine transaminase reaction (ORNTArm), which converts oxoglutaric acid and ornithine into glutamate-5-semialdehyde and glutamate, was predicted to rescue bioenergetic failure and improve metabolite exchanges for both the synaptic and non-synaptic PD models.
    Discussion: The predicted differences in ATP contribution between models highlight the bioenergetic differences between these neuronal components, thereby contributing to the selective vulnerability observed in PD. The observed differences in metabolite exchanges reflect distinct metabolic patterns between these neuronal components. Additionally, mitochondrial ornithine transaminase was predicted to be the potential bioenergetic rescue target for both the synaptic and non-synaptic PD models. Further research is needed to validate these dysfunction mechanisms across different components of dopaminergic neurons and to explore targeted therapeutic strategies for PD patients.
    Keywords:  Parkinson’s disease; bioenergetics; modeling; non-synaptic; synaptic
    DOI:  https://doi.org/10.3389/fncom.2025.1594330
  39. Nature. 2025 Jun 16.
    Mice with human cells developed using 'game-changing' technique.
    Smriti Mallapaty.
      
    Keywords:  Brain; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01898-z
  40. Mol Genet Metab. 2025 Jun 04. pii: S1096-7192(25)00149-0. [Epub ahead of print]145(4): 109158
    Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China.
    Yang Liu, Danmin Shen, Tianyu Song, Chaolong Xu, Xin Duan, Minhan Song, Tongyue Li, Ying Zou, Ruoyu Duan, Zhimei Liu, Suzhou Zhao, Fang Fang.
       OBJECTIVE: To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations.
    METHODS: This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS).
    RESULTS: Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3-60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, n = 18; SPI, n = 13; LP, n = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS < 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (p < 0.05). In terms of genetics, all patients were compound heterozygous variants in the ECHS1 gene, with 21 novel variants identified. The most common variant was the c.489G > A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes.
    CONCLUSIONS: This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G > A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.
    Keywords:  ECHS1 gene; Leigh syndrome; Prognosis; Synonymous variant; Urinary metabolite
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109158
  41. Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00167-2. [Epub ahead of print]145(4): 109176
    Antioxidant therapy in inborn metabolic diseases.
    Felix Heimes, Lea-Sophie Berendes, Luciana Hannibal, Julien Park.
      Oxidative stress contributes to the pathophysiology of several inherited metabolic diseases (IMDs). The quality and extent of clinical evidence for the use of antioxidant therapies in IMDs have yet to be ascertained. Despite frequent clinical use, robust evidence from large-scale trials is limited. The strongest support comes from studies on idebenone in Leber's hereditary optic neuropathy, showing improvements in visual outcomes. For other antioxidants and conditions, evidence is mixed or constrained by small sample sizes and short trial durations. Coenzyme Q10 in mitochondrial diseases, vitamin E in lipid disorders, and N-acetylcysteine in various IMDs have shown some promise, but evidence is heterogeneous. Challenges include optimizing dosing, dissecting oxidative stress mechanisms across disorders, and overcoming pharmacokinetic limitations. High-grade evidence exists for the clinical efficacy of N-acetyl-L-leucine for both Niemann Pick type C disease and other lysosomal storage diseases, though its potential antioxidant effect is indirect. This review highlights the need for larger trials with standardized, clinically relevant outcomes. Future research should explore oxidative stress mechanisms, targeted therapies, and combination approaches. While antioxidants hold potential, evidence remains limited, warranting cautious use and further investigation to define their role in these rare but cumulatively impactful disorders. SYNOPSIS: This review finds limited robust evidence for antioxidant therapies in inherited metabolic diseases, highlighting the need for larger trials and more targeted approaches.
    Keywords:  Antioxidant therapy; Clinical trials; Oxidative damage; ROS scavenging
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109176
  42. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]
    The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
    Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.
      Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.
    Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
  43. Nature. 2025 Jun;642(8068): 572
    We need to show AI what didn't work as well as what did.
    Monika A Davare.
      
    Keywords:  Machine learning; Research management
    DOI:  https://doi.org/10.1038/d41586-025-01908-0
  44. FASEB J. 2025 Jun 30. 39(12): e70609
    LSMEM2, Localized at the Neuromuscular Junction, Modulates Mitochondrial Integration in Skeletal Muscles.
    Eman Elrefaei, Satoru Yamazaki, Issei Yazawa, Yusuke Takahashi, Naoki Ito, Nozomi Hayashiji, Yuya Nishida, Ichizo Nishino, Seiji Takashima, Yasunori Shintani.
      In addition to the canonical metabolism-regulating function, Adenosine monophosphate-activated protein kinase (AMPK) has noncanonical functions, in which AMPK spatiotemporally phosphorylates specific sets of substrates. Recently, we identified LSMEM2, a novel substrate of AMPK in the heart. LSMEM2 is a membrane protein localized at the intercalated disc (ICD), whose function is currently under investigation. Interestingly, LSMEM2 is also expressed in the skeletal muscles. As skeletal muscles lack a homophilic intercellular junction corresponding to the ICD in the heart, predicting the role of LSMEM2 in skeletal muscles is difficult. In this study, we identified that LSMEM2 is expressed in skeletal muscles, specifically at the neuromuscular junction (NMJ). LSMEM2-knockout mice showed no histological abnormalities, suggesting that LSMEM2 is not essential for skeletal muscle development. The overexpression of full-length wild-type or C-del mutant of LSMEM2 led to the tubular aggregate formation with functional abnormality in male mice. RNA sequence analysis revealed that the gene sets of mitochondrial oxidative phosphorylation and vesicle-mediated transport are enriched in LSMEM2 overexpression. Furthermore, histological analysis demonstrated the accumulation of swollen subsarcolemmal mitochondria in LSMEM2-overexpressing skeletal muscles. The study findings suggest that LSMEM2 may play a role in the pathogenesis of skeletal muscle diseases.
    Keywords:  intercalated disc (ICD); membrane protein; neuromuscular junction (NMJ); skeletal muscle diseases; subsarcolemmal mitochondria; tubular aggregate
    DOI:  https://doi.org/10.1096/fj.202402152R
  45. Elife. 2025 Jun 16. pii: e107882. [Epub ahead of print]14
    Multiple roles for a mitochondrial enzyme.
    Xicong Tang, Hongyu Qiu.
      The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
    Keywords:  aging; arginase; fibrosis; heart; human; inflammation; macrophages; medicine; mouse; rat
    DOI:  https://doi.org/10.7554/eLife.107882
  46. HGG Adv. 2025 Jun 16. pii: S2666-2477(25)00072-7. [Epub ahead of print] 100469
    Identification of technically challenging variants - whole genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases.
    Hong Kong Genome Project
      The total burden of rare diseases is significant worldwide with over 300 million people being affected. Many of the rare diseases have both well-defined clinical phenotypes and established genetic causes. However, a remarkable proportion of patients with high clinical suspicion of a rare disease remain genetically undiagnosed and stuck in the diagnostic odyssey after having a cascade of conventional genetic tests. One of the major factors contributing to this is that many types of variants are technically intractable to whole exome sequencing (WES). In this study, the added diagnostic power of whole genome sequencing (WGS) for patients with clinically suspected rare diseases was assessed by detecting technically challenging variants. 3,169 cases from the Hong Kong Genome Project (HKGP) were reviewed and 322 patients having high clinical suspicion of a rare disorder with well-established genetic etiology were identified. Notably, 180 patients have performed at least one previous genetic test. Through a PCR-free short read WGS and a comprehensive in-house analytic pipeline, causative variants were found in 138 patients (138 of 322, 42.9%), in which 30 of them (30 of 138, 21.7%) are attributed to technically challenging variants. These included 6 variants in low coverage regions with PCR bias, 2 deep intronic variants, 2 repeat expansions, 19 structural variants, and 2 variants in genes with homologous pseudogene. The study demonstrated the indispensable diagnostic power of WGS in detecting technically challenging variants and the capability to serve as an all-in-one test for patients with high clinical suspicion of rare diseases.
    DOI:  https://doi.org/10.1016/j.xhgg.2025.100469
  47. Nucleic Acids Res. 2025 Jun 20. pii: gkaf532. [Epub ahead of print]53(12):
    An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.
    Caitlin Specht, Alejandro Tapia, Sarah Penrod, Gabriela A Soriano, Aya Awawdeh, Sarah A Alshawi, Cody A White, Jean-Denis Beaudoin, Emma H Doud, Oscar Vargas-Rodriguez, Yunjie Huang, Jeffery M Tharp.
      Nonsense mutations that introduce premature termination codons (PTCs) into protein-coding genes are responsible for numerous genetic diseases; however, there are currently no effective treatment options for individuals affected by these mutations. One approach to combat nonsense-related diseases relies on the use of engineered suppressor transfer RNAs (sup-tRNAs) that facilitate translational stop codon readthrough, thereby restoring full-length protein synthesis. While several sup-tRNAs have shown promising results in preclinical models, many exhibit low PTC suppression efficiency, precluding their use as therapeutics. For example, glutamic acid (Glu) codons represent one of the most common sites for nonsense mutations, yet existing sup-tRNAs are ineffective at suppressing Glu-to-Stop mutations. To address this limitation, here we describe a rationally designed sup-tRNA (tRNAGluV13) with greatly improved ability to suppress PTCs occurring at Glu codons. We demonstrate that tRNAGluV13 efficiently restores protein synthesis from multiple nonsense-containing reporter genes, faithfully installing Glu in response to PTCs. Additionally, we demonstrate that tRNAGluV13 can functionally rescue pathogenic PTCs that cause hereditary breast and ovarian cancer syndrome and cystic fibrosis. The ability of tRNAGluV13 to effectively suppress one of the most common PTC mutations should greatly expand the potential of sup-tRNA-based therapeutics.
    DOI:  https://doi.org/10.1093/nar/gkaf532
  48. Cell Signal. 2025 Jun 16. pii: S0898-6568(25)00363-8. [Epub ahead of print] 111948
    Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
    Kai Ma, Haoxuan Sun, Xiaoyun Wu, Jinping Quan, Rong Tang, Weiwei Liu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.
      Adipocyte hyperplasia refers to the increase in the number of adipocytes, whereas adipocyte hypertrophy pertains to the enlargement of individual adipocytes resulting from the accumulation of lipid droplets. In this study, we found that activation of the STING signalling pathway occurs during adipogenic differentiation of 3 T3-L1 preadipocytes. Interestingly, inhibiting the STING pathway by using STING antagonist H151 or siRNA targeting STING promotes adipocyte differentiation and increases adipocyte numbers, while activation of STING inhibits adipogenic differentiation. Silencing the STING canonical downstream IRF3, or inhibiting the proton channel activity of STING enhances adipogenic differentiation, confirming the negative modulation of adipogenic differentiation by STING. In vivo, intraperitoneal injection of H151 into mice with a high-fat diet further enhances the adipocyte hyperplasia, as shown by the increased volume of adipose tissues, but consistent sizes of adipocytes. During the adipogenic differentiation of 3 T3-L1 cells, DRP1-mediated mitochondrial fission is enhanced, and causes mitochondrial DNA leakage, which in turn activates the STING pathway. However, inhibition of mitochondrial fission represses adipogenic differentiation of 3 T3-L1 cells in spite of the down-regulation of STING pathway. Therefore, our results indicate that adipogenic differentiation is associated with DRP1-induced mitochondrial fission. However, the leakage of mitochondrial DNA caused by DRP1-induced mitochondrial fission activates the STING signalling pathway, which negatively regulates adipogenic differentiation. Tissue specific reduction of DRP1-associated mitochondrial fission or STING enhancement might be new strategies for the therapy of obesity-associated diseases.
    Keywords:  3 T3-L1 cells; Adipocyte differentiation; DRP1; Mitochondria; STING
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111948
  49. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00473-3. [Epub ahead of print]85(12): 2263-2264
    Rewriting cancer's code: A micropeptide's mitochondrial mission.
    George A Calin, Tanvi H Visal.
      In this issue of Molecular Cell, Zhu et al.1 uncover a lncRNA-derived micropeptide that disrupts mitochondrial RNA processing, revealing a new layer of metabolic vulnerability in hepatocellular carcinoma (HCC).
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.034
  50. STAR Protoc. 2025 Jun 19. pii: S2666-1667(25)00315-6. [Epub ahead of print]6(3): 103909
    Protocol to implement saturation mutagenesis-reinforced functional assays to resolve small-sized variants in disease-related genes.
    Logan O Gauthier, Ziyi Wang, Kenneth K Ng, Shushu Huang, Yafei Mao, Monkol Lek, Kaiyue Ma.
      Determining the functional impacts of disease-causing genetic variants presents consistent challenges in the genetic disease field. Here, we present a protocol for implementing saturation mutagenesis-reinforced functional assays to generate functional scores for small-sized variants in disease-related genes. We describe procedures for nucleofection to establish cell line platforms, programmed allelic series with common procedures (PALS-C) cloning for saturation mutagenesis, fluorescence-based cell sorting, next-generation sequencing, and functional score generation. This framework holds potential for high-throughput and cost-effective interpretation of unresolved variants in a broad array of disease genes. For complete details on the use and execution of this protocol, please refer to Ma et al.1.
    Keywords:  CRISPR; Cell Biology; Flow Cytometry; Genetics; Genomics; High-Throughput Screening; Molecular Biology; Sequencing
    DOI:  https://doi.org/10.1016/j.xpro.2025.103909
  51. Nature. 2025 Jun 20.
    'Super-healing' animals inspire human treatments.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Genomics; Proteomics; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01901-7
  52. Transl Pediatr. 2025 May 30. 14(5): 1059-1064
    Kearns-Sayre syndrome presenting with fanconi syndrome: a case report.
    Yixiu Lu, Shan Jian, Min Qian, Zhengqing Qiu, Min Wei, Juan Xiao, Hongmei Song, Zhenjie Zhang.
       Background: Kearns-Sayre syndrome (KSS) is a mitochondrial genetic disorder characterized by progressive external ophthalmoplegia, short stature, atrioventricular block, and proximal renal tubular dysfunction. While Fanconi syndrome is a recognized renal manifestation of KSS, it is rare as the initial presenting feature. This report describes the clinical and genetic features of a child with KSS who initially presented with Fanconi syndrome.
    Case Description: A 10-year-old girl, initially diagnosed with Fanconi syndrome at 3 years of age, exhibited growth retardation by age 5 years and bilateral ptosis by age 8 years. In July 2022, her age of 10 years, she developed diabetes mellitus and third-degree atrioventricular block. The patient presented for medical evaluation. Upon examination, she was found to have sensorineural hearing loss, hyperlactatemia, elevated cerebrospinal fluid protein, decreased folate levels, and renal insufficiency. Muscle biopsy revealed ragged red fibers, and mitochondrial gene analysis confirmed the diagnosis of KSS. Whole-exome sequencing identified a heterozygous mutation in the DNA2 gene (c.865C>T, p.R286X) along with a 7,521-base pair mitochondrial DNA deletion. Symptoms improved with nutritional mitochondrial therapy.
    Conclusions: Mitochondrial mutations may contribute to the development of Fanconi syndrome. Fanconi syndrome may present as the initial manifestation of KSS. KSS should be considered in pediatric patients presenting with Fanconi syndrome and extrarenal manifestations, such as ptosis.
    Keywords:  Fanconi syndrome; Kearns-Sayre syndrome (KSS); case report; pediatric nephrology
    DOI:  https://doi.org/10.21037/tp-2025-138
  53. Front Bioeng Biotechnol. 2025 ;13 1585736
    Enzymatic approaches to nicotinic acid synthesis: recent advances and future prospects.
    Rahul Vikram Singh, Vipin Chandra Kalia, Krishika Sambyal, Bakul Singh, Anurag Kumar, Jung-Kul Lee.
      Biocatalyst-mediated reactions have led to revolutionary transformations in the organic synthesis of pharmaceuticals, drugs, and other chemicals. Nicotinic acid (vitamin B3) is an essential precursor for nicotinamide adenine dinucleotide (NAD+) biosynthesis and is vital for numerous metabolic processes. Since the human body cannot synthesize nicotinic acid, it relies on external sources. Therefore, nicotinic acid synthesis has gained huge attraction. In recent years, the industrial production of nicotinic acid has increasingly shifted from traditional chemical methods to more biocatalytic processes, leveraging the power of biocatalysts. This review highlights the biocatalyst-mediated synthesis of nicotinic-acid- and nitrile-metabolizing enzymes through state-of-the-art omics-based techniques to improve enzyme catalytic efficiency and stability via various approaches. Future research prospects and challenges associated with nicotinic acid production are also discussed.
    Keywords:  biocatalysis; biotransformation; immobilization; nitrilase; omics technology
    DOI:  https://doi.org/10.3389/fbioe.2025.1585736
  54. Lancet Neurol. 2025 Jul;pii: S1474-4422(25)00175-9. [Epub ahead of print]24(7): 614-624
    Friedreich's ataxia-a rare multisystem disease.
    FACROSS study group
      Friedreich's ataxia is a rare autosomal recessive neurodegenerative disease. Most patients have a homozygous GAA repeat expansion in the FXN gene, resulting in a deficiency of the mitochondrial protein frataxin. Disease onset occurs typically in adolescence but can vary widely, ranging from early childhood to late adulthood. Friedreich's ataxia is increasingly recognised as a multisystem disorder, affecting not only the nervous system, but also the heart and musculoskeletal system, and metabolism. Common extraneural manifestations include cardiomyopathy, which is the most common cause of mortality, and also scoliosis and diabetes. Despite research advances, the phenotypical heterogeneity of patients with Friedrich's ataxia remains inadequately explained by current knowledge of the underlying genetics. The approval of omaveloxolone by the US Food and Drug Administration and the European Medicines Agency has been a pharmacological milestone; however, further research addressing complex interorgan interactions is crucial for a better understanding of the multisystem nature of Friedreich's ataxia and the development of targeted treatment approaches.
    DOI:  https://doi.org/10.1016/S1474-4422(25)00175-9
  55. Dis Model Mech. 2025 Jun 01. pii: dmm052275. [Epub ahead of print]18(6):
    Mutant zebrafish lacking slc25a22a show spontaneous seizures and respond to the anti-seizure medication valproic acid.
    So-Hyun Lee, Ting Liang, Gopalakrishnan Chandrasekaran, Jun Zhang, Seong Soon Kim, Sundareswaran Varier Parvathi, Seok Won Lee, Eun-Seo Cho, Hee-Young Shin, Young-Gyu Yoon, Jihoon Jo, Myung Ae Bae, Seok-Yong Choi, Myeong-Kyu Kim.
      Epilepsy is a neurological disorder associated with abnormal neuronal activity in the central nervous system, resulting in recurrent seizures. Various anti-seizure medications (ASMs) are effective against epilepsy. However, approximately one-third of patients still do not respond to currently available ASMs either alone or in combination because the etiology of their epilepsy remains unclear. To create a novel zebrafish epilepsy model, we analyzed the exomes of 400 Korean patients with epilepsy via whole-exome sequencing. We found 39 candidate genes and investigated these genes through in situ hybridization and loss-of-function studies, identifying SLC25A22, encoding a mitochondrial glutamate carrier, as a potential epilepsy gene. Subsequently, we generated zebrafish slc25a22a mutants and observed that they displayed spontaneous seizures, high-voltage deflections in local field potentials, and elevated Ca2+ levels propagating from the forebrain to the spinal cord. Of nine ASMs tested, valproic acid (VPA) was able to suppress spontaneous seizure activities in slc25a22a mutant larvae, highlighting the unique anti-seizure effect of VPA in this model. Our findings provide valuable insights into the pathogenesis of epilepsy and suggest slc25a22a as a potential target for novel ASM development.
    Keywords:   slc25a22a ; Anti-seizure medications; Epilepsy; Glutamate carrier; Mitochondria
    DOI:  https://doi.org/10.1242/dmm.052275
  56. Cancer Res. 2025 Jun 20.
    Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
    Natalia V Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M Szulc, Elizabeth G Hill, Alexander V Alekseyenko, Huseyin Cimen, Jessica H Hartman, Christina Voelkel-Johnson, Michael B Lilly, John J Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.
      Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4042
  57. Trends Endocrinol Metab. 2025 Jun 12. pii: S1043-2760(25)00119-5. [Epub ahead of print]
    Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise.
    Jin Ma, Annie Yujin Son, Youlim Son, Ping-Yuan Wang, Paul M Hwang.
      Exercise-induced inflammation is regarded as a response to muscle damage from mechanical stress, but controlled immune signaling can be beneficial by promoting metabolic adaptation which, for example, decreases obesity and lowers the risk of diabetes. In addition to oxidative metabolism, mitochondria play a central role in initiating innate immune signaling. We review recent work that has identified the cGAS-STING-NF-κB signaling pathway, activated by the downregulation of mitochondrial proteins CHCHD4 and TRIAP1, as mediating skeletal muscle adaptation to exercise training as well as potentially promoting cellular resilience to environmental stresses. Notably, CHCHD4 haploinsufficiency prevents obesity in aging mice; therefore, this innate immune signaling pathway could be targeted to achieve some of the health benefits of exercise.
    Keywords:  CHCHD4; TRIAP1; exercise; fiber type; innate immunity; metabolism; mtDNA; obesity
    DOI:  https://doi.org/10.1016/j.tem.2025.05.004
  58. Nat Immunol. 2025 Jun 17.
    Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
    Hongxu Xian, Kosuke Watari, Masafumi Ohira, Jonathan S Brito, Peng He, Janset Onyuru, Elina I Zuniga, Hal M Hoffman, Michael Karin.
      Stress-induced oxidized mitochondrial DNA (Ox-mtDNA) fragments enter the cytoplasm, activating the NLRP3 inflammasome and caspase-1 and enabling gasdermin-D-mediated circulatory release of mtDNA. Elevated amounts of circulating mtDNA, presumably oxidized, have been detected in older individuals and patients with metabolic or autoimmune disorders. Here we show that sustained Ox-mtDNA release, triggered by a prototypical NLRP3 inflammasome activator, induces autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells, are elicited by in vitro-generated Ox-mtDNA, but not by non-oxidized mtDNA. Although both mtDNA forms are internalized by pDCs and induce interferon-α, only Ox-mtDNA stimulates autocrine interleukin (IL)-1β signaling that induces co-stimulatory molecules and IL-21, which enable mouse and human pDCs to induce functional TFH differentiation, supportive of autoantibody production. These findings underscore the role of pDC-generated IL-1β in autoantibody production and highlight Ox-mtDNA as an important autoimmune trigger, suggesting potential therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41590-025-02179-7
  59. Nat Struct Mol Biol. 2025 Jun 13.
    Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.
    Nicholas A Popp, Rachel L Powell, Melinda K Wheelock, Kristen J Holmes, Brendan D Zapp, Kathryn M Sheldon, Shelley N Fletcher, Xiaoping Wu, Shawn Fayer, Alan F Rubin, Kerry W Lannert, Alexis T Chang, John P Sheehan, Jill M Johnsen, Douglas M Fowler.
      Despite widespread advances in DNA sequencing, the functional consequences of most genetic variants remain poorly understood. Multiplexed assays of variant effect can measure the function of variants at scale but cannot readily be applied to the ~10% of human genes encoding secreted proteins. Here we develop a flexible, scalable human cell surface display method, multiplexed surface tethering of extracellular proteins (MultiSTEP), to study the consequences of missense variation in coagulation factor IX (FIX), a serine protease in which genetic variation can cause hemophilia B. We combine MultiSTEP with a panel of antibodies to detect FIX secretion and post-translational modification (PTM), measuring 44,816 variant effects for 436 synonymous variants and 8,528 of the 8,759 possible F9 missense variants. Almost half of missense variants impact secretion, PTM or both. We also identify functional constraints on secretion within the signal peptide and for nearly all gain or loss of cysteine variants. Secretion scores correlate strongly with FIX levels in hemophilia B and reveal that loss-of-secretion variants are more often associated with severe disease. Integration of the secretion and PTM scores enables reclassification of 63.1% of F9 variants of uncertain significance in the My Life, Our Future hemophilia genotyping project. Lastly, we show that MultiSTEP can be applied to other secreted proteins, thus demonstrating that MultiSTEP is a multiplexed, multimodal and generalizable method for systematically assessing variant effects in secreted proteins at scale.
    DOI:  https://doi.org/10.1038/s41594-025-01582-w
  60. Orphanet J Rare Dis. 2025 Jun 13. 20(1): 306
    The m.3290T > C variant might be a protective factor against the pathogenic m.3243 A > G variant: a case study.
    Ning Zhang, Zhikang Zhang, Ying Zhang, Xun Su, Yuzhou Gao, Jing Yang, Weiwei Zou, Dongmei Ji, Yunxia Cao.
      The mitochondrial m.3243 A > G variant is a prevalent mitochondrial disease mutation that causes multisystem maternal inheritance disorders. While clinical severity typically correlates with mutation load, symptom manifestation may be influenced by other variants and environmental factors. Notably, the m.3290T > C variant has been hypothesized as a potential protective variant for m.3243 A > G pathogenicity, though clinical evidence remains limited. Here we reported a six-generation Chinese pedigree carrying both m.3243 A > G and homoplasmic m.3290T > C variants. Clinical and genetic analyses revealed that carriers with extremely high m.3243 A > G heteroplasmy (> 95%) exhibited severe symptoms, whereas those with moderate or high levels showed limited or no clinical symptoms. Our findings provide novel evidence for the protective role of m.3290T > C in mitigating m.3243 A > G pathogenicity, highlighting its potential clinical significance.
    Keywords:  MELAS; Mitochondrial DNA; Mitochondrial disease; m.3243A > G; m.3290T > C
    DOI:  https://doi.org/10.1186/s13023-025-03774-5
  61. Cell Mol Life Sci. 2025 Jun 14. 82(1): 238
    Resting Ca2+ fluxes protect cells from fast mitochondrial fragmentation, cell stress responses, and immediate transcriptional reprogramming.
    Caroline Fecher, Annemarie Sodmann, Felicitas Schlott, Juliane Jaepel, Franziska Schmitt, Isabella Lengfelder, Thorsten Bischler, Bernhard Nieswandt, Konstanze F Winklhofer, Robert Blum.
      Homeostatic calcium ion (Ca2+) fluxes between the endoplasmic reticulum, cytosol, and extracellular space occur not only in response to cell stimulation but also in unstimulated cells. Using murine astrocytes as a model, we asked whether there is a signaling function of these resting Ca2+ fluxes. The data showed that endoplasmic reticulum (ER) Ca²⁺ depletion, induced by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition, resulted to prolonged Ca²⁺ influx and mitochondrial fragmentation within 10 to 30 min. This mitochondrial fragmentation could be prevented in Ca2+-free medium or by inhibiting store-operated Ca2+ entry (SOCE). Similarly, attenuation of STIM proteins, which are vital ER Ca2+ sensors, protected mitochondrial morphology. On the molecular level, ER Ca2+ depletion, achieved either by removing extracellular Ca2+ or through acute SERCA inhibition, led to changes in gene expression of about 13% and 41% of the transcriptome within an hour, respectively. Transcriptome changes were associated with universal biological processes such as transcription, differentiation, or cell stress. Strong increase in expression was observed for the transcription factor ATF4, which is under control of the kinase PERK (EIF2AK3), a key protein involved in ER stress. Corroborating these findings, PERK was rapidly phosphorylated in Ca2+-free medium or after acute pharmacological inhibition of SOCE. In summary, resting, homeostatic Ca2+ fluxes prevent immediate-early cell stress and transcriptional reprogramming.
    Keywords:  Calcium signaling; ER calcium; ER calcium leak; Mitochondrial fragmentation; Resting calcium fluxes; Store-operated calcium entry; Transcriptome changes
    DOI:  https://doi.org/10.1007/s00018-025-05745-2
  62. Biochim Biophys Acta Proteins Proteom. 2025 Jun 11. pii: S1570-9639(25)00023-8. [Epub ahead of print]1873(5): 141085
    Human mitochondrial pyrophosphatase hPPA2: In vitro and in silico study of the factors affecting its function.
    Svetlana Kurilova, Nataliya Vorobyeva, Ekaterina Bezpalaya, Marina Serebryakova, Elena Rodina.
      Biallelic mutations in a nuclear gene PPA2 in human encoding mitochondrial inorganic pyrophosphatase hPPA2 cause mitochondrial disfunctions leading to severe cardiac pathology. This protein catalyzes a Mg2+-dependent hydrolysis of pyrophosphate, a by-product of many biosynthetic reactions, thereby providing a thermodynamic pull for these reactions. In order to better understand molecular mechanisms of mitochondrial disfunction caused by mutations in PPA2 gene, detailed characterization of a metabolic role of hPPA2 is required. In this work, we study the in vitro effects of a panel of metabolites, as well as other factors, on the recombinant hPPA2 activity. This study is complemented with the in silico assessment of possible mechanisms of observed patterns. We demonstrate that at Mg2+ concentrations typical for the mitochondrial matrix hPPA2 works at under-saturation and therefore the regulatory factors changing Mg2+ concentration will have a significant impact on hPPA2 activity. We also demonstrate that hPPA2 activity is regulated by a redox state of cysteine residues. Mass-spectrometry analysis reveals four Cys residues modified by 4-hydroxy-Hg-benzoate, as well as an SS bridge formation within an hPPA2 monomer. Finally, we found that selected metabolites including intermediates of central metabolism affect hPPA2 activity. In silico analysis of hPPA2 allows a structural insight into the observed properties. Of a special interest is an W-loop, unique for PPA2 proteins from animals and shared with acidocalcisomal soluble pyrophosphatases from kinetoplastids, that may be involved in interaction with small-molecule effectors.
    Keywords:  Activity regulation; Effectors; Mitochondrial; Pyrophosphatase; Structural model
    DOI:  https://doi.org/10.1016/j.bbapap.2025.141085
  63. Physiol Rep. 2025 Jun;13(12): e70405
    Short-term dietary methionine restriction with high fat diet counteracts metabolic dysfunction in male mice.
    Marissa I McGilvrey, Bethany Fortier, Diana Cooke, Maryam A Mahdi, Benjamin Tero, Christian M Potts, Abigail Kaija, Larisa Ryzhova, Carolina Cora, Adam Richardson, Douglas Guzior, Ilka Pinz, Calvin Vary, Robert A Koza, Gene Ables, Lucy Liaw.
      Dietary methionine restriction (MetR) promotes metabolic health, and we tested the impact of short durations of MetR on high fat diet (HFD)-induced metabolic dysfunction with the maintenance of HFD. Male C57BL/6J mice were fed HFD from 10 to 25 weeks of age, then maintained on HFD or fed HFD with 80% reduced methionine (HFD-MetR) for 3, 5, or 10 days. Blood, liver, adipose tissue, and aortae underwent phenotypic assessment, proteomics, and metabolomics. HFD-MetR induced rapid weight loss and robust metabolic improvement within 10 days. Significant reductions in body weight, circulating triglycerides, glucose, insulin, adipokines and hepatokines reflected metabolic health. Proteomics revealed enriched metabolic signatures in perivascular adipose tissue (PVAT) and structural remodeling signatures in aorta. Metabolomics identified a cardioprotective signature in blood plasma, and activated mitochondrial activity and energy production in liver and brown adipose tissue. HFD-MetR reversed metabolic dysfunction, and novel proteomic and metabolomic signatures were identified. Multi-organ molecular changes in lipid metabolism, mitochondrial function, and bioenergetics are predicted to impact adipose tissue and liver function and cardiovascular health. Our identification of rapid changes in protein and metabolite signatures with accelerated restoration of metabolic health can be leveraged to evaluate biomarkers of metabolic health and disease in a translational context.
    Keywords:  adipose tissue; high fat diet; metabolomics; methionine restriction; proteomics
    DOI:  https://doi.org/10.14814/phy2.70405
  64. Cell. 2025 Jun 11. pii: S0092-8674(25)00572-0. [Epub ahead of print]
    Perturb-Multimodal: A platform for pooled genetic screens with imaging and sequencing in intact mammalian tissue.
    Reuben A Saunders, William E Allen, Xingjie Pan, Jaspreet Sandhu, Jiaqi Lu, Thomas K Lau, Karina Smolyar, Zuri A Sullivan, Catherine Dulac, Jonathan S Weissman, Xiaowei Zhuang.
      Metazoan life requires the coordinated activities of thousands of genes in spatially organized cell types. Understanding the basis of tissue function requires approaches to dissect the genetic control of diverse cellular and tissue phenotypes in vivo. Here, we present Perturb-Multimodal (Perturb-Multi), a paired imaging and sequencing method to construct large-scale, multimodal genotype-phenotype maps in tissues with pooled genetic perturbations. Using imaging, we identify perturbations in individual cells while simultaneously measuring their gene expression profiles and subcellular morphology. Using single-cell sequencing, we measure full transcriptomic responses to the same perturbations. We apply Perturb-Multi to study hundreds of genetic perturbations in the mouse liver. Our data suggest the genetic regulators and mechanisms underlying the dynamic control of hepatocyte zonation, the unfolded protein response, and steatosis. Perturb-Multi accelerates discoveries of the genetic basis of complex cell and tissue physiology and provides critical training data for emerging machine learning models of cellular function.
    Keywords:  RCA-MERFISH; hepatocyte stress response; in vivo pooled screening; lipid droplet accumulation; liver zonation; machine learning morphology; multimodal phenotyping; multiplexed RNA imaging; multiplexed protein imaging; scRNA-seq
    DOI:  https://doi.org/10.1016/j.cell.2025.05.022
  65. Nat Commun. 2025 Jun 20. 16(1): 5355
    Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
    Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  66. Front Neurosci. 2025 ;19 1602149
    Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
    Luis Armando Valenzuela-Ahumada, Octavio Fabián Mercado-Gómez, Rubi Viveros-Contreras, Rosalinda Guevara-Guzmán, Alberto Camacho-Morales.
      Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.
    Keywords:  ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2025.1602149
  67. Nature. 2025 Jun 19.
    AI slashes time to produce gold-standard medical reviews - but sceptics urge caution.
    Helen Pearson.
      
    Keywords:  Machine learning; Medical research; Research data
    DOI:  https://doi.org/10.1038/d41586-025-01942-y
  68. J Biol Chem. 2025 Jun 14. pii: S0021-9258(25)02226-4. [Epub ahead of print] 110376
    Structural biology of Parkinson's Disease-associated Leucine-Rich Repeat Kinase 2 (LRRK2).
    Andres E Leschziner.
      Leucine Rich Repeat Kinase 2 (LRRK2) has gone, in a little over two decades, from a novel gene linked to cases of Parkinson's Disease (PD) in one family to being the main actionable target for PD therapeutics, with several clinical trials targeting it currently underway. While much remains to be understood about LRRK2-including, chiefly, why its increased activity is linked to PD-much has also been learned. One of the areas where our knowledge has increased exponentially in a very short time is the structural biology of LRRK2. The goal of this review is to provide a survey of the current landscape of LRRK2 structural biology with an emphasis on the functional insights that structures have provided.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110376
  69. Hum Genomics. 2025 Jun 21. 19(1): 70
    Toward streamline variant classification: discrepancies in variant nomenclature and syntax for ClinVar pathogenic variants across annotation tools.
    Yu-An Chen, Tzu-Hang Yuan, Jia-Hsin Huang, Yu-Bin Wang, Tzu-Mao Hung, Chien-Yu Chen, Pei-Lung Chen, Jacob Shujui Hsu.
       BACKGROUND: High-throughput sequencing has revolutionized genetic disorder diagnosis, but variant pathogenicity interpretation is still challenging. Even though the human genome variation society (HGVS) provides recommendations for variant nomenclature, discrepancies in annotation remain a significant hurdle.
    RESULTS: In this study, we evaluated the annotation concordance between three tools-ANNOVAR, SnpEff, and variant effect predictor (VEP)-using 164,549 two-star variants from ClinVar. The analysis used HGVS nomenclature string-match comparisons to assess annotation consistency from each tool, corresponding coding impacts, and associated ACMG criteria inferred from the annotations. The analysis revealed variable concordance rates, with 58.52% agreement for HGVSc, 84.04% for HGVSp, and 85.58% for the coding impact. SnpEff showed the highest match for HGVSc (0.988), while VEP bettered for HGVSp (0.977). The substantial discrepancies were noted in the loss-of-function (LoF) category. Incorrect PVS1 interpretations affected the final pathogenicity and downgraded PLP variants (ANNOVAR 55.9%, SnpEff 66.5%, VEP 67.3%), risking false negatives of clinically relevant variants in reports.
    CONCLUSIONS: These findings highlight the critical challenges in accurately interpreting variant pathogenicity due to discrepancies in annotations. To enhance the reliability of genetic variant interpretation in clinical practice, standardizing transcript sets and systematically cross-validating results across multiple annotation tools is essential.
    Keywords:  ACMG guideline; ClinVar; HGVS nomenclature; Variant annotation; Variant interpretation
    DOI:  https://doi.org/10.1186/s40246-025-00778-x
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒22 at 12:02.