bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–06–28
75 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.
  2. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  3. Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
  4. Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
  5. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
  6. The TOM Complex in the Outer Membrane of Mitochondria: A Supramolecular Assembly for Protein Import.
  7. A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
  8. Proteolytic coordination of the OXPHOS Life Cycle.
  9. Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
  10. Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
  11. Paradoxical hypolibido in a hyperandrogenic male with POLG-related mitochondrial disease.
  12. DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.
  13. A ratiometric fluorescent reporter of mitochondrial sodium.
  14. Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
  15. Neurodegenerative NMNAT2 Deficiency Promotes APP Processing in a SARM1-Dependent Manner.
  16. Biallelic TMEM126B Variants as a Novel Cause of Kidney Failure-Implications for Mitochondrial Genetic Testing in Nephrology: A Response Letter.
  17. Programmed axon degeneration gene variants in human disease.
  18. Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
  19. Loss of PINK1 causes age-dependent mitochondrial trafficking deficits in nigrostriatal dopaminergic neurons via aberrant p38 MAPK activation.
  20. Activity of DNA- and RNA-Guided Prokaryotic Argonautes in Human Mitochondria.
  21. PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.
  22. Persistence of large mtDNA rearrangements linked to premature aging in Pol γ exonuclease-deficient mice.
  23. FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
  24. Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
  25. BCAS-3 is required for the progression of autophagosome formation to degrade paternal mitochondria in Caenorhabditis elegans.
  26. Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
  27. A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.
  28. Diagnostic Yield and Clinical Impact of Comprehensive WES/WGS Testing Beyond Common Genetic Causes in Hereditary Optic Atrophy.
  29. Mitochondrial stress response drives microglial senescence.
  30. Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
  31. Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
  32. Pseudouridine synthase PUS1 and initiation factor mtIF2 are human mitoribosomal small subunit assembly factors.
  33. Differential effects of tropomyosin paralogs on mitochondrial dynamics in Saccharomyces cerevisiae.
  34. Robust and sensitive ELISA detection of total and activated PRKN.
  35. Compensatory Intercellular Mitochondrial Transfer Improves Bioenergetics in P301L Tau-Affected Neuronal Cells.
  36. Automated reanalysis of genomic data for rare disease diagnostics at scale.
  37. E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.
  38. Cardiomyopathy and mitochondrial encephalomyopathy in a female child associated with a heterozygous X-linked AIFM1 variant.
  39. Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
  40. Expanding the Mutational Spectrum of ACADVL: Integrative Characterization of the p.Ser72Phe Variant in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
  41. Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.
  42. Dual CRISPR/Cas9 correction of compound heterozygous MARS2 mutations in the iPSC line ISMMSi060-A from a patient with COXPD25.
  43. Mitochondria‑endoplasmic reticulum contact site nexus: Molecular integration, disease pathogenesis and therapeutic opportunities (Review).
  44. A Four-Year Prospective Pilot Study of Newborn Screening for Late-Onset Proximal Urea-Cycle Disorders in Hyogo Prefecture in Japan.
  45. Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review.
  46. Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
  47. The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency.
  48. EXPRESS: Intercellular Mitochondrial Transfer in Ischemic Stroke: Emerging Roles of Microglia.
  49. Meta-analysis of DNA methylation aging signatures in 17 human tissues.
  50. Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.
  51. Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
  52. An immune-associated mitochondrial DNA variant with sex differences reveals a putative novel microprotein called MASL.
  53. Multi-ancestry analysis of POLG variants in Parkinson's disease.
  54. Artificial Intelligence in Rare Diseases: Workflow-Integrated Precision Kidney Care.
  55. GPU-accelerated MitoGraph for high-throughput three-dimensional mitochondrial morphology analysis.
  56. Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.
  57. Engineering drug-responsive replication machinery for precise control of self-amplifying RNA.
  58. Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
  59. Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.
  60. Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
  61. Multimodal Sequencing and Reanalysis Approaches to End the Diagnostic Odyssey of Individuals with Suspected Rare Monogenic Diseases.
  62. A pediatric case of citrin deficiency presenting with recurrent hypertriglyceridemic pancreatitis-a case report.
  63. A α-synuclein aggregation inhibitor exerts neuroprotective effects via mitochondrial resilience in Parkinson's disease.
  64. High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.
  65. Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
  66. Reversible one-step acylation facilitates mitochondrial delivery of functional RNA.
  67. Population-scale detection of methylation outliers from long-read genome sequencing.
  68. CRISPR's next act: the companies editing the epigenome to treat disease.
  69. Assembly of the catalytic module and the rotor of human ATP synthase.
  70. Generative AI and Language Models in Human Genetics and Health: From Variant Interpretation to Clinical Decision Support.
  71. Analysis of genetic risk factors for Leber hereditary optic neuropathy in the Polish population.
  72. De Novo MFN2 p.Arg95Met in Severe Charcot-Marie-Tooth Disease Type 2A.
  73. Mechanisms and functions of intercellular mitochondria transfer to and from macrophages.
  74. Enzyme Assemblies in Nucleotide Metabolism: Structure, Regulation, and Disease Implications.
  75. Implementation of a medical genomics program for rare diseases in Uruguay.
  1. Adv Exp Med Biol. 2026 ;1514 299-330
    Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.
    Runyu Guo, Maojun Yang.
      Mitochondria are considered the central organelle in cellular energy metabolism and an integral platform for signal transduction. Respiratory chain complexes are the most abundant and critical protein machines in mitochondria. Thanks to advancing technologies such as cryo-EM, molecular dynamics simulation, and FRET-based live imaging, though still under hot debate, we have now gained a much deeper insight into the organization, regulation, and functional mechanism of the respiratory chain. Accordingly, developing novel compounds targeting mitochondria is particularly appealing, for mitochondria dysfunction might be the underlying cause of many annoying human diseases, including metabolic syndromes, neurodegenerative diseases, cardiovascular diseases, and tumors.
    Keywords:  Complex I; Drug discovery; Electron transport chain; Mitochondria; Mitochondrial disorders; Respiratory chain complexes; Signaling; Structural biology; Supercomplexes
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_11
  2. bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.
      Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.64898/2026.06.09.730804
  3. Nat Commun. 2026 Jun 23. pii: 5563. [Epub ahead of print]17(1):
    Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
    Laura Pérez Pañeda, Jelena Misic, Tereza Kadavá, Nils-Göran Larsson, Albert J R Heck.
      Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F1-TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.
    DOI:  https://doi.org/10.1038/s41467-026-74730-5
  4. Nat Commun. 2026 Jun 21.
    Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
    Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.
      Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-74103-y
  5. Nat Neurosci. 2026 Jun 26.
    The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
    Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.
      Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02320-1
  6. Adv Exp Med Biol. 2026 ;1514 85-111
    The TOM Complex in the Outer Membrane of Mitochondria: A Supramolecular Assembly for Protein Import.
    Stephan Nussberger, Robin Ghosh, Shuo Wang.
      Currently, there is no comprehensive physical model explaining how unfolded polypeptide chains with diverse characteristics are transported into the mitochondria. On a molecular scale, the kinetics of how transit polypeptides approach, are captured by the protein translocation machinery at the outer mitochondrial membrane, and cross the protein translocation pore to enter the intermembrane space remain unclear. This knowledge gap is primarily due to the lack of dynamic single-molecule data on the "protein-conducting channels" involved in mitochondrial protein translocation. In this chapter, we explore the recently resolved sub-nanometer cryo-EM structures, which are a prerequisite for a fundamental understanding of the translocation mechanism, and our existing knowledge of the mitochondrial two-pore outer membrane protein translocation machinery (TOM complex). Particularly intriguing are recent findings from single-molecule TIRF microscopy indicating that the TOM core complex can function as a mechanosensor, with the pores closing upon interaction with nearby membrane structures. We emphasize novel and unexpected correlations between the structural components of the TOM complexes and their dynamic behavior within the membrane environment.
    Keywords:  Droplet interface bilayer membranes; Electron cryo-microscopy; Mechanosensitivity; Mitochondria; Native mass spectrometry; Protein import; Single-molecule fluorescence microscopy; TOM complex
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_5
  7. Mol Cell. 2026 Jun 26. pii: S1097-2765(26)00389-8. [Epub ahead of print]
    A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
    Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      How mitochondrial respiration is tightly regulated by energy demand remains incompletely defined. When mammalian cells switch from glucose to galactose as a carbon source, we observed the enhanced assembly of respiratory chain complexes accompanied by a marked reduction in TMEM141, a mitochondrial inner membrane protein. Loss of TMEM141 increased mitochondrial respiration and promoted complex I assembly, whereas galactose-induced complex I assembly was markedly blunted in TMEM141-deficient cells. TMEM141 interacts with the complex I assembly factor TIMMDC1, limiting its association with complex I subunits. TMEM141 is degraded by the mitochondrial proteases AFG3L2 and YME1L1, and galactose treatment strengthens their interactions. TMEM141 deficiency increases oxidative damage and mtDNA release, leading to activation of the cGAS-STING pathway. In Drosophila, dTMEM141 localizes to mitochondria, modulates mitochondrial activity, and is required for glial cell integrity in the eye. Together, our findings reveal TMEM141 as a negative regulator of complex I assembly that adapts to oxidative phosphorylation (OXPHOS) demands.
    Keywords:  Drosophila; OXPHOS; mitochondria; mitochondrial protease; respiration complex
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.018
  8. Biochem J. 2026 Jul 08. 483(7): 1253-1280
    Proteolytic coordination of the OXPHOS Life Cycle.
    Nataliia Nechytailo, Karolina Szczepanowska.
      The mitochondrial oxidative phosphorylation (OXPHOS) system consists of multimeric, highly ordered protein complexes critical for energy production and metabolic wiring in the cell. Recent discoveries in mitochondrial proteolysis, facilitated by advances in proteomic approaches, have transformed the view of mitochondrial proteases from a simple quality-control system into a dynamically coordinated network of enzymes that actively shape the status of the OXPHOS machinery. Mapping OXPHOS-associated proteolytic circuits has uncovered specialized functions of individual proteases and identified key interaction sites. The present review outlines how mitochondrial proteases regulate the OXPHOS life cycle: expression, delivery, assembly, long-term maintenance, and disposal of mitochondrial respiratory complexes. We summarize past findings and highlight emerging concepts, including asynchronous OXPHOS turnover, cofactor-driven proteolysis, and bioenergetics-coupled degradation. Progress in these areas will deepen our understanding of how proteases coordinate the OXPHOS life cycle.
    Keywords:  mitochondria; mitochondrial proteases; mitochondrial respiratory complexes; oxidative phosphorylation; regulatory proteolysis; turnover
    DOI:  https://doi.org/10.1042/BCJ20250120
  9. Int J Mol Sci. 2026 Jun 18. pii: 5517. [Epub ahead of print]27(12):
    Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
    Vladislav Simonov, Sergey Rastorguev.
      Mitochondrial DNA (mtDNA) mutations are associated with a diverse spectrum of diseases and pose a significant threat to human health. Despite their importance as therapeutic targets, the unique structural and electrochemical properties of mitochondria-most notably the impermeable inner mitochondrial membrane and the high membrane potential-present formidable challenges for the targeted delivery of therapeutic agents. Currently, there are no approved curative treatments for patients harboring pathogenic mtDNA mutations. In this review, we discuss recent advancements in gene therapy for mitochondrial genome-related disorders, with a particular focus on allotopic expression of mtDNA-encoded genes and mitochondrial genome editing technologies. We conclude that allotopic expression currently stands as the most promising approach for near-term clinical implementation. But we also pay great attention to programmable nucleases and base editors utilizing RNA-independent DNA recognition which are evolving with remarkable speed.
    Keywords:  DdCBE; allotopic expression; gene therapy; mitoCRISPR; mitoTALEN; mitoZFN; mitochondrial manipulation; mtDNA
    DOI:  https://doi.org/10.3390/ijms27125517
  10. Cell Commun Signal. 2026 Jun 22.
    Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
    Qingqi Zhang, Junyan Gao, Yiting Yang, Ping Guo, Huiqin Gao, Shuaiyong Zhao, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Hao Liu, Yunzeng Zou.
      Mitochondria-associated endoplasmic reticulum membrane (MAM), which serves as a signaling hub for interactions between the endoplasmic reticulum (ER) and mitochondria, dynamically coordinates innate immune processes by regulating calcium homeostasis, lipid metabolism, mitochondrial dynamics, mitochondrial protein modifications, and autophagy. MAM regulates calcium homeostasis to govern mitochondrial energy metabolism and inflammasome activation; maintains lipid metabolism for membrane integrity to support antiviral signaling pathways; controls mitochondrial fission and fusion dynamics, processes that are closely associated with mitochondrial DNA (mtDNA) release; regulates mitochondrial protein modifications to fine-tune the function of proteins localized at MAM; and facilitates the clearance of damaged mitochondria and leaked mtDNA through autophagy. Most critically, MAM dysfunction and innate immune dysregulation form a vicious cycle: immune activation disrupts MAM integrity, and MAM abnormalities exacerbate the release of mitochondrial damage-associated molecules, continuously driving overactivation of pathways such as inflammasomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby promoting the development of autoimmune diseases. This review synthesizes current literature on the molecular mechanisms by which MAM regulates innate immunity. We summarize how disruptions in MAM-mediated mitochondrial homeostasis contribute to innate immune imbalance. By integrating these findings, we highlight potential intervention nodes. This underscores the clinical relevance of targeting MAM in immune-related pathological conditions.
    Keywords:  Innate immunity; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitochondrial homeostasis; MtDNA
    DOI:  https://doi.org/10.1186/s12964-026-03013-9
  11. J Sex Med. 2026 Jun 05. pii: qdag187. [Epub ahead of print]23(7):
    Paradoxical hypolibido in a hyperandrogenic male with POLG-related mitochondrial disease.
    Hector Rodrigo Gonzalez-Carranza, Luis Antonio Reyes-Vallejo.
      
    Keywords:  hyperandrogenism; libido; mitochondrial diseases; testosterone
    DOI:  https://doi.org/10.1093/jsxmed/qdag187
  12. J Neurodev Disord. 2026 Jun 26.
    DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.
    T B Baum, J Costanzo, C Bodnya, D P Boulton, M C Caino, D Mogilenko, A Zhelonkin, V Gama.
      With the advent of exome sequencing, a growing number of children are being identified with de novo loss-of-function mutations in the dynamin 1-like (DNM1L) gene, which encodes the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1). Mutations in DRP1 result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of human induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro. High-resolution time-lapse imaging of transport in neuronal projections revealed mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicated mutation-dependent alterations in synaptic development and gene expression of calcium-regulatory genes. Disruptions in calcium dynamics were confirmed using live functional recordings of 65-200 days in vitro (DIV) mutant DRP1 cortical neurons. These findings strongly suggest that altered mitochondrial morphology in DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
    Keywords:  DRP1; Mitochondria; Mitochondrial fission; Neurons
    DOI:  https://doi.org/10.1186/s11689-026-09713-0
  13. Nat Chem Biol. 2026 Jun 22.
    A ratiometric fluorescent reporter of mitochondrial sodium.
    Koushambi Mitra, Soyoung Kim, Daphne Oettinger, Sanjeev Uthishtran, Qian Zhao, Aneesh Tazhe Veetil, Joseph R Ramirez, Hening Lin, Senthil Arumugam, Yamuna Krishnan.
      Cells cope with salt stress, hypoxia or elevated cytosolic Ca2+ by regulating their mitochondrial Na+ levels. The discovery of the mitochondrial Na+/Ca2+ exchanger and its disease relevance has revealed the need to map mitochondrial Na+ in situ. Here we describe a ratiometric fluorescent reporter for Na+, denoted MitRatiNa, that reports mitochondrial Na+ levels independent of membrane potential and in diverse cell lines. Na+ in individual mitochondria varies greatly and, depending on cell type, can be as low as 1-5 mM or as high as 40 mM on average. We demonstrate that mitochondrial Na+ increases during cytosolic Ca2+ elevation, inhibition of glycolysis or respiration. Mitochondria in skin fibroblasts from healthy humans show a high Na+ population that disappears in fibroblasts of persons with mitochondrial diseases. The newfound ability to map absolute Na+ at the resolution of single mitochondria enables the dissection of regulatory mechanisms for mitochondrial Ca2+ and Na+ and potential identification of new therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41589-026-02253-7
  14. Nat Cell Biol. 2026 Jun 26.
    Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
      
    DOI:  https://doi.org/10.1038/s41556-026-02008-5
  15. Cells. 2026 Jun 17. pii: 1100. [Epub ahead of print]15(12):
    Neurodegenerative NMNAT2 Deficiency Promotes APP Processing in a SARM1-Dependent Manner.
    Andrea Enriquez, Sen Yang, Karen Ling, Paymaan Jafar-Nejad, Hui-Chen Lu.
      Metabolic dysfunction and proteinopathy are hallmarks of neurodegenerative disease, yet their mechanistic interplay remains poorly understood. Here, we show that loss of the neuronal NAD+-synthesizing enzyme Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) disrupts amyloid precursor protein (APP) processing in cortical neurons, leading to accumulation of APP C-terminal fragments (APP-CTFs). NMNAT2 deficiency lowers the NAD+/NADH redox ratio coincident with APP-CTF buildup. Temporal profiling reveals a biphasic increase in APP-CTFs, with an initial gradual rise followed by rapid accumulation, paralleling the expansion of differentially expressed proteins. Pathway analysis indicates early activation of JNK/MAPK signaling, followed by late-stage suppression of mitochondrial pathways and induction of endoplasmic reticulum stress and unfolded protein response programs. Seahorse analyses reveal early glycolytic impairment followed by deficits in mitochondrial respiration. Knockdown of the NAD+ hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores mitochondrial function and normalizes APP-CTF levels in NMNAT2 knockout neurons, whereas NAD+ supplementation provides only modest rescue. Together, these data demonstrate that neuronal NAD+ depletion drives progressive, SARM1-dependent disruption of glucose metabolism and proteostasis, impairing APP processing. The NMNAT2-SARM1 axis thus links metabolic stress to proteinopathy and highlights SARM1 as a central mediator of neurodegenerative dysfunction.
    Keywords:  APP processing; NAD+ metabolism; NMNAT2; SARM1; proteostasis
    DOI:  https://doi.org/10.3390/cells15121100
  16. Clin Genet. 2026 Jun 25.
    Biallelic TMEM126B Variants as a Novel Cause of Kidney Failure-Implications for Mitochondrial Genetic Testing in Nephrology: A Response Letter.
    Sarah Hammond, Dervla M Connaughton.
      Graphical abstract illustrating the clinical presentation, molecular mechanism, and diagnostic implications of biallelic TMEM126B variants associated with progressive kidney disease. The case involved a 47-year-old male with childhood exercise intolerance, possible hypertrophic cardiomyopathy, and progressive kidney failure. Initial comprehensive inherited kidney disease panel testing was nondiagnostic; subsequent updated exome sequencing identified a homozygous TMEM126B variant (c.635G>T; p.Gly212Val). TMEM126B encodes a mitochondrial complex I assembly factor, and pathogenic variants impair complex I assembly and mitochondrial function, contributing to multisystem disease including exercise intolerance, kidney disease and cardiomyopathy. The case highlights the expanding phenotypic spectrum associated with TMEM126B and the importance of periodic gene panel updates and systematic reanalysis to improve diagnostic yield and patient care.
    Keywords:   TMEM126B ; genetic testing; kidney failure; mitochondrial complex I deficiency; mitochondrial nephropathy
    DOI:  https://doi.org/10.1111/cge.70202
  17. Exp Neurol. 2026 Jun 24. pii: S0014-4886(26)00256-6. [Epub ahead of print] 115891
    Programmed axon degeneration gene variants in human disease.
    Eleanor L Hopkins, Pete A Williams.
       BACKGROUND: Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide adenine dinucleotide (NAD) through loss of the pro-survival enzyme NMNAT2 and activation of the pro-degenerative NADase SARM1. Recent genetic studies have identified pathogenic variants in PAD pathway enzymes associated with severe neurodegenerative phenotypes.
    MAIN BODY: Pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1 have been identified and will be discussed in this review. NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms. NMNAT1 variants are well-characterized causes of Leber Congenital Amaurosis type 9, while NMNAT2 variants result in peripheral neuropathies with childhood onset. SARM1 gain-of-function variants with constitutively active NADase activity are enriched in amyotrophic lateral sclerosis patients.
    CONCLUSION: These findings demonstrate that maintaining proper NAD homeostasis is crucial for axon survival, and disruption through genetic variants leads to distinct neurodegenerative outcomes. Understanding these rare variants provides insight into PAD mechanisms and supports development of broad-spectrum neuroprotective therapies targeting this pathway. Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation, offering hope for treating multiple neurodegenerative diseases.
    Keywords:  Axon pathology; NAD metabolism; NAMPT; NMNAT; Neurodegeneration; Peripheral neuropathy; Programmed axon degeneration; SARM1; Wallerian degeneration
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115891
  18. Mol Neurobiol. 2026 Jun 26. pii: 728. [Epub ahead of print]63(1):
    Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
    Sanket Pramanik, Biplab Debnath, Aganta Chakraborty, Anas Islam, Shrabasti Mullick, Priya Chaudhary, Rajarshi Nath, Dinesh Kumar Chellappan, Mohini Mondal, Sumel Ashique.
      Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.
    Keywords:  DdCBE (DddA-derived Cytosine Base Editors); Heteroplasmy Correction; MitoTALENs; Mitochondria-Targeted CRISPR/Cas Systems; Mitochondrial Genome Editing; Neurodegenerative Disorders; Oxidative Stress & Mitochondrial Dysfunction; Precision Medicine
    DOI:  https://doi.org/10.1007/s12035-026-06008-2
  19. NPJ Parkinsons Dis. 2026 Jun 24.
    Loss of PINK1 causes age-dependent mitochondrial trafficking deficits in nigrostriatal dopaminergic neurons via aberrant p38 MAPK activation.
    Jingyu Zhao, Yuanxin Chen, Lianteng Zhi, Qing Xu, Juan Subiry, Zebang Chen, Shiquan Cui, Hui Zhang, Chenjian Li.
      Mutations in PTEN-induced putative kinase 1 (PINK1) cause early-onset, autosomal-recessive Parkinson's disease (PD). While previous studies have shown age-related declines in dopamine release and ATP levels in Pink1-/- mice, the mechanisms remain unclear. Using a novel TH-Mito-Dendra2 transgenic mouse model to label dopaminergic neuron mitochondria, we show that PINK1 loss leads to age-dependent defects in axonal mitochondrial trafficking in acute brain slices. These deficits are characterized by reduced anterograde transport and increased mitochondrial stalling. Pharmacological induction of reactive oxygen species (ROS) and calcium release impaired mitochondrial mobility. Consistent with this, Pink1 knockout mice exhibited elevated mitochondrial calcium, oxidation levels, and p38 MAPK hyperactivation. Treatment with a calcium channel blocker and p38 inhibitor SB202190 restored mitochondrial motility and increased anterograde transport. Together, our findings suggest that PINK1 loss disrupts mitochondrial trafficking by disturbing calcium and redox homeostasis via the p38 pathway, contributing to PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41531-026-01443-3
  20. Cells. 2026 Jun 22. pii: 1129. [Epub ahead of print]15(12):
    Activity of DNA- and RNA-Guided Prokaryotic Argonautes in Human Mitochondria.
    Beatrisa Rimskaya, Ekaterina Kropocheva, Iaroslava Ponomareva, Lada Karchemkina, Lidiya Lisitskaya, Daria Gelfenbein, Egor Ulashchik, Vadim Shmanai, Andrey Kulbachinskiy, Ilya Mazunin.
      Precise manipulation of mitochondrial DNA (mtDNA) by CRISPR-Cas systems remains challenging, largely due to inefficient import of guide RNAs, motivating the exploration of alternative programmable nucleases. Here, we show that prokaryotic Argonaute nucleases (pAgos) of various classes can be efficiently targeted to human mitochondria. Using the Su9 mitochondrial targeting sequence from Neurospora crassa, we achieved robust mitochondrial import of four pAgos-DecAgo, CbuAgo, KmaAgo and RslAgo. As a functional readout of their activity in cells, we targeted the single-stranded D-loop region, which plays a central role in mtDNA replication and maintenance, reasoning that cleavage at this site was expected to potentially result in a reduction in mtDNA copy number. Of the four enzymes, only RNA-guided DecAgo induced a pronounced reduction in mtDNA levels, decreasing copy number approximately fivefold within 48 h. Unexpectedly, this effect occurred independently of exogenous guides, suggesting that DecAgo may utilize endogenous mitochondrial guide RNAs. These findings identify DecAgo as an active nuclease in human mitochondria and reveal a previously unrecognized mode of targeting, highlighting the need to further investigate the underlying mechanism and the potential role of endogenous guide molecules, as well as improving targeting specificity.
    Keywords:  D-loop; mitochondria; mtDNA copy number; prokaryotic argonautes
    DOI:  https://doi.org/10.3390/cells15121129
  21. bioRxiv. 2026 Jun 09. pii: 2026.06.04.729996. [Epub ahead of print]
    PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.
    Gabriella Fiorino, Damian N Di Florio, Deshaun H Hadley, Owen A Ross, Fabienne C Fiesel, Wolfdieter Springer.
      Genetic loss of the mitochondrial control enzyme PINK1 leads to Parkinson's disease, characterized by dopaminergic neuron degeneration and neuroinflammation, yet its role in glia remains poorly understood. To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.06.04.729996
  22. Nucleic Acids Res. 2026 Jun 22. pii: gkag648. [Epub ahead of print]54(12):
    Persistence of large mtDNA rearrangements linked to premature aging in Pol γ exonuclease-deficient mice.
    Shilan Wu, Scott A Lujan, Adam B Burkholder, Nadee Nissanka, Matthew J Longley, Piotr Mieczkowski, Thomas A Kunkel, Carlos T Moraes, William C Copeland.
      Mitochondrial DNA (mtDNA) mutations are hallmarks of aging. mtDNA in all opisthokonts is replicated exclusively by DNA Polymerase γ (Pol γ; encoded by POLG). PolgD257A/D257A mice, lacking Pol γ exonuclease proofreading (exo-), exhibit premature aging and higher mtDNA mutation rates than Polgwt/wt (exo+) mice. Using short-read sequencing and the ultra-sensitive LostArc indel-junction detection pipeline, we analyzed mtDNA from exo- and exo+ mice across 10 tissues. Indel-junction frequency, endpoint sequence context, and inferred indel size varied systematically by tissue and exonuclease state. Exo- tissues, especially post-mitotic tissues, evidenced exceptionally high burdens of mtDNA large indels (mtDNALIs). These create covalently closed, circular, double-stranded mtDNA that persists despite often lacking replication origins. This suggests limited removal of aberrant circular double-stranded DNA, particularly in post-mitotic tissues. mtDNALI endpoint sequence contexts in exo+ and exo- tissues mimic those in young and elderly human muscle and are dominated by sequence-dependent and -independent indel mechanisms, respectively. Long-read sequencing recapitulated short-read junction patterns, including endpoint concentration near the 7S DNA 3' end, but also revealed mtDNA circles with multiple mtDNALIs, including deletions and duplications. Together, these results implicate accumulation of mtDNALIs, compounded by insufficient mechanisms for eliminating closed circular aberrant mtDNA, as contributing to the premature aging phenotype.
    DOI:  https://doi.org/10.1093/nar/gkag648
  23. Sci Adv. 2026 Jun 26. 12(26): eaec8143
    FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
    Qian Zhang, Hangyu Dong, Yayun Jiang, Zihao Wang, Jiasheng Li, Ye Tian.
      Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in Caenorhabditis elegans, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPRmt). Loss of fubl-3 disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPRmt, and extend lifespan. Notably, human FUBP1 rescues fubl-3 mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8143
  24. Biomolecules. 2026 Jun 09. pii: 842. [Epub ahead of print]16(6):
    Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
    Giampaolo Morciano, Ruggiero Gorgoglione, Vito Porcelli, Amer Ahmed, Pasquale Scarcia, Angelo Vozza, Francesco Massimo Lasorsa, Giuseppe Fiermonte, Luigi Palmieri.
      Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.
    Keywords:  SLC25 carriers; metabolism; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.3390/biom16060842
  25. iScience. 2026 Jul 17. 29(7): 116345
    BCAS-3 is required for the progression of autophagosome formation to degrade paternal mitochondria in Caenorhabditis elegans.
    Takuya Norizuki, Taeko Sasaki, Yuji Suehiro, Shohei Mitani, Waka Kojima, Koji Yamano, Noriyuki Matsuda, Miyuki Sato.
      In the nematode Caenorhabditis elegans, autophagy degrades paternal mitochondria after fertilization to ensure the maternal inheritance of mitochondrial DNA. We previously showed that the autophagy adaptor ALLO-1 is first targeted to paternal mitochondria and then recruits the autophagy machinery. However, the mechanisms underlying local autophagosome formation remain unclear. Here, our forward genetic screen identified a WD40 repeat domain-containing protein, BCAS-3, and its interactor, PHAF-1, as essential factors for paternal mitochondrial degradation. After fertilization, BCAS-3 and PHAF-1 are recruited to the paternal mitochondria, and the loss of these genes impairs the progression of autophagosome formation. We further show that BCAS-3 recruitment is regulated downstream of the WD40 repeat domain-containing core autophagy proteins, ATG-18 and EPG-6, but BCAS-3 also contributes to further ATG-18 accumulation around paternal mitochondria. These findings suggest that the interplay between BCAS-3 and ATG-18 underlies the progression of autophagosome formation during paternal mitochondrial degradation.
    Keywords:  cell biology; developmental biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116345
  26. Biomed Pharmacother. 2026 Jun 26. pii: S0753-3322(26)00735-3. [Epub ahead of print]201 119699
    Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
    Li-Tzu Wang, Han-Ying Jhuang.
      Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
    Keywords:  Clinical trials; Gene therapy; Leber hereditary optic neuropathy; MELAS; Primary mitochondrial disease; Translational medicine; Trial design
    DOI:  https://doi.org/10.1016/j.biopha.2026.119699
  27. Biochim Biophys Acta Mol Cell Res. 2026 Jun 24. pii: S0167-4889(26)00076-5. [Epub ahead of print]1873(6): 120178
    A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.
    Marcelo Mesa Costa-Lima, Fernando Gomes, Thaynara Roberta Damaceno, Mário H Barros.
      The hotdog-fold acyl-CoA thioesterases (ACOTs) are enzymes typically related to lipid metabolism and are widely spread across the tree of life, but many members of this group are poorly characterized. In this work, through in silico analyzes we identified the MICOS-associated mitochondrial proteins of unknown function Mrx3 and Fmp10 as two putative ACOTs in Saccharomyces cerevisiae with structural homology to the mammalian thioesterases Them4 and Them5, which possess a conserved motif that is catalytic toward thioester hydrolysis. Lipidomics analyses revealed that the mrx3Δ and fmp10Δ mutants have lower free fatty acid (FFA) levels with concomitant accumulation of storage lipids, besides a decreased pool of cardiolipin species. During our functional investigation, we observed that the absence of either protein partially restores respiratory capacity in the leu5Δ strain, whose mutation has been previously linked to very slow respiratory growth due to severe Coenzyme A (CoA) depletion in the mitochondrial matrix. We verified that the respiratory defect of the leu5Δ mutant is also related to a defect in the respiratory chain given the low NADH-dependent oxygen consumption rate and is specifically linked to defective Complex IV activity. The strain's growth defect was exacerbated by deletion of the glycine transporter HEM25 and was ameliorated by either δ-aminolevulinic acid (ALA, a heme precursor) or iron supplementation. These results may indicate that the leu5Δ strain has a subtle heme deficiency. We propose a model in which Mrx3 and Fmp10 control the mitochondrial acyl-CoA/CoA ratio through a thioesterase activity, which finely modulates the mitochondrial membrane lipidome, with a concomitant effect in heme biosynthesis. In the leu5Δ mutant, there is a disturbed metabolic homeostasis. Deleting these hotdog-fold proteins cause increased acyl-CoA levels and partially restores metabolic balance, potentially by repartitioning carbon flux through the tricarboxylic acid (TCA) cycle to replenish succinyl-CoA using the limited available CoA pool, which may be sufficient to restore heme biosynthesis. This mechanism highlights the critical role of CoA compartmentalization and the underlying connection of distinct metabolic pathways.
    Keywords:  Coenzyme A (CoA) transport; Heme biosynthesis; Mitochondrial lipid metabolism; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120178
  28. Clin Genet. 2026 Jun 27.
    Diagnostic Yield and Clinical Impact of Comprehensive WES/WGS Testing Beyond Common Genetic Causes in Hereditary Optic Atrophy.
    Katrine M Johannesen, Karen Grønskov, Line Kessel, Sarah Linea von Holstein, Lisbeth Birk Møller, Mette Kjøbæk Gundestrup Andersen, Marianne Søndergaard Khinchi, Steffen Hamann, Marianne Wegener, Mette Bertelsen.
      Hereditary optic atrophy is characterized by degeneration of retinal ganglion cells and may result from a wide range of genetic etiologies. While pathogenic variants in OPA1 and primary mitochondrial variants causing Leber hereditary optic neuropathy (LHON) account for a substantial proportion of cases, many patients remain genetically unsolved. We evaluated the diagnostic yield and clinical impact of comprehensive whole exome/genome sequencing (WES/WGS)-based virtual panel testing in 62 partially pre-screened individuals with suspected hereditary optic atrophy. A total of 51 genes associated with optic atrophy and mitochondrial DNA variants were analyzed. Clinical data were systematically retrieved from medical records, including information on extraocular manifestations. A genetic diagnosis was established in 21 patients (33.9%). Pathogenic or likely pathogenic variants in OPA1 accounted for 57.1% of solved cases, whereas 42.9% involved other genes, including WFS1, ACO2, NR2F1, UCHL1, CACNA1F, and COQ2. In the majority of patients with non-OPA1 findings, the genetic diagnosis prompted additional clinical evaluation, surveillance, or therapeutic intervention. Our findings demonstrate that broad WES/WGS-based testing increases diagnostic yield and expands the genetic spectrum beyond OPA1 and LHON, frequently revealing syndromic conditions with direct clinical implications. Comprehensive genomic testing with broader gene panels should therefore be considered part of the diagnostic workup when hereditary optic atrophy is suspected.
    Keywords:  genetics; ophthalmogenetics; optic atrophy
    DOI:  https://doi.org/10.1111/cge.70203
  29. Nat Neurosci. 2026 Jun 26.
    Mitochondrial stress response drives microglial senescence.
    Luca Peruzzotti-Jametti, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s41593-026-02264-6
  30. Am J Physiol Heart Circ Physiol. 2026 Jun 27.
    Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
    Alexandre Gonçalves, Elaine Zhelan Chen, Hosna Rastegarpouyani, Aurélia Araújo Fernandes, Inês N Alves, Vasco Sequeira, Chulan Kwon, Stephen P Chelko, Maicon Landim-Vieira.
      Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
    Keywords:  Desmoglein-2; arrhythmogenic cardiomyopathy; mitochondria
    DOI:  https://doi.org/10.1152/ajpheart.00368.2026
  31. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731211. [Epub ahead of print]
    Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
    Bo J Price, Sai Sangeetha Balasubramaniam, Adam L Hughes.
      Cells undergoing metabolic transitions rapidly remodel mitochondria through coordinated expansion and reorganization of the mitochondrial proteome. How the outer mitochondrial membrane (OMM) accommodates acute increases in newly synthesized proteins before organelle adaptation is complete remains poorly understood. Here we show that mitochondrial-derived compartments (MDCs), multilamellar domains that form from the OMM and selectively sequester OMM-associated cargo, arise during metabolic perturbations associated with acute mitochondrial biogenesis, including glucose restriction, carbon-source switching, and salt stress. In these situations, MDC formation requires the energy-sensing kinase Snf1 and derepression of the transcriptional repressor Mig1, linking MDC induction to transcriptional programs that increase mitochondrial protein expression. Activation of mitochondrial biogenesis in the absence of metabolic changes is sufficient to trigger MDCs, whereas disruption of mitochondrial protein targeting and import prevents MDC formation and causes mislocalization of outer membrane cargos. Together, these findings, combined with previous observations that MDCs are induced by hydrophobic protein overexpression, mistargeting, and metabolic perturbations, support an emerging model in which MDCs function as adaptive outer-membrane remodeling domains that buffer outer membrane protein load during mitochondrial adaptation.
    DOI:  https://doi.org/10.64898/2026.06.09.731211
  32. Nat Commun. 2026 Jun 24. pii: 5564. [Epub ahead of print]17(1):
    Pseudouridine synthase PUS1 and initiation factor mtIF2 are human mitoribosomal small subunit assembly factors.
    Vivek Singh, Dmitrii Shiriaev, Lorina Bilalli, Anas Khawaja, Joanna Rorbach.
      Assembly of the mitochondrial ribosome (mitoribosome) is a crucial step in mitochondrial gene expression. This process facilitates mitochondrial translation, which produces essential subunits of the oxidative phosphorylation machinery-the cell's primary energy-producing machinery. Disruptions in mitoribosome assembly can lead to severe human diseases. Given its fundamental importance, detailed structural analysis of mitoribosome assembly pathways is essential for advancing our understanding of mitochondrial function in both health and disease. In this study, we characterize twelve distinct assembly states of the mitoribosomal small subunit (mtSSU) isolated from human cells. Our findings reveal the intricate details of the final maturation stages of the mtSSU platform, decoding center, and the 3'-end of 12S rRNA. This process is governed by coordinated actions of assembly factors that ensure precise, stepwise rRNA folding and the integration of mitoribosomal proteins into the developing subunit. Our approach identifies pseudouridine synthase PUS1 and initiation factor mtIF2 as assembly factors, expanding their known roles beyond mt-tRNA maturation and translation, respectively. In addition, the identified assembly intermediates provide insight into the modular nature of mtSSU biogenesis in mitochondria and further link late-stage assembly to the acquisition of translational competence.
    DOI:  https://doi.org/10.1038/s41467-026-74700-x
  33. Mol Biol Cell. 2026 Jun 24. mbcE25090461
    Differential effects of tropomyosin paralogs on mitochondrial dynamics in Saccharomyces cerevisiae.
    Freya Cardozo, Aakansha Paliwal, Adwaita Bose, Swagata Adhikary, Sunil Laxman, Patrick D'Silva, Saravanan Palani.
      The actin cytoskeletal network is closely associated with mitochondria and performs crucial functions in mitochondrial movement, inheritance, and fission-fusion. Although its role in mitochondrial division is established, the specific contributions of actin-binding proteins (ABPs) remain unclear. Here, we report the role of tropomyosin, an ABP, in modulating mitochondrial morphology and dynamics. We demonstrate that loss of Tpm1 and Tpm2 in Saccharomyces cerevisiae differentially alters mitochondrial morphology. Tpm1 deletion results in fragmented mitochondria, whereas Tpm2 deletion produces an elongated tubular morphology. Through live-cell imaging, we show the localization of both paralogs to mitochondria, providing direct evidence of their association with the organelle. Microscopy-based analysis of fission-fusion frequencies revealed no change in the Tpm1 deletion, whereas Tpm2 deletion showed a decrease in these events, with a concomitant increase in the fusion factor Mgm1. Further, we characterized the overall health of mitochondria in the Tpm deletion mutants. Fragmented mitochondria in the Tpm1 deletion were hyperpolarized and exhibited increased mass and activity with elevated OCR, ATP levels, and basal ROS. In contrast, the tubular morphology of the Tpm2 deletion did not impair mitochondrial health. Overall, our findings suggest that Tpm modulates mitochondrial morphology and dynamics through its association with the actin cytoskeletal network.
    DOI:  https://doi.org/10.1091/mbc.E25-09-0461
  34. Autophagy. 2026 Jun 24.
    Robust and sensitive ELISA detection of total and activated PRKN.
    Jens O Watzlawik, Bernardo A Bustillos, Claudia Rodriguez Martinez, Dennis W Dickson, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer, Fabienne C Fiesel.
      Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.
    Keywords:  Autophagy; P-S65-PRKN; PARK2; PINK1; biomarker; mitochondria; mitophagy; parkin; parkinson disease; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2026.2694658
  35. Cells. 2026 Jun 17. pii: 1101. [Epub ahead of print]15(12):
    Compensatory Intercellular Mitochondrial Transfer Improves Bioenergetics in P301L Tau-Affected Neuronal Cells.
    Aurélien Riou, Aline Broeglin, Andreas Papassotiropoulos, Anne Eckert, Amandine Grimm.
      Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of abnormal tau protein, leading to mitochondrial dysfunction. Because of neurons' high energy demands, such impairments significantly contribute to neuronal vulnerability. Recent evidence indicates that mitochondria can be transferred between cells to support energy-deficient cells through intercellular mitochondrial transfer (IMT). Given the impact of pathological tau on mitochondrial transport and cytoskeletal dynamics, we hypothesized that IMT is altered in tauopathies. We investigated IMT from astrocytes to neurons, as well as the influence of abnormal tau protein on this process, using co-cultures of SH-SY5Y cells (neuronal model) and A172 cells (astrocytic model). Key data were then confirmed in human iPSC-derived neurons and astrocytes. We show that IMT is enhanced in the presence of abnormal tau and occurs predominantly through contact-dependent mechanisms. Transferred mitochondria were either integrated into the host mitochondrial network, degraded in lysosomes, or remained isolated in the recipient cells' cytosol. This transfer improved cellular respiration and was associated with increased bioenergetics in pathological cells. Together, our results highlight IMT as a link between tau pathology and neuronal metabolic adaptation, suggesting that this process reflects an endogenous metabolic adaptation holding therapeutic potential to mitigate energy deficits in neurodegenerative diseases.
    Keywords:  astrocytes; intercellular mitochondrial transfer; mitochondria; neurons; tauopathies
    DOI:  https://doi.org/10.3390/cells15121101
  36. Nat Med. 2026 Jun 24.
    Automated reanalysis of genomic data for rare disease diagnostics at scale.
    Matthew J Welland, K D Ahlquist, Paul De Fazio, Christina Austin-Tse, Lynn Pais, Laura Wedd, Samantha Bryen, Rocio Rius, Michael Franklin, Caitlin Morrison, Giles Hall, Laura Gauthier, Alex Bloemendal, David I Francis, Andrew J Mallett, Amali Mallawaarachchi, Paul J Lockhart, Richard Leventer, Ingrid E Scheffer, Katherine B Howell, Karin S Kassahn, Hamish S Scott, Julie McGaughran, John Christodoulou, David R Thorburn, Bryony A Thompson, Chirag V Patel, Greg Smith, Anne O'Donnell-Luria, Simon Sadedin, Heidi L Rehm, Sebastian Lunke, Jeremiah Wander, Kaitlin E Samocha, Cas Simons, Daniel G MacArthur, Zornitza Stark.
      Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necessary to ensure scalability, adoption and sustainability of iterative reanalysis. We developed Talos, an open-source tool that automates variant prioritization by integrating dynamically updated gene-disease and variant-level evidence with inheritance-aware filtering and validated its performance using data from 1,089 individuals with rare disease. Trio-based analysis identified 90% of known diagnoses, returning 1.3 variants per case on average. Variant burden reduced to one variant per 200 cases on iterative monthly reanalysis. Application to an unselected cohort of 4,735 undiagnosed individuals identified 241 diagnoses (5.1% yield): 78 (32%) due to new gene-disease relationships, 54 (22%) due to new variant-level evidence and 109 (45%) due to improved analysis strategies. Our automated, iterative reanalysis model demonstrates the feasibility of delivering frequent, systematic reanalysis at scale.
    DOI:  https://doi.org/10.1038/s41591-026-04477-5
  37. EMBO Rep. 2026 Jun 22.
    E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.
    Fernando Valdivieso-Rivera, Vanessa O Furino, Carlos E Leher, Ariane M Zanesco, Monara Kaélle Cruz, Flavia C Gan, Adriana Leandra Santoro, Lara Regina-Ferreira, Giovanna Leite Santos, Tiago Gonçalves, Luiz Osório Leiria, Pedro M Moraes-Vieira, Roger Frigério Castilho, Shingo Kajimura, Marcelo A Mori, Licio A Velloso, Carlos H Sponton.
      Brown adipose tissue (BAT) counteracts obesity-related metabolic dysfunction through both thermogenic and non-thermogenic means. However, substantial evidence indicates that obesity negatively affects BAT mitochondrial morphology and oxidative capacity, impairing systemic energy homeostasis. Motivated by this apparent contradiction, we investigate the relationship between obesity and mitochondrial dynamics, as the underlying mechanisms remain incompletely understood. Here, we identify E4BP4 as a transcriptional repressor that prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction by inhibiting ceramide synthesis in brown fat. Specifically, E4BP4 interacts with PRDM16 to repress Cers6 mRNA expression and consequently reduces C16:0 ceramide levels by binding to a 65 kb upstream enhancer region of the Cers6 gene. Notably, the preservation of mitochondrial integrity in BAT by E4BP4 gain-of-function improves systemic glucose homeostasis, independent of weight loss. Collectively, our findings establish E4BP4 as a molecular safeguard against obesity-induced mitochondrial fragmentation and oxidative dysfunction, primarily by suppressing ceramide synthesis in brown fat.
    DOI:  https://doi.org/10.1038/s44319-026-00826-0
  38. Mol Cell Pediatr. 2026 Jun 22. pii: 34. [Epub ahead of print]13(1):
    Cardiomyopathy and mitochondrial encephalomyopathy in a female child associated with a heterozygous X-linked AIFM1 variant.
    Christoph Sandmann, Swathi Gudapati, Johannes A Mayr, Rami Abou Jamra, Alexander Kovacevic, Steffen Syrbe.
       BACKGROUND: AIFM1 encodes the X-linked oxidoreductase 'apoptosis-inducing factor 1, mitochondrial' that mediates caspase-independent programmed cell death and is involved in redox metabolism. To date, cardiac involvement has been reported in four patients with AIFM1 variants, primarily presenting as ventricular hypertrophy, but its clinical course and prognosis remain not well understood.
    METHODS: We report the first affected female with a heterozygous AIFM1 variant who developed infantile-onset mitochondrial encephalomyopathy and cardiomyopathy with initial ventricular hypertrophy, that progressed to left ventricular dilation and chronic heart failure. In addition, we review the available literature on AIFM1-associated cardiomyopathy to contextualize clinical findings.
    RESULTS: Genetic testing identified a heterozygous AIFM1 variant, c.506C > T (p.Pro169Leu), with extremely skewed X-inactivation (98:2) in a female. The patient presented with infantile-onset mitochondrial encephalomyopathy. Echocardiography at 8 months revealed marked left ventricular hypertrophy with preserved systolic function. During follow-up, the cardiac phenotype progressively evolved into dilated cardiomyopathy with systolic dysfunction by 2.5 years of age, necessitating initiation of heart failure therapy.
    CONCLUSIONS: A heterozygous AIFM1 variant can result in disease manifestation in females. The phenotypic spectrum of AIFM1-related disease includes cardiomyopathy, typically characterized by early-onset cardiac hypertrophy that may progress to ventricular dilatation and heart failure. This case highlights the importance of early recognition and careful cardiac monitoring in affected individuals, including female variant carriers.
    Keywords:  Cardiomyopathy; Genetic diseases; Inborn; Mitochondrial Encephalomyopathies; Mitochondrial diseases; Pediatrics; Rare diseases
    DOI:  https://doi.org/10.1186/s40348-026-00246-z
  39. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607
    Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
    Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.
      Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.
    Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2026.117607
  40. Genes (Basel). 2026 May 31. pii: 649. [Epub ahead of print]17(6):
    Expanding the Mutational Spectrum of ACADVL: Integrative Characterization of the p.Ser72Phe Variant in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
    Francesca Dinatolo, Lucia D'Antona, Radha Procopio, Valentina Rocca, Elisa Lo Feudo, Samuele Martino, Adele Dattola, Fernanda Fabiani, Emma Colao, Rosario Amato, Francesco Trapasso, Margherita Ruoppolo, Giulia Frisso, Daniela Concolino, Nicola Perrotti, Giuseppe Viglietto, Rodolfo Iuliano.
       BACKGROUND/OBJECTIVES: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of mitochondrial fatty acid β-oxidation caused by pathogenic variants in ACADVL. The clinical spectrum is highly heterogeneous, ranging from lethal neonatal cardiomyopathy to late-onset myopathy. This study aims to characterize the rare c.215C>T (p.Ser72Phe) variant, identified in compound heterozygosity with the common pathogenic allele c.848T>C (p.Val283Ala) in a male neonate detected by newborn screening (NBS).
    METHODS: Genetic analysis was performed using Sanger sequencing on the proband and his family members. The pathogenicity of the p.Ser72Phe variant was evaluated through multiple bioinformatic predictors and interpreted according to ACMG/AMP guidelines. To understand the functional impact on the protein, structural modeling was conducted using FoldX 4.0 for energy calculations and UCSF ChimeraX for the visualization of conformational changes and cofactor-binding site perturbations in the VLCAD homodimer.
    RESULTS: At the end of the first postnatal week, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of dried blood spots of the proband revealed a markedly abnormal acylcarnitine profile, with C14:1 levels (1.837 μmol/L) approximately five times above the reference range. Clinical reports documented hypoketotic hypoglycemia, consistent with VLCADD. Segregation analysis demonstrated transmission of both variants within the family, with additional heterozygous and homozygous carriers identified. Bioinformatic predictions uniformly classified p.Ser72Phe as deleterious. This variant has an extremely low allele frequency and affects a highly conserved residue in the FAD-binding domain. Structural modeling with FoldX yielded a mean ΔΔG of +22.63 ± 5.48 kcal/mol, indicating a significant localized thermodynamic burden. Inspection of the mutant model in ChimeraX showed perturbation of the side-chain orientation and attenuation of the local hydrogen-bonding network at the FAD-binding site, together with increased steric packing around residue 72. Taken together, the clinical, genetic, and structural evidence support reclassification of p. Ser72Phe as likely pathogenic according to ACMG criteria, specifically applying the ClinGen ACADVL VCEP specifications.
    CONCLUSIONS: This study expands the ACADVL mutational spectrum and underscores the value of integrating sequencing, segregation, and structural bioinformatics in interpreting rare variants detected through NBS.
    Keywords:  ACADVL; fatty acid oxidation disorders; newborn screening; p.Ser72Phe variant; very long-chain acyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.3390/genes17060649
  41. Int J Biol Sci. 2026 ;22(11): 6035-6063
    Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.
    Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Kristina Xiao Liang.
      Astrocyte dysfunction plays a pivotal role in the pathogenesis of POLG-related mitochondrial diseases, yet the underlying mechanisms remain poorly understood. Here, we employed human iPSC-derived astrocytes, cortical organoids and astrocyte-neuron co-culture systems to model POLG mutations and investigate astrocyte-mediated neurotoxicity. Single-cell transcriptomic profiling revealed a marked expansion of A1 neurotoxic astrocytes, depletion of A2 neuroprotective astrocytes, and reduction of neuronal populations in POLG organoids. A1 astrocytes exhibited transcriptional signatures of mitochondrial dysfunction, inflammatory signaling (TGF-β, JAK-STAT), impaired neuro-supportive functions, and activation of senescence, autophagy, and proteostasis stress pathways. Co-cultured dopaminergic neurons displayed impaired morphology and widespread transcriptional downregulation of mitotic, cytoskeletal, and synaptic genes, along with activation of inflammatory and ion transport pathways. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) attenuated astrocyte reactivity, reduced IL-6 and CXCL1 secretion, improved neuronal structure and synaptic marker expression, and increased mtDNA copy number and ATP production in POLG astrocytes. Our study identifies NAD⁺ augmentation as a promising strategy to mitigate astrocyte-driven pathology in mitochondrial encephalopathies.
    DOI:  https://doi.org/10.7150/ijbs.119262
  42. Stem Cell Res. 2026 Jun 19. pii: S1873-5061(26)00137-6. [Epub ahead of print]95 104041
    Dual CRISPR/Cas9 correction of compound heterozygous MARS2 mutations in the iPSC line ISMMSi060-A from a patient with COXPD25.
    Norman N Liu, Erdene Baljinnyam, Ruiqi Hu, Sophia E Salemi, Bryn D Webb, Samuele G Marro.
      We previously described the induced pluripotent stem cell (iPSC) line ISMMSi060-A derived from a patient with Combined Oxidative Phosphorylation Deficiency 25 (COXPD25) carrying compound heterozygous pathogenic variants in the mitochondrial methionyl-tRNA synthetase gene, MARS2. Here, we report the generation of the isogenic control line ISMMSi060-A-1 by CRISPR/Cas9-mediated correction of the MARS2 variants c.424C>T (p.Arg142Trp) and c.550C>T (p.Gln184*). The corrected line retained normal morphology, pluripotency, genomic integrity, and differentiation capacity, providing a valuable resource to study MARS2-related mitochondrial dysfunction and therapeutic strategies for COXPD25.
    DOI:  https://doi.org/10.1016/j.scr.2026.104041
  43. Int J Mol Med. 2026 Aug;pii: 227. [Epub ahead of print]58(2):
    Mitochondria‑endoplasmic reticulum contact site nexus: Molecular integration, disease pathogenesis and therapeutic opportunities (Review).
    Yi Liu, Xianda Che, Wei Wei, Chong Teng, Huimin Li.
      Mitochondria‑endoplasmic reticulum contact sites (MERCs) are dynamic, nanoscale membrane domains that serve as crucial signaling hubs for inter‑organellar communication. These specialized interfaces are maintained by a complex network composed of tethering, promoter, and disruptor proteins and coordinate a wide range of cellular processes, such as calcium and zinc ion homeostasis, lipid biosynthesis and transfer, redox signaling, mitochondrial dynamics (fission, fusion and mitophagy), autophagy, apoptosis, inflammation and cellular senescence. Accordingly, the structural and functional integrity of MERCs is vital for cellular adaptation and survival. Nevertheless, MERC plasticity is often impaired in various human pathologies. Alterations in MERC composition, abundance, or function are regarded as pathogenic mechanisms in neurodegenerative diseases, metabolic disorders, cardiovascular conditions, cancer and orthopedic diseases. Common manifestations of MERC dysfunction include disrupted ion signaling, bioenergetic failure, excessive oxidative stress, and impaired organelle quality control. Therefore, targeted modulation of MERCs represents a promising therapeutic avenue. However, translating this potential into clinical practice faces considerable challenges. This is because MERC function is dynamic, context‑dependent and dualistic; both excessive and deficient coupling can drive pathology. Future progress hinges on deciphering the precise regulatory codes that govern MERC assembly, developing tools for real‑time, high‑resolution in vivo analysis, and designing innovative, cell‑type‑specific interventions that normalize rather than simply inhibit or enhance MERC function. A multidisciplinary approach integrating spatial proteomics, super‑resolution imaging, and advanced disease modeling is warranted for unlocking the full diagnostic and therapeutic potential of these organelle contact sites.
    Keywords:  endoplasmic reticulum; mitochondria; mitochondrial‑associated membranes; mitochondria‑endoplasmic reticulum contact sites
    DOI:  https://doi.org/10.3892/ijmm.2026.5898
  44. Int J Neonatal Screen. 2026 Jun 04. pii: 39. [Epub ahead of print]12(2):
    A Four-Year Prospective Pilot Study of Newborn Screening for Late-Onset Proximal Urea-Cycle Disorders in Hyogo Prefecture in Japan.
    Tomoko Lee, Miki Matsui, Yoko Yokoyama, Ryosuke Bo, Hiroyuki Awano, Dai Kataoka, Masaaki Ueda, Toshinori Minato, Hironori Kobayashi, Yuki Hasegawa, Kei Murayama, Yasuhiro Takeshima.
      Proximal urea-cycle disorders (PUCDs), including N-acetylglutamate synthase deficiency (NAGSD), ornithine transcarbamylase deficiency (OTCD), and carbamoyl phosphate synthase 1 deficiency (CPS1D), cause hyperammonemia and impair neurological outcomes. Early detection of late-onset forms allows presymptomatic intervention to prevent hyperammonemia; however, reliable newborn screening (NBS) markers are lacking. This prospective pilot study in Hyogo Prefecture, Japan, evaluated hypocitrullinemia as a screening marker for late-onset PUCDs. Newborns with citrulline levels below the 0.05th percentile on NBS between June 2020 and May 2024 were enrolled in the study. Confirmatory diagnosis of PUCDs was performed using plasma amino acids, urinary organic acids, and genetic testing. During the first period (101,172 newborns), 11 newborns exhibited hypocitrullinemia; 10 underwent further evaluation. One newborn was diagnosed with CPS1D (compound heterozygous CPS1 variants); another was later diagnosed with Leigh syndrome. The remaining eight cases were false positives, often associated with prematurity, poor feeding, or gastrointestinal disorders. A second dried blood spot (DBS) card protocol was introduced in the second period (34,694 newborns), reducing false positives. One neonatal-onset OTCD case was detected, and citrulline levels were normalized in six of the seven other cases. In summary, hypocitrullinemia can identify presymptomatic PUCDs, and requesting a second DBS card reduces false positives, supporting its feasibility for incorporation into NBS programs.
    Keywords:  N-acetylglutamate synthase deficiency; carbamoyl phosphate synthase 1 deficiency; citrulline; hyperammonemia; hypocitrullinemia; inborn errors of metabolism; mitochondrial disease; newborn screening; ornithine transcarbamylase deficiency; proximal urea-cycle disorders
    DOI:  https://doi.org/10.3390/ijns12020039
  45. Front Physiol. 2026 ;17 1836651
    Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review.
    Jing Zhu, Ligang Tong, Anand Thirupathi.
      PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that orchestrates ubiquitin-dependent mitophagy together with the E3 ligase Parkin. Both physiological and pathological conditions rapidly recruit PINK1, and timely PINK1 degradation in healthy mitochondria determines whether it supports or harms the cell. Thus, the tight regulation of PINK1 balances its negative effects. In this context, introducing physical exercise as one of the strategies can fine-tune PINK1/Parkin pathways by triggering transient energy stress and moderate increases in reactive oxygen species (ROS) that promote PINK1 stabilization on the outer mitochondrial membrane, enhance Parkin recruitment via sensitizing various molecular signaling, such as AMPK-PGC-1α and FOXOs. However, the mechanism underlying a specific exercise mode that triggers PINK1-mediated selective removal of mitochondrial damage remains unknown. Therefore, this review will synthesize mechanistic approaches to how different exercise paradigms modulate PINK1 function, recruit PINK1 dynamics, and regulate downstream signaling, to define exercise prescriptions as adjunctive strategies.
    Keywords:  PINK1; Parkin; mitochondria; mitophagy; neurons; physical exercise
    DOI:  https://doi.org/10.3389/fphys.2026.1836651
  46. Mol Metab. 2026 Jun 20. pii: S2212-8778(26)00090-6. [Epub ahead of print] 102406
    Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.
    Yoshinori Osaki, Yuhei Mizunoe, Yoshimi Nakagawa, Takafumi Miyamoto, Ryo Fujita, Song-Iee Han, Masaya Araki, Masataka Tomoda, Kenta Kainoh, Hiroshi Ohno, Hitoshi Iwasaki, Takashi Matsuzaka, Hirohito Sone, Ken Ohashi, Shun Ishibashi, Motohiro Sekiya, Hitoshi Shimano.
       OBJECTIVES: Statins (HMG-CoA reductase inhibitors) are associated with myopathy, yet the precise in vivo mechanisms underlying this association remain unclear. Emerging evidence implicates a deficiency of geranylgeranyl pyrophosphate (GGPP), a key downstream isoprenoid metabolite of the mevalonate pathway. We employed novel muscle-specific genetic mouse models to elucidate the roles of GGPP and Rab geranylgeranyl transferase β (RabGGT-β) in the development of myopathy.
    METHODS: Using doxycycline-inducible Cre-LoxP technology, we generated three skeletal muscle-specific knockout (KO) models: Hmgcr-DimKO, Rabggtb-DimKO, and combined Hmgcr/Rabggtb-DimKO mice. The severity of myopathy was evaluated based on serum creatine kinase levels and histological examination. Mitochondrial mass and function were rigorously quantified. Prenylation deficit in Rabggtb-DimKO mice was confirmed via subcellular fractionation. To validate GGPP's involvement, rescue experiments were conducted using its precursor, geranylgeraniol (GGOH).
    RESULTS: Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration. Rabggtb-DimKO mice developed myopathy later than Hmgcr-DimKO mice; however, in Hmgcr/Rabggtb-DimKO mice, myopathy was dramatically accelerated and more severe. Across all models, mitochondrial dysfunction emerged early-preceding clinical signs of myopathy-consistent with a causal relationship.
    CONCLUSIONS: Our findings demonstrate that myopathy induced by HMGCR deficiency is primarily driven by GGPP depletion in a mouse model. Furthermore, impaired RabGGT-β-mediated protein geranylgeranylation represents a critical downstream mechanism that aggravates the myopathic phenotype. Early mitochondrial abnormalities may contribute to the pathogenesis of myopathy due to disruption of the mevalonate pathway.
    Keywords:  Geranylgeranyl pyrophosphate; HMG-CoA reductase; Myopathy; Rab geranylgeranyl transferase; Skeletal muscle; Slow-twitch muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102406
  47. J Physiol Biochem. 2026 Jun 23. pii: 59. [Epub ahead of print]82(1):
    The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency.
    Mikhail V Dubinin, Konstantin N Belosludtsev.
      Mitochondrial Ca²⁺ dysregulation is a central pathogenic event in skeletal muscle disorders, yet the dichotomy between overload and deficiency is often overlooked. This review summarizes mechanisms governing mitochondrial Ca²⁺ transport and sarcoplasmic reticulum-mitochondria communication. We examine prerequisites of Ca²⁺ overload, including RyR1/SERCA dysfunction and mitochondrial calcium uniporter (MCU) complex remodeling, leading to suppressed ATP synthesis, reactive oxygen species overproduction, and necrosis. Conversely, we address mitochondrial Ca²⁺ deficiency in aging, sarcopenia, and diabetes, resulting from altered MCU stoichiometry and reduced organelle tethering, causing metabolic inflexibility and impaired antioxidant defense. Additionally, therapeutic strategies limiting Ca²⁺ overload and prospects of pharmacological MCU activation to enhance bioenergetics in sarcopenia are discussed.
    Keywords:  Calcium signaling; MCU complex; Mitochondrial Ca²⁺ deficiency; Mitochondrial Ca²⁺ overload; Sarcoplasmic reticulum-mitochondria coupling; Skeletal muscle
    DOI:  https://doi.org/10.1007/s13105-026-01197-9
  48. J Cereb Blood Flow Metab. 2026 Jun 25. 271678X261465848
    EXPRESS: Intercellular Mitochondrial Transfer in Ischemic Stroke: Emerging Roles of Microglia.
    Hong Yang, Xinyu Sun, Jie Jiang, Jinzhou Yu.
      Mitochondrial dysfunction is a central driver of injury following cerebral ischemia-reperfusion, linking energy failure, oxidative stress, and inflammation. Intercellular mitochondrial transfer has been proposed as an adaptive mechanism to support metabolic homeostasis in the injured brain. While astrocyte-to-neuron transfer is supported by in vivo evidence, microglia-mediated transfer stays less well defined. Here, we review three proposed pathways: tunneling nanotube (TNT)-mediated transfer of intact mitochondria, extracellular vesicle (EV)-mediated transfer of mitochondrial components, and gap junction-associated signaling. TNT-mediated transfer is most closely associated with bioenergetic rescue, whereas EV-mediated processes primarily influence intercellular signaling. In parallel, mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial DNA, cardiolipin, and cytochrome c, can activate innate immune pathways and contribute to post-ischemic inflammation. The functional consequences of mitochondrial exchange vary according to donor-cell state, cargo integrity, and disease stage.
    DOI:  https://doi.org/10.1177/0271678X261465848
  49. Nat Aging. 2026 Jun 26.
    Meta-analysis of DNA methylation aging signatures in 17 human tissues.
    Macsue Jacques, Kirsten Seale, Sarah Voisin, Anna Lysenko, Robin Grolaux, Bernadette Jones-Freeman, Severine Lamon, Mandhri Abeysooriya, Itamar Levinger, Carlie Bauer, Adam P Sharples, Aino Heikkinen, Elina Sillanpaa, Miina Ollikainen, Cassandra Smith, James R Broatch, Navabeh Zarekookandeh, Linn Gillberg, Ida Blom, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev, Matthew Taper, Cassandra Malecki, Sean Lal, Nathalie Saurat, Steve Horvath, Andrew Teschendorff, Nir Eynon.
      Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular disorder across tissues. Network analysis revealed tightly connected gene clusters that are not modified by beneficial interventions, alongside a more modifiable cluster linked to NAD+ metabolism, supporting NAD+ as a potential therapeutic target in aging. A gene encoding a cell-adhesion protein, PCDHGA1, emerged as a conserved hub across tissues, implicating cell-to-cell communication pathways in aging across multiple organs. Our methylation atlas therefore provides a resource for dissecting the molecular basis of human aging and for identifying potential biomarkers and translational therapies.
    DOI:  https://doi.org/10.1038/s43587-026-01164-5
  50. Pharmaceutics. 2026 Jun 12. pii: 730. [Epub ahead of print]18(6):
    Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.
    Eva Costanzi, Luca Fontana, Francesca Giroldo, Silvia Coco.
      Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.
    Keywords:  extracellular vesicles; immunomodulation; mesenchymal stromal/stem cells; mitochondrial EVs; neurodegeneration; neuroinflammation; preconditioning
    DOI:  https://doi.org/10.3390/pharmaceutics18060730
  51. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731205. [Epub ahead of print]
    Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
    Austin K Murchison, Julia C Heiby, Hansen Tao, Matthew J Matrongolo, Alessandro Ori, Monther Abu-Remaileh.
      Zinc is an essential structural and enzymatic cofactor for roughly 10% of proteins, including transcription factors, metabolic enzymes, and cytoskeletal components. It also supports critical functions across organelles such as gene regulation in the nucleus, protein folding in the endoplasmic reticulum, and energy production and antioxidant defense in mitochondria. Despite these indispensable roles, the cellular mechanism that recycles zinc to maintain homeostasis during zinc deficiency remains poorly understood. Here, we identify a biphasic response to zinc limitation, which involves the rapid degradation of the zinc-storing metallothionein followed by the degradation, in an autophagy-dependent manner, of other zinc-binding proteins. We show that metallothionein is rapidly imported into the mitochondria to be degraded by the mitoprotease LONP1. Zinc starvation leads to severe mitochondrial dysfunction and metallothionein degradation allows local zinc release to alleviate nutrient stress. Our results reveal a non-canonical, mitochondria-mediated degradation pathway for a nutrient-storing protein that mobilizes zinc locally to maintain metabolic homeostasis and establish mitochondria as active hubs for nutrient recycling.
    DOI:  https://doi.org/10.64898/2026.06.09.731205
  52. Immun Ageing. 2026 Jun 23.
    An immune-associated mitochondrial DNA variant with sex differences reveals a putative novel microprotein called MASL.
    Ana R Silverstein, Thalida E Arpawong, Eileen M Crimmins, Tae Jung Oh, Rong Lu, Melanie Flores, Hiroshi Kumagai, Junxiang Wan, Hemal H Mehta, Kelvin Yen, Brendan Miller, Yeachan Lee, Anna Nogalska, Pinchas Cohen.
      The use of mitochondrial wide association studies (MiWAS) to link mitochondrial DNA variants (mtSNPs) to phenotypes of interest has uncovered important connections between mitochondrial genes and human health. The recent introduction of a re-annotated mitochondrial genome that accounts for small open reading frames (sORFs) with protein coding potential suggests the existence of mitochondrial-derived microproteins, many of which remain uncharacterized. Thus, considering the re-annotated mitochondrial genome when conducting genomic analyses such as MiWAS facilitates the mapping of mtSNPs back to microprotein-encoding sORFs and uncovers interactions between mitochondrial microproteins and biological systems. Here, we employ MiWAS of venous blood samples from the Health and Retirement Study (HRS) and identify a mtSNP associated with sex-specific changes to immune composition. After accounting for re-annotation, we map the identified mtSNP back to a sORF that encodes a novel microprotein, termed MASL (Mitochondrial Associated Small d-Loop peptide). Complementary phenome-wide association studies (PheWAS) in HRS and and UK Biobank confirm interactions between this mtSNP and immune phenotypes of interest, and our targeted RNA-Seq method (mitoSNP-seq) elucidates sex-differences in gene expression and functional pathways potentially altered by this mtSNP that may be relevant to the associated microprotein. Early characterization of the MASL microprotein shows sex-differences in circulating MASL levels in human plasma, and sex-specific interactions when comparing male and female mice treated with synthesized MASL. Together, the results of this study not only contribute to our understanding of mitochondrial dynamics in immunity, but also provide early characterization of a novel mitochondrial-derived microprotein with sex-specific modulatory effects.
    Keywords:  Genomics; Immunity; Metabolism; Mitochondria; Mitochondrial microproteins; Sex-dimorphism
    DOI:  https://doi.org/10.1186/s12979-026-00576-6
  53. medRxiv. 2026 Jun 08. pii: 2026.06.07.26354811. [Epub ahead of print]
    Multi-ancestry analysis of POLG variants in Parkinson's disease.
    Global Parkinson’s Genetics Program (GP2)
       Introduction: Variants in the polymerase gamma ( POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson's disease (PD); yet, results remain inconclusive.
    Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.
    Methods: We leveraged multi-ancestry genetic data from the Global Parkinson's Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.
    Results: Five PD cases carried potentially biallelic rare pathogenic/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.
    Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG -related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.
    DOI:  https://doi.org/10.64898/2026.06.07.26354811
  54. Clin Pract. 2026 May 27. pii: 101. [Epub ahead of print]16(6):
    Artificial Intelligence in Rare Diseases: Workflow-Integrated Precision Kidney Care.
    Charat Thongprayoon, Francesco Pesce, Wisit Cheungpasitporn.
      Rare diseases affect over 300 million individuals worldwide yet remain underdiagnosed and poorly characterized due to fragmented data, small cohorts, and phenotypic heterogeneity. Advances in artificial intelligence (AI) are enabling integration of genomics, imaging, electronic health records, and patient-generated data to support diagnosis, phenotyping, prognosis, and therapeutic discovery. In kidney care, these capabilities are reflected in tools for genomic variant prioritization, AI-assisted histopathology, and integrated risk stratification models for rare and complex kidney diseases. This review synthesizes current AI applications across the rare disease continuum and proposes a clinically grounded framework to distinguish exploratory models from systems that are methodologically robust and operationally deployable. We highlight advances that address data sparsity and heterogeneity, alongside persistent challenges in validation, generalizability, equity, and workflow integration. Finally, we outline future directions, including federated learning, digital twins, and AI-driven clinical decision agents, as pathways toward precision-guided, workflow-integrated rare disease care.
    Keywords:  artificial intelligence; clinical decision support; genomic diagnosis; nephrology; rare diseases
    DOI:  https://doi.org/10.3390/clinpract16060101
  55. BMC Bioinformatics. 2026 Jun 20.
    GPU-accelerated MitoGraph for high-throughput three-dimensional mitochondrial morphology analysis.
    Siddharth Nahar, Zichen Wang, Eric Arkfeld, Gillian McMahon, Hiroyuki Hakozaki, Johannes Schöneberg.
      MitoGraph is a widely used tool for the automated segmentation of mitochondrial networks in three-dimensional (3D) fluorescence microscopy. However, the emergence of advanced live-cell microscopes such as lattice light-sheet microscopy (LLSM) has produced massive four-dimensional (4D, 3D+time) datasets that highlight a critical bottleneck: current CPU-based implementations are computationally prohibitive, often requiring days or weeks to process. To address this limitation, we developed MitoGraph-GPU, a Python-based GPU implementation that accelerates the dominant filtering steps by vectorizing Hessian/eigenvalue and vesselness computations using CuPy, and streamlines network processing with faster skeletonization and topology analysis. Tested across budding yeast and human lung organoid datasets, MitoGraph-GPU achieves up to 11× speedup in yeast cells and 30× speedup in per-frame segmentation of lung cells. Segmentation fidelity is preserved, with  ~99.9% agreement in maximum intensity projections of segmented images, and minimal differences in downstream measurements. Critically, this throughput enables practical analysis of large 4D datasets : in an LLSM organoid use case (10 movies, 60 frames, ~ 50 cells per movie), total processing time decreases from ~ 500 h on CPU to ~ 20 h on GPU (25× faster). By producing accurate mitochondrial surfaces and skeletons, MitoGraph-GPU can serve as an efficient segmentation module for downstream mitochondrial tracking and analyses, enabling scalable high-throughput 4D mitochondrial phenotyping.
    Keywords:  Fluorescence microscopy; GPU acceleration; Image processing; Image segmentation; Mitochondria; Network analysis
    DOI:  https://doi.org/10.1186/s12859-026-06441-z
  56. Int J Biol Sci. 2026 ;22(11): 5706-5734
    Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.
    HaoQi Huang, YuLu Chen, Yi Lu, ZiLong Yuan, Ahmed Zahoor, LiPing Ren, YuanYuan Luo, BaoCai Zhong, Jian Huang, Hui Chen, Lin Ning.
      Cuproptosis and ferroptosis are two major forms of metal-dependent cell death, characterized by mitochondrial proteotoxicity and lipid peroxidation, respectively, and are broadly implicated in diverse disease contexts. Here, by integrating mechanistic, biological, and disease-associated evidence, we propose the metal-metabolism-redox vulnerability axis, which describes cellular states under metal stress as a continuous space defined by metal homeostasis, mitochondrial metabolism, and redox balance. Within this space, cuproptosis and ferroptosis correspond to distinct execution regions rather than independent processes. Building on this concept, we further establish a metallo-redox-metabolic framework to explain how key state variables and their coupling relationships determine execution bias and drive dynamic transitions between death modalities. This framework reframes metal-dependent cell death as a state-driven system rather than a collection of discrete pathways and provides a unified perspective for understanding its roles in complex diseases. In addition, we outline predictive and testable hypotheses and highlight the importance of multi-omics integration and artificial intelligence based modeling in capturing cellular state and enabling dynamic prediction. Collectively, this work provides a conceptual foundation for understanding metal-driven cell fate decisions and for developing state-oriented therapeutic strategies.
    Keywords:  bioinformatics; cuproptosis; ferroptosis; metal-dependent programmed cell death; metallo-redox-metabolic framework
    DOI:  https://doi.org/10.7150/ijbs.132221
  57. Nat Biomed Eng. 2026 Jun 23.
    Engineering drug-responsive replication machinery for precise control of self-amplifying RNA.
    Parisa Yousefpour, Justin R Gregory, Kristen Si, Jan Lonzaric, Yingzhong Li, Junmin Wang, Kashif Qureshi, Amir Ledbetter, Mariane B Melo, Alexander Hostetler, Ashley A Lemnios, Jonathan Dye, Linette Rodriguez, Tanaka K Remba, Rachel Yeung, Melissa Güereca, Yuebao Zhang, Shengwei Wu, Yizhou Dong, Ron Weiss, Darrell J Irvine.
      Precise, reversible control of gene expression from self‑amplifying RNA (saRNA) remains difficult, limiting the therapeutic flexibility of this otherwise potent platform. Although alphavirus‑derived saRNAs encode non‑structural proteins that drive RNA replication and offer an intrinsic regulatory point, no existing approach has enabled direct, drug‑dependent control of this machinery for high‑fidelity modulation of expression. Here we engineer saRNA constructs whose replication is activated by the approved small‑molecule drug trimethoprim, using drug‑responsive degradation domains fused to individual non‑structural proteins to regulate self‑amplification. As each replication protein contributes differently to RNA copying, we systematically screened fusion configurations and identified an optimal design combining modified replication proteins with a regulated payload. This construct achieved more than a 104‑fold difference between on and off states with negligible background expression. In mice, oral trimethoprim enabled tunable, reversible and temporally programmed expression patterns. When encoding a human immunodeficiency virus antigen, an escalating trimethoprim regimen enhanced germinal centre responses, a key determinant of antibody affinity maturation. This drug‑regulated saRNA platform provides a controllable and clinically compatible strategy for vaccines, immunotherapies and gene therapies.
    DOI:  https://doi.org/10.1038/s41551-026-01723-6
  58. Cells. 2026 Jun 16. pii: 1091. [Epub ahead of print]15(12):
    Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
    Mei Ma, Jialin Li, Wentao Pang, Ziyi Zhang, Yong Zhang, Hai Bo.
      Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes.
    Keywords:  Drp1; ROS; exercise; mitochondrial adaptation; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/cells15121091
  59. bioRxiv. 2026 Jun 09. pii: 2026.06.05.730515. [Epub ahead of print]
    Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.
    Katarina A Cohen, Arnav Jhawar, Gilberto Garcia, Naiara Goni, Megan Chen, Athena Alcala, Ryo Higuchi-Sanabria, Danielle L Schmitt.
      Methionine is an essential amino acid, used for protein synthesis, redox homeostasis, and methylation reactions throughout the cell. However, the compartmentalized dynamics of methionine have remained elusive, due to a lack of available tools to measure methionine with high spatial and temporal resolution. To address this limitation, we have developed a single fluorescent protein-based methionine optical reporter (Meteor) which reports subcellular changes in methionine with high dynamic range. Using Meteor, we demonstrate the subcellular uptake of methionine in multiple cell lines into several locations, including the mitochondrial matrix. Furthermore, we use Meteor to illuminate the dynamics of the methionine cycle in the cytoplasm and nucleus, finding cancer cells can rapidly increase methionine from metabolic precursors in both locations. Finally, demonstrated that Meteor can be used to visualize methionine dynamics in vivo using Caenorhabditis elegans . Thus, we have developed a new tool to measure methionine dynamics across scales with high dynamic range and spatiotemporal resolution.
    DOI:  https://doi.org/10.64898/2026.06.05.730515
  60. Hum Mol Genet. 2026 Jun 12. pii: ddag023. [Epub ahead of print]35(12):
    Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
    Rianne J Baelde, Leander A Vonk, Edgar E Nollet, Ricardo A Galli, Alexcia Fortes Monteiro, Sultan Bastu, Bornale Das, Michel van Weeghel, Bauke V Schomakers, Kasper T Vinten, Marloes van den Berg, Jolanda van der Velden, Riekelt H Houtkooper, Nicol C Voermans, Edoardo Malfatti, Coen A C Ottenheijm, Josine M de Winter.
      Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.
    Keywords:  Congenital myopathy; Mitochondria; NAD+ metabolism; Nemaline myopathy; Skeletal muscle
    DOI:  https://doi.org/10.1093/hmg/ddag023
  61. Genes (Basel). 2026 May 31. pii: 647. [Epub ahead of print]17(6):
    Multimodal Sequencing and Reanalysis Approaches to End the Diagnostic Odyssey of Individuals with Suspected Rare Monogenic Diseases.
    Catherine A Brownstein, Jill A Madden, Wanqing Shao, Casie A Genetti, Jason Chin, Vincent D Ustach, Monica H Wojcik, Anna Madden, Nathaniel Edisis, Heng Li, Daniel A Johnson, Kirsty McWalter, Jessica Noya, Klaus Schmitz-Abe, Shira Rockowitz, Pankaj B Agrawal, Scott Newman, Joseph M Devaney, Paul Kruszka, Alan H Beggs.
       BACKGROUND/OBJECTIVES: Genomic testing has transformed rare-disease diagnostics, yet a substantial proportion of individuals remain without a molecular diagnosis even after short-read exome sequencing (SR-ES) or short-read genome sequencing (SR-GS) and repeated conventional analysis.
    METHODS: To address this persistent gap, we evaluated a coordinated multimodal reanalysis framework for deeply investigated families with suspected monogenic disease. Six families (20 individuals; 8 affected individuals) that had remained unsolved after prior comprehensive testing were reviewed prospectively in weekly interdisciplinary case conferences over one year. Available data included SR-ES, SR-GS, long-read genome sequencing (LR-GS), RNA-seq, optical genome mapping, mobile-element analysis, and mitochondrial genome analysis. The goal was not to test a single modality in isolation, but to assess whether systematic escalation across complementary assays plus continued reinterpretation could improve case resolution.
    RESULTS: Three families (50%) achieved a reportable molecular diagnosis, two (33%) yielded strong candidate findings requiring additional evidence, and one (17%) remained without a definitive new molecular diagnosis, although reinterpretation of a previously identified NOTCH3 variant provided a possible partial explanation. Resolved cases included compound-heterozygous variants in KLHL40, a 119 kb multi-exon deletion in TTN, and a recurrent insertion in RNU4-2. Candidate findings included biallelic NARS2 variants and a 1.3 kb intragenic deletion involving ZEB2. Functional transcriptomic analyses supported the KLHL40 and TTN diagnoses but did not demonstrate a splicing consequence for the candidate NARS2 intronic variant in cardiac tissue.
    CONCLUSIONS: This small pilot cohort is not intended to estimate general diagnostic yield, but it demonstrates that a coordinated multimodal framework can reveal different sources of added value, including structural variant discovery, orthogonal functional support, and reinterpretation of existing short-read data as knowledge evolves. These findings underscore that archived short-read exome and genome data can retain substantial diagnostic value years after initial testing, particularly when reanalyzed with updated pipelines, expanded disease gene knowledge, and orthogonal multimodal evidence. Adoption of iterative, team-based multimodal strategies may help resolve the most complex unsolved rare-disease cases.
    Keywords:  RNA-seq; diagnostic odyssey; iterative reanalysis; long-read sequencing; multimodal genomics; rare disease; variant interpretation
    DOI:  https://doi.org/10.3390/genes17060647
  62. Front Pediatr. 2026 ;14 1816553
    A pediatric case of citrin deficiency presenting with recurrent hypertriglyceridemic pancreatitis-a case report.
    Ruyi Ye, Puhong Zhang, Yong Gu, Gang Feng, Yue Qu, Hongchuan Zhang, Wei Wei, Lizhu Huang.
      Citrin deficiency (CD) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the SLC25A13 gene, which encodes the mitochondrial aspartate-glutamate carrier 2, also known as citrin. We describe an 11-year-old Chinese boy presenting with recurrent acute pancreatitis secondary to severe hypertriglyceridemia during the FTTDCD/post-NICCD stage of citrin deficiency. The patient was relatively thin (his height and weight were at the 10th percentile on the growth curve for Chinese children), had a strong preference for soy products and an aversion to carbohydrates. Laboratory tests at presentation revealed severe hypertriglyceridemia (28.96 mmol/L), with a previously documented peak of 30.35 mmol/L. Abdominal computed tomography showed diffuse pancreatic enlargement and peripancreatic inflammatory changes, which, together with compatible abdominal pain, supported the diagnosis of acute pancreatitis. Genetic sequencing identified compound heterozygous pathogenic mutations in the SLC25A13 gene (exon 9: c.852_855delTATG; intron 6: c.615+5G > A). Plasma ammonia and citrulline levels were within normal limits. All of these findings supported a diagnosis of failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) in the post-NICCD phase. Management involved plasma exchange, a high-protein/high-fat/low-carbohydrate diet, and medium-chain triglyceride (MCT) supplementation, leading to clinical improvement. However, poor dietary adherence during follow-up resulted in two readmissions for recurrent pancreatitis. This case highlights that citrin deficiency should be considered in children with recurrent acute pancreatitis associated with severe hypertriglyceridemia, especially when accompanied by carbohydrate aversion and unusual dietary preferences, even in the absence of hyperammonemia or hypercitrullinemia.
    Keywords:  SLC25A13 gene; citrin deficiency; failure to thrive and dyslipidemia caused by citrin deficiency; hypertriglyceridemia; hypertriglyceridemic pancreatitis
    DOI:  https://doi.org/10.3389/fped.2026.1816553
  63. J Adv Res. 2026 Jun 22. pii: S2090-1232(26)00508-4. [Epub ahead of print]
    A α-synuclein aggregation inhibitor exerts neuroprotective effects via mitochondrial resilience in Parkinson's disease.
    Ye Peng, Junrui Ye, Hongyun Wang, Shasha Wang, Wenfei Wang, Xu Yan, Shifeng Chu, Ruifang Zheng, Zhao Zhang, Naihong Chen.
       INTRODUCTION: The pathogenesis of Parkinson's disease (PD) is driven by a vicious cycle of α-synuclein (α-Syn) aggregation and mitochondrial collapse. Breaking this pathogenic loop requires disease-modifying therapeutics capable of destabilizing the toxic structural core of α-Syn while simultaneously rescuing bioenergetic failure, highlighting an urgent need for novel dual-action neuroprotective agents.
    OBJECTIVES: To identify and characterize A14, a novel small-molecule modulator, and evaluate its dual capacity to inhibit α-Syn fibrillization and mitigate downstream mitochondrial deficits in PD.
    METHODS: Structure-based virtual screening was employed to identify A14 as a targeted inhibitor of the α-Syn fibril β-sheet interface. Its biophysical mechanisms were elucidated using multi-dimensional structural assays. In cellular models and A53T α-Syn transgenic mice, systematically evaluated the therapeutic efficacy, wherein transcriptomics and transmission electron microscopy were adopted to detect mitochondrial integrity, and functional magnetic resonance imaging (fMRI) together with electrophysiology were utilized for the assessment of nigral circuit function.
    RESULTS: A14 binds the β-sheet core of α-Syn fibrils with high affinity (Kd = 27.9 ± 2.16 nM), significantly reducing β-sheet content from 21.4% to 9.3% and redirecting the aggregation trajectory into small (< 20 nm), protease-sensitive intermediates. In neuronal models, A14 robustly reduced intracellular α-Syn inclusions via direct biophysical modulation, independent of major proteostasis pathways. In vivo, A14 disrupted the pathological interaction between α-Syn and mitochondria, rescuing cristae ultrastructure, oxidative phosphorylation, and overall bioenergetics. This coordinated restoration of proteostasis and mitochondrial function prevented dopaminergic neuron loss, normalized cortico-basal ganglia-nigral functional connectivity, and significantly ameliorated motor deficits in A53T transgenic mice.
    CONCLUSIONS: Our findings demonstrate that the A14 engages complementary mechanisms to inhibit α-Syn aggregation and rescue mitochondrial deficits. This dual action stabilizes proteostasis and sustains mitochondrial functionality, nominating A14 as a promising therapeutic candidate for the treatment of PD.
    Keywords:  Mitochondria dysfunction; Parkinson’s disease; Small molecule; α-Synuclein
    DOI:  https://doi.org/10.1016/j.jare.2026.06.026
  64. Mol Genet Metab. 2026 Jun 22. pii: S1096-7192(26)00480-4. [Epub ahead of print]148(4): 110197
    High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.
    Andrea S Pereyra, Filip Jevtovic, Adam J Amorese, Chien-Te Lin, P Darrell Neufer, Espen E Spangenburg, Jessica M Ellis.
      Carnitine palmitoyltransferase 2 (CPT2) deficiency is an inherited autosomal recessive disorder of fatty acid oxidation, which commonly manifests in adolescences and adulthood as muscle weakness and recurrent rhabdomyolysis, limiting physical activity and compromising quality of life. Despite the recognition and avoidance of known triggers such as exercise, fasting, and stress, many patients suffer unexplained periodic episodes of muscle breakdown. While avoidance of fatty meals is recommended, the impact of high-fat consumption alone on muscle biology of CPT-deficient patients is not well defined. Mice with muscle specific CPT2-deletion (Cpt2Sk-/-) and control littermates, were placed on control or high-fat diet (HFD) (60% kcal) for up to 8 weeks. Muscle contractility, transcriptional and protein signatures, mitochondrial metabolic capacity, and histopathology were determined. After 8 weeks on the diet, Cpt2Sk-/- ex vivo muscle force production was significantly reduced by high-fat feeding in the glycolytic EDL and oxidative soleus muscles. In response to HFD, Cpt2Sk-/- muscle mitochondrial respiratory capacity was significantly reduced, despite increased mitochondrial biogenesis, across various muscles. Importantly, HFD further deteriorated the structural integrity of oxidative soleus muscle in CPT2-deficient mice, characterized by reduced fiber size and the presence of ragged red fibers. Together, these data indicate that chronic high dietary fat intake exacerbates the underlying mitochondrial and myopathic dysfunction caused by CPT2 deficiency. This diet-induced worsening of muscle pathology may provide a mechanistic explanation for the symptom exacerbation experienced by individuals with CPT2 deficiency following fatty food consumption.
    Keywords:  Carnitine palmitoylcarnitine transferase 2; Contraction; Fatty acid oxidation disorders; High-fat diet; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110197
  65. bioRxiv. 2026 Jun 12. pii: 2026.06.11.731694. [Epub ahead of print]
    Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
    Andrea L Cote, Claire L McIntyre, Joshua A Acklin, Lillian R Delacruz, Yunping Qiu, Irwin J Kurland, Alison E Ringel.
      Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8 + T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.
    DOI:  https://doi.org/10.64898/2026.06.11.731694
  66. Chem Sci. 2026 Jun 11.
    Reversible one-step acylation facilitates mitochondrial delivery of functional RNA.
    Yuli Zhuang, Xia Liu, Yuxuan Shen, Qiuyue Wang, Zhimin Lin, Qian Zeng, Xin Chen, Linye Jiang, Shao Q Yao, Jingyan Ge.
      Mitochondria-targeted RNA therapeutics hold promise for treating mitochondrial disorders and cancer, yet effective mitochondrial gene modulation remains challenging due to the strong negative charge and intrinsic instability of RNA, which hinder transport across the mitochondrial double membrane. Herein, we demonstrate, for the first time, mitochondrial RNA delivery enabled by reversible 2'-hydroxyl (2'-OH) acylation chemistry. Installation of a triphenylphosphonium (TPP)-bearing acyl group at the RNA 2'-OH in a single step creates a plug-and-play platform that simultaneously enhances RNA stability and directs selective mitochondrial accumulation, while allowing spontaneous recovery of native RNA structure and activity. In cell-based assays, this strategy enables efficient and selective silencing of mitochondria-encoded genes with minimal off-target effects. Importantly, in vivo delivery of siND1 selectively suppresses MTND1 expression without affecting MTCO1 and significantly inhibits tumor growth in a xenograft model. Conclusively, this work establishes reversible RNA acylation as a simple and versatile chemical framework for mitochondrial RNA delivery and therapy.
    DOI:  https://doi.org/10.1039/d6sc01497f
  67. medRxiv. 2026 Jun 11. pii: 2026.06.09.26355279. [Epub ahead of print]
    Population-scale detection of methylation outliers from long-read genome sequencing.
    Undiagnosed Diseases Network, Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium
       Background: Aberrant DNA methylation can mediate the functional effects of rare genetic variation and contribute to imprinting disorders, repeat expansion diseases, and other pathogenic regulatory mechanisms. Long-read sequencing technologies now enable genome-wide detection of CpG methylation alongside genetic variation from a single assay. However, methods for systematic identification and interpretation of methylation outliers from long-read sequencing data remain limited.
    Methods: We developed METAFORA, a computational workflow for detecting methylation outlier regions from PacBio and Oxford Nanopore long-read sequencing data. METAFORA constructs population-level methylation references, segments the genome into correlated CpG blocks, infers technical and biological sources of variation through hidden factor estimation, models uncertainty due to variable depth sequencing, and computes covariate-adjusted methylation outlier scores for individual samples. We applied METAFORA across large long-read sequencing cohorts and integrated methylation outliers with multi-omic data. METAFORA is implemented as a snakemake workflow available at https://github.com/tjense25/METAFORA .
    Results: METAFORA identified methylation outlier regions associated with rare structural variants, tandem repeat expansions, and imprinting abnormalities. We found outlier regions were enriched for molecular outliers across transcriptomic and chromatin accessibility datasets, supporting their functional relevance in gene regulation. In a representative case, METAFORA identified an imprinting defect affecting the GNAS locus associated with an STX16 deletion.
    Conclusions: METAFORA enables scalable detection and interpretation of methylation outliers from long-read sequencing data and provides a framework for integrating epigenetic outliers with genomic and multi-omic analyses. These approaches may improve interpretation of rare regulatory variation and support discovery of clinically relevant epigenetic abnormalities in genomic medicine.
    DOI:  https://doi.org/10.64898/2026.06.09.26355279
  68. Nature. 2026 Jul;655(8121): 26-28
    CRISPR's next act: the companies editing the epigenome to treat disease.
    Roxanne Khamsi.
      
    Keywords:  CRISPR-Cas9 genome editing; Epigenetics; Gene therapy; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-01976-w
  69. EMBO J. 2026 Jun 26.
    Assembly of the catalytic module and the rotor of human ATP synthase.
    Jiuya He, Joe Carroll, Shujing Ding, Jiao Li, Ian M Fearnley, John E Walker.
      Human ATP synthase is a molecular rotary machine bound in inner mitochondrial membranes, built from twenty-eight subunits of seventeen kinds, two encoded in mitochondrial DNA, the remainder in nuclear genes. The machine consists of a rotor and an interacting stator. Turning of the rotor driven by a transmembrane proton motive force effects a cycle of structural changes in the catalytic part of the stator, producing three ATP molecules per rotation. Here, to establish how the stator and rotor are assembled, we deleted subunits and known assembly factors from human cells, purified and accumulated assembly intermediate complexes, and characterized them by gel analysis and mass spectrometry, allowing us to propose pathways of assembly of the rotor and the catalytic F1-module of the stator. These observations provide opportunities for further development by structural analysis of the accumulated intermediates. The compositions of the various assembly intermediates support the view that ATP synthase arose via independent evolution of its three constituent structural components, the catalytic F1-module, the peripheral stalk module, and the membrane-associated Fo-module.
    DOI:  https://doi.org/10.1038/s44318-026-00842-9
  70. Genes (Basel). 2026 Jun 22. pii: 723. [Epub ahead of print]17(6):
    Generative AI and Language Models in Human Genetics and Health: From Variant Interpretation to Clinical Decision Support.
    Yael Pinchevsky Itan, Yuval Itan.
      Generative artificial intelligence (AI) is transforming biological and medical research and data analysis. Beyond analyzing existing information, these models can learn complex patterns and generate new data such as realistic protein sequences, genetic variants, or clinical notes. In molecular biology, language-like sequence models can read and generate DNA, RNA, and amino acid sequences to predict genetic variant effects, design new proteins, and explore molecular functions. In medicine, large language models (LLMs) trained on biomedical literature and electronic health records (EHRs) can summarize clinical findings, identify patterns, and provide decision support for clinicians and healthcare providers. Additionally, synthetic data generation can help protect patient privacy and augment existing disease datasets. While these advances make tasks that were previously impractical possible at scale, they also carry major risks, including producing convincing but incorrect results, reflecting hidden biases in the training data, and underperforming when real-world conditions change.
    Keywords:  clinical decision support; clinical genomics; electronic health records; generative artificial intelligence; genomic language models; large language models; protein design; retrieval-augmented generation; synthetic health data; variant interpretation
    DOI:  https://doi.org/10.3390/genes17060723
  71. J Appl Genet. 2026 Jun 27.
    Analysis of genetic risk factors for Leber hereditary optic neuropathy in the Polish population.
    Julia Sikorska, Maciej R Krawczyński, Magdalena Korwin, Monika Ołdak, Ewa Bartnik, Katarzyna Tońska, Agnieszka Piotrowska-Nowak.
      Leber hereditary optic neuropathy (LHON) is primarily caused by pathogenic mitochondrial DNA (mtDNA) variants, most commonly the m.11778G>A variant in the MT-ND4 gene. The presence of this variant alone is insufficient to trigger disease symptoms, of which vision loss is the hallmark. Given the incomplete penetrance and inter-population variability in modifying factors, this study aimed to investigate two previously proposed genetic risk factors for LHON in the Polish population. Using quantitative PCR, we measured the mtDNA copy number in peripheral blood of affected and unaffected carriers of the m.11778G>A variant. In addition, we assessed the frequency of the PRICKLE3 c.157C>T variant in symptomatic, asymptomatic and control individuals using PCR-RFLP. Our results indicate that mtDNA copy number was not associated with LHON symptom manifestation in the Polish cohort under conditions tested, in contrast to previously reported associations in other populations. In addition, the PRICKLE3 c.157C>T variant was absent in our cohort, indicating that it is not a common modifier of LHON penetrance in the Polish population. These findings suggest that the incomplete penetrance of LHON in the Polish population may involve other modifying factors, such as yet unidentified nuclear DNA variants.
    Keywords:   PRICKLE3 ; LHON; Penetrance; Polish population; mtDNA copy number; qPCR
    DOI:  https://doi.org/10.1007/s13353-026-01090-7
  72. J Peripher Nerv Syst. 2026 Sep;31(3): e70136
    De Novo MFN2 p.Arg95Met in Severe Charcot-Marie-Tooth Disease Type 2A.
    Hsi-Yen Lee, Wen-Ling Cheng, Shin-Hung Pan, Chia-Ju Lee, Yau-Huei Wei, Chin-San Liu.
       BACKGROUND AND AIMS: Mitofusin 2 (MFN2)-related Charcot-Marie-Tooth disease type 2A (CMT2A) is often associated with early onset, severe progressive weakness, distal wasting, and reduced motor and sensory response amplitudes.
    CASE REPORT: We report a 30-year-old Taiwanese woman with infancy-onset, severe axonal sensorimotor neuropathy, progressive distal weakness and wasting, optic atrophy, bilateral sensorineural hearing loss, hypophonia, and wheelchair dependence from adolescence. Nerve conduction study was consistent with severe chronic axonal sensorimotor polyneuropathy. Whole-exome sequencing identified a heterozygous de novo Mitofusin 2 (MFN2) variant, NM_014874.4:c.284G>T, predicting p.Arg95Met.
    INTERPRETATION: This case expands the genotypic spectrum of MFN2-related Charcot-Marie-Tooth disease type 2A and supports the clinical importance of the Arg94/Arg95 region in severe early-onset MFN2 neuropathy.
    Keywords:  Charcot–Marie–tooth disease type 2A; MFN2; optic atrophy; p.Arg95Met; sensorineural hearing loss
    DOI:  https://doi.org/10.1111/jns.70136
  73. J Immunol. 2026 Jun 07. pii: vkag147. [Epub ahead of print]215(6):
    Mechanisms and functions of intercellular mitochondria transfer to and from macrophages.
    Wentong Jia, Jonathan R Brestoff.
      Cell-to-cell communication is essential for maintaining homeostasis and coordinating complex biological processes in multicellular organisms. Classically, cells communicate using secreted peptides and metabolites and through cell contact-dependent signaling. Emerging studies over the past 20 years indicate that many cell types, including innate immune cells such as macrophages, participate in a process called intercellular mitochondria transfer, in which macrophages either donate their own mitochondria to other cells or accept mitochondria originating from another cell type. This raises the intriguing possibility that macrophages use mitochondria transfer as a mechanism of cell-to-cell communication. In this review, we describe the distinct mechanisms and functional roles of mitochondria transfer in macrophages across different organ systems and highlight how this biology contributes to health maintenance and disease pathogenesis.
    Keywords:  acceptor; cell-to-cell communication; donor; intercellular mitochondria transfer; macrophage
    DOI:  https://doi.org/10.1093/jimmun/vkag147
  74. Adv Exp Med Biol. 2026 ;1514 255-298
    Enzyme Assemblies in Nucleotide Metabolism: Structure, Regulation, and Disease Implications.
    Jack P Boylan, Timothy D Iles, Alexis Nguyen, Anthony M Pedley.
      Nucleotide biosynthesis is essential for cell growth and relies on the coordination of both salvage and de novo pathways to satisfy intracellular needs. While traditionally, the regulation of these pathways has been attributed to factors like substrate availability, genetic rewiring, and metabolite-driven feedback inhibition, recent findings have unveiled a new, more complex layer of regulation. Enzymes within these pathways assemble into dynamic supramolecular protein assemblies, such as metabolons and filaments, which findings suggest might influence enzymatic activity and regulate nucleotide flux. Advances in fluorescence microscopy and cryo-electron microscopy have enhanced our ability to characterize the spatial and temporal dynamics, as well as the biophysical properties, of these assemblies. In this chapter, we explore the diverse higher-order purine and pyrimidine metabolic enzyme assemblies, highlight how state-of-the-art microscopy has transformed our understanding of their structures and regulatory roles in nucleotide biosynthesis, and discuss their implications in human disease.
    Keywords:  Biomolecular condensates; Filaments; Metabolism; Metabolon; Nucleotide; Protein complexes; Purine; Pyrimidine; Regulation
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_10
  75. Orphanet J Rare Dis. 2026 Jun 24.
    Implementation of a medical genomics program for rare diseases in Uruguay.
    Camila Simoes, María Fernanda Domínguez, Soledad Rodriguez, Mariana Moraes, María Paula Frade, Mariana Brandes, Martín Graña, Lucía Sosa, Santiago Fontenla, Alejandra Tapié, Nicolás Dell'Oca, Olaf Riess, José Tort, Hugo Naya, Víctor Raggio, Lucia Spangenberg.
       BACKGROUND: Rare diseases (RDs) affect an estimated 7% of the global population and comprise ~7,000 heterogeneous conditions, most of which have a genetic etiology. Despite their collective burden, RDs pose major diagnostic challenges, often resulting in prolonged diagnostic odysseys with substantial clinical, emotional, and economic consequences. Next generation sequencing technologies such as whole exome (WES) and whole genome sequencing (WGS) have transformed RD diagnostics in high-resource settings. In contrast, the use of such technologies in Latin America remains uneven due to structural, regulatory, and economic constraints. In addition, the underrepresentation of admixed populations in genomic databases further complicates variant interpretation, reducing the diagnostic yield. In this context, we created the first genomic medicine program for rare diseases in Uruguay to address these challenges by implementing next-generation sequencing (NGS) strategies for diagnosis.
    MATERIAL AND METHODS: Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed on a cohort of 203 patients with suspected RD belonging to the Uruguayan public healthcare system. Variant prioritization was conducted using established bioinformatics pipelines integrating population frequency filtering, inheritance models, functional impact, and phenotype-driven clinical interpretation. Implementation of population-aware variant interpretation strategies was critical in this admixed population, helping to reduce false-positive findings arising from the underrepresentation of Latin American populations in global reference databases. This framework was built through sustained collaboration between academic institutions and healthcare providers, with a strong emphasis on local capacity building in clinical genetics, molecular diagnostics, and bioinformatics.
    RESULTS: To date, we have analyzed a total of 203 patients: 172 using WES, 29 using WGS, and 11 using mitochondrial DNA sequencing (9 of whom were also analyzed by WES). The overall diagnostic yield was 48% for WES and 31% for WGS. The program significantly shortened diagnostic trajectories and enabled actionable clinical insights in a substantial proportion of cases.
    CONCLUSIONS: Our experience shows that comprehensive genomic diagnostics for RDs can be successfully carried out in emerging genomic medicine settings through integrated workflows and sustained investment in human capital. This initiative represents a scalable model for other low income countries seeking to incorporate genomic medicine into public healthcare systems and highlights the importance of regional genomic data to improve diagnostic accuracy and equity.
    Keywords:  Exome sequencing; Genetic diagnostic; Genome sequencing; Medical genomics; Rare diseases
    DOI:  https://doi.org/10.1186/s13023-026-04387-2
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒28 at 9:12.