bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–07–26
sixty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
  2. Delineation and Phenotypic Expansion of TOP3A-Related Mitochondrial Disease in Childhood.
  3. Biallelic SCO2 Variants Presenting as Motor-Predominant Axonal Neuropathy With Complex IV Deficiency.
  4. Molecular Mechanisms Underlying FCCP-Induced Mitophagyin Human Airway Smooth Muscle Cells.
  5. Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
  6. Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.
  7. Immune Modulatory Therapy for Severe Dengue Hemorrhagic Fever in a Patient With Mitochondrial Complex I Deficiency: A Case Report.
  8. Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
  9. TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
  10. Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
  11. Quantum-Informed Perspectives on Mitochondrial Bioenergetics and Redox Signaling in Cardiovascular Disease.
  12. Mitochondrial capsules: A revolutionary organelle therapy for mitochondrial and neurodegenerative diseases.
  13. VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
  14. HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
  15. The power of one: The unexpected benefits of correcting a single tissue in multisystem mitochondrial disease.
  16. The long road to a rare diagnosis: A Malaysian case of childhood-onset progressive myoclonus, ataxia, and retinal dystrophy with biopsy features suggestive of mitochondrial dysfunction.
  17. Distinct sources and effects of mitochondrial reactive oxygen species.
  18. Mitochondrial translation termination, recycling, reinitiation, and rescue for in-frame and out-of-frame contexts.
  19. Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism.
  20. Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure.
  21. Cellular thermal shift assay of subcellular isolates to evaluate drug-membrane target interactions.
  22. 3D nanoscale reconstruction of human airway multiciliogenesis reveals cellular architecture remodeling and cilia-mitochondria link via rootlets.
  23. Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
  24. Mitochondrial engineering strategies in yeast cell factories.
  25. A Homozygous Founder ELAC2 Variant in Kuwaiti Infants With Fatal Cardiomyopathy and Refractory Severe Lactic Acidosis: A Retrospective Review of the Clinical, Cardiological and Molecular Findings.
  26. Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
  27. SMCP Maintains ROS Homeostasis During Sperm Mitochondrial Sheath Assembly.
  28. Mitochondrial carbonic anhydrases VA and VB: Metabolic roles and clinical significance.
  29. Mathematical Modelling of the Mitochondrial Dicarboxylate Carrier (SLC25A10).
  30. LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy.
  31. Aglycemia triggers alternative electron transport to sustain mesenchymal stem cell survival under anoxia.
  32. Mito-interpreter: An online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of mitochondrial DNA variants.
  33. ER-mitochondria contact sites and organelle stress in asthma.
  34. Toward a comprehensive modification landscape of yeast mitochondrial tRNAs using Nanopore direct RNA sequencing and dihydrouridine sequencing.
  35. Tubulin autoregulation tunes microtubule dynamics to support multicellular architecture and viability.
  36. Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.
  37. Disrupted Mitochondrial Quality Control in Atherosclerotic Disease: Mitophagy and Dynamics in Focus.
  38. SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair.
  39. Mitochondria poor but capacity rich? The paradox of podocyte respiration.
  40. A Case of Paroxysmal Exercise-Induced Dyskinesia Expands the Phenotypic spectrum of NAXE-Related Encephalopathy.
  41. TOP3A pathogenic variants presenting as dilated cardiomyopathy and heart failure in three pediatric cases.
  42. Systematic reanalysis of next-generation sequencing data in 101 neuromuscular disorder families enhances diagnostic yield, reveals intronic variants, and identifies a novel disease gene.
  43. Miro1-mediated mitochondrial transfer boosts stem cell therapy for muscle atrophy via restoring mitochondrial homeostasis.
  44. Fly neurons carry a molecular 'timestamp' that encodes their birth order.
  45. Human genetics across levels of biological organization.
  46. Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
  47. Large-scale Whole-Exome Sequencing Defines the Protein-Coding Architecture of Retinal Structure, Visual Function, and Major Blinding Diseases.
  48. Evaluating cases of possible insertional mutagenesis after AAV gene therapy.
  49. Mitochondrial tRNA biogenesis, modifications and disease relevance.
  50. Personalized gene therapy relieves severe epilepsy in two boys.
  51. Unraveling missing variants through target capture-based long-read sequencing in autosomal recessive disorders.
  52. CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to Nicotinamide Mononucleotide (NMN)-Induced Expression Rescue in Metabolic Tissues.
  53. Reprogramming Glial Cell Metabolism via a tRNA Fragment Preserves Vision in Retinal Neurodegeneration.
  54. SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.
  55. SelO-mediated NAD+ hydrolysis safeguards mitochondrial homeostasis.
  56. Variant Curation and Classification in Rare Disease Genomics: Standards and Emerging Tools for Single-Nucleotide Variant Analysis.
  57. Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.
  58. Numerical simulation of mitochondrial systems for ATP generation and membrane transport.
  59. Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
  60. Epigenetic and 3D genome reprogramming during the aging of the human hippocampus.
  61. Microbiome-associated metabolites, valerobetaine and homocarnitine, inhibit carnitine transport via OCTN2.
  62. A scalable plate reader-based protocol to measure mitochondrial respiration in embryonic hearts.
  63. Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
  64. Mitochondrial stress-induced cuproptosis: a metabolic bridge to reprogramming the GBM immune microenvironment.
  65. The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.
  66. Patients' lived experience of thymidine kinase 2 deficiency: the online survey-based assessment of TK2d patient perspectives study.
  1. JCI Insight. 2026 Jul 22. pii: e199182. [Epub ahead of print]11(14):
    Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
    David Alsina, Diana Rubalcava-Gracia, Kristina Bubb, Rodolfo Garcia-Villegas, Akos Vegvari, Roberta Filograna, Florian A Rosenberger, Camilla Koolmeister, Nils-Göran Larsson.
      Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.
    Keywords:  Cell biology; Metabolism; Mitochondria; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.199182
  2. Am J Med Genet A. 2026 Jul 20.
    Delineation and Phenotypic Expansion of TOP3A-Related Mitochondrial Disease in Childhood.
    Rodrigo T Starosta, Marisa W Friederich, Graeme Preston, Lily Walson, Julie Hong Yin, Steven Lang, Hanna J Tadros, Yue Wang, Elizabeth Mizerik, David Mirsky, Daniella H Hock, David A Stroud, Rossana Sanchez Russo, Fernando Scaglia, Eva Morava, Johan L K Van Hove.
      TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.
    Keywords:  Leigh disease; TOP3A; cardiac transplantation; cardiomyopathy; helicase; mitochondrial DNA maintenance
    DOI:  https://doi.org/10.1002/ajmg.a.70248
  3. J Peripher Nerv Syst. 2026 Sep;31(3): e70150
    Biallelic SCO2 Variants Presenting as Motor-Predominant Axonal Neuropathy With Complex IV Deficiency.
    Adriana P Rebelo, Katie Lutz, Tiffany Grider, Craig M Zaidman, Michael E Shy, Stephan Zuchner.
       BACKGROUND AND AIMS: SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor-predominant axonal neuropathy presentation associated with biallelic SCO2 variants.
    METHODS: Clinical, genetic, and functional studies were performed in a 15-year-old female presenting with axonal neuropathy. Functional studies were conducted in patient-derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX.
    RESULTS: The patient presented with a motor-predominant axonal neuropathy consistent with Charcot-Marie-Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient-derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss-of-function mechanism.
    INTERPRETATION: These findings demonstrate that SCO2-related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.
    DOI:  https://doi.org/10.1111/jns.70150
  4. Am J Physiol Lung Cell Mol Physiol. 2026 Jul 23.
    Molecular Mechanisms Underlying FCCP-Induced Mitophagyin Human Airway Smooth Muscle Cells.
    Sanjana Mahadev Bhat, Oscar A Ramirez Ramirez, Gary C Sieck.
      Mitophagy is a selective autophagic process that eliminates damaged mitochondria, which is essential for mitochondrial quality control and cellular homeostasis. The most extensively characterized mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane (OMM), where it recruits and phosphorylates Parkin at serine 65 (pParkinS65), activating its E3 ligase activity. Active pParkinS65 initiates the ubiquitination (Ub) of OMM proteins resulting in the engulfment and lysosomal degradation of damaged (depolarized) mitochondria. Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial uncoupler, is widely used to experimentally induce mitochondrial depolarization and initiate PINK1-Parkin-dependent mitophagy; however, mitophagic responses to FCCP vary across cell types. In the present study, we hypothesized that, in human airway smooth muscle (hASM) cells, FCCP-induced mitochondrial depolarization activates the PINK1-Parkin-mediated mitophagy pathway, culminating in the clearance of damaged mitochondria. We observed that exposing hASM cells to 1 µM FCCP for 6 h induced mitochondrial depolarization and a decrease in the volume of intact mitochondria. This mitochondrial depolarization triggered the accumulation of PINK1 in the mitochondria, which mediated phosphorylation of pParkinS65 and an increase in pUbS65 proteins. Confocal imaging of labeled mitochondria and lysosomes demonstrated increased colocalization of mitochondria with lysosomes, and mitophagic flux was confirmed using a pH-sensitive mitochondrial reporter mKeima. Collectively, these findings demonstrate that FCCP robustly activates the canonical PINK1-Parkin mitophagy pathway in hASM cells, providing mechanistic insight into mitochondrial quality control, with potential relevance to airway diseases characterized by mitochondrial dysfunction and altered hASM function.
    Keywords:  FCCP; Mitochondrial Quality Control; Mitophagy; PINK1; Parkin
    DOI:  https://doi.org/10.1152/ajplung.00050.2026
  5. J Neurol Sci. 2026 Jul 13. pii: S0022-510X(26)00377-1. [Epub ahead of print]489 126095
    Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
    Giulia Ferrera, Federica Invernizzi, Manuela Spagnolo, Eleonora Lamantea, Isabella Moroni, Anna Ardissone.
       OBJECTIVE: Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking.
    METHODS: We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed.
    RESULTS: Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1).
    INTERPRETATION: Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.
    Keywords:  Complex I; Leukoencephalopathy; Mitochondrial disorders; Riboflavin; Treatable
    DOI:  https://doi.org/10.1016/j.jns.2026.126095
  6. Mitochondrion. 2026 Jul 22. pii: S1567-7249(26)00085-1. [Epub ahead of print] 102195
    Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.
    Ismail Gouiza, Aymane Bouzidi, Meriem Hechmi, Majida Charif, Abir Zioudi, Nadia Kheriji, Hela Boudabous, Mouna Zribi, Safa Khatrouch, Raoudha Kebaili, Ilhem Ben Youssef-Turki, Mediha Trabelsi, Slim Abdelmoula, Ichraf Kraoua, Amel Ben Chehida, Rym Kefi, Guy Lenaers.
      Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.
    Keywords:  Bioinformatic analysis; Genetic diagnosis; Leigh syndrome; Mitochondrial diseases; North Africa; Tunisia
    DOI:  https://doi.org/10.1016/j.mito.2026.102195
  7. Am J Med Genet A. 2026 Jul 24.
    Immune Modulatory Therapy for Severe Dengue Hemorrhagic Fever in a Patient With Mitochondrial Complex I Deficiency: A Case Report.
    Audra N Iness, Ameya S Walimbe, Emily R Strouphauer, Michio Hirano, Alejandro D Iglesias, Valentina Emmanuele, Caitlin C Griffin, Sheldon L Kaplan, William A Gomes, Karen K Moeller, Stephen F Kralik, Fernando Scaglia.
      Dengue virus (DENV) poses a serious global health challenge, particularly in cases of dengue hemorrhagic fever (DHF). Patients with preexisting mitochondrial disorders may be at increased risk for complications due to the specific impact of DENV on mitochondrial-dependent cellular processes and immune function. We describe a 16-year-old male with known mitochondrial complex I deficiency caused by a homozygous likely pathogenic variant in NDUFV1 who subsequently developed DHF. His illness was marked by rapidly worsening weakness, respiratory distress, intracranial hemorrhage, and seizures. His clinical course was further complicated by encephalitis, arachnoiditis, and myelitis requiring extensive immunomodulation. He received corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange (PLEX), which led to improvement and partial recovery of functional status. This case highlights several rare complications of dengue fever, the impact of DENV on mitochondrial function, and underscores the complexity of managing infectious diseases in individuals with underlying mitochondrial disorders.
    Keywords:  Leigh syndrome; dengue hemorrhagic fever; dengue virus; mitochondrial disease
    DOI:  https://doi.org/10.1002/ajmg.a.70258
  8. Nucleic Acids Res. 2026 Jul 17. pii: gkag720. [Epub ahead of print]54(14):
    Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
    Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.
      Accurate replication of the mitochondrial genome (mtDNA) depends on DNA polymerase γ (Pol γ), yet its strand-displacement activity has been reported with varying outcomes across studies. Here we show that human Pol γ carries out robust, processive strand-displacement synthesis under physiological divalent metal-ion concentrations. We identify two functional classes of metal-binding sites: high-affinity sites that support DNA synthesis and unwinding, and low-affinity sites that selectively suppress unwinding without impairing polymerase activity. Pol γ efficiently displaces DNA/DNA duplex and RNA/DNA hybrids, supporting a role in RNA primer removal during mtDNA replication. Cryo-EM structures of Pol γ bound to fork-mimicking DNA reveal conformational states corresponding to progressive duplex unwinding and identify structural elements that facilitate strand displacement. These findings establish a metal-dependent mechanism for Pol γ activity and reconcile previous discrepancies in its reported unwinding capacity.
    DOI:  https://doi.org/10.1093/nar/gkag720
  9. Mol Genet Metab. 2026 Jul 19. pii: S1096-7192(26)00503-2. [Epub ahead of print]149(1-2): 110220
    TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
    Claire-Marine Bérat, Giulia Barcia, Pauline Gaignard, Zahra Assouline, Elisa De La Cruz, Marie-Céline François-Heude, Agathe Roubertie, Claude Cances, Louis Dufour, Marianne Alison, Olivier Patat, Aurélien Trimouille, Samira Ait-El-Mkadem Saadi, Agnès Rötig, Marie Hully, Cécile Rouzier, Isabelle Desguerre, Nathalie Boddaert, Manuel Schiff.
       BACKGROUND: TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management.
    OBJECTIVE: To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes.
    METHODS: We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease.
    RESULTS: The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes.
    CONCLUSION: TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
    Keywords:  Dystonia; Leigh syndrome; Mitochondrial disease; Mitochondrial respiratory chain complex III; Spastic paraparesis; TTC19
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110220
  10. Nat Struct Mol Biol. 2026 Jul 23.
    Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
    Xiaolong Liu, Hongjun Cai, Hao Wang, Xueyin Zhou, Yutong Zhang, Shuai Liu, Jiajun Zhu, Long Li.
      Metabolite carriers that control essential metabolite transport are imported into mitochondria through the TOM and TIM22 complexes. How TOM and TIM22 coordinate in human mitochondria has remained largely unknown. Here we show that human TOM and TIM22 assemble into a supercomplex that seamlessly couples carrier translocation across the outer and inner membranes, unlike in yeast where the two complexes appear to function separately. Cryo-electron microscopy structures of the human TOM-TIM22 supercomplex reveal unpaired carrier transmembrane segments traversing the TOM channel along a hydrophobic path and exiting through an unexpected lateral groove outside the channel. The membrane-bound small Tim subunits provide the substrate entry site for TIM22, while a membrane-exposed groove of TIM22 serves as the exit for carrier insertion into the inner membrane. These findings provide insights into the human carrier translocation pathway at molecular resolution and establish the TOM-TIM22 supercomplex as a central organizing unit of mitochondrial carrier import.
    DOI:  https://doi.org/10.1038/s41594-026-01849-w
  11. Am J Physiol Heart Circ Physiol. 2026 Jul 24.
    Quantum-Informed Perspectives on Mitochondrial Bioenergetics and Redox Signaling in Cardiovascular Disease.
    Francesco Tona.
      
    Keywords:  Bioenergetics; Cardiovascular disease; Heart failure; Mitochondria; Redox signaling
    DOI:  https://doi.org/10.1152/ajpheart.00308.2026
  12. Mol Ther. 2026 Jul 20. pii: S1525-0016(26)00590-3. [Epub ahead of print]
    Mitochondrial capsules: A revolutionary organelle therapy for mitochondrial and neurodegenerative diseases.
    Yaguang Zhang, Xuyang Yang, Mingtian Wei.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.022
  13. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123
    VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
    Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.
      Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.
    Keywords:  VAMP7; glia; mitochondrial dynamics
    DOI:  https://doi.org/10.1073/pnas.2603069123
  14. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2619864123
    HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
    Jiamin Yi, Qin Yang, Chunzhuang Zhou, Yunfei Zhu, Yingfeng Tu, Lin Zhao, Min Tang, Junhong Qin, Tao Long, Tianxing Li, Ping Li, Zikang Gong, Qilin Wang, Xin Yong, Da Jia.
      The HECT-type E3 ubiquitin ligase HUWE1 is a critical regulator of protein homeostasis, genome stability, and neurodevelopment. Variants in HUWE1 are linked to X-linked intellectual disability (XLID), yet a significant number of HUWE1 variants are noncatalytic, leaving their disease mechanisms unresolved. Here, we identify an AMBRA1-RMC1-HUWE1 signaling axis that directs HUWE1-mediated ubiquitination to mitochondria to regulate neural development. In zebrafish, noncatalytic HUWE1 variants found in XLID patients (M375I, G660R, and H669Q) recapitulate key neurodevelopmental deficits, including impaired brain growth and motor neuron defects. Global ubiquitin profiling reveals that these variants selectively disrupt the ubiquitination of mitochondrial proteins without affecting nuclear substrates. Mechanistically, AMBRA1 acts as a mitochondrial scaffold that recruits RMC1, enabling HUWE1 localization to mitochondria through direct interaction with RMC1. Disruption of this recruitment by disease-associated HUWE1 variants prevents mitochondrial targeting and impairs mitochondrial substrate ubiquitination. Notably, Urolithin A treatment ameliorates neurodevelopmental phenotypes in HUWE1-deficient zebrafish. Together, our findings define an AMBRA1-organized mitochondrial recruitment pathway in which RMC1 links HUWE1 to mitochondria, explain noncatalytic HUWE1-associated XLID, and suggest mitochondrial quality-control enhancement as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1073/pnas.2619864123
  15. Mol Ther. 2026 Jul 20. pii: S1525-0016(26)00594-0. [Epub ahead of print]
    The power of one: The unexpected benefits of correcting a single tissue in multisystem mitochondrial disease.
    Carlos T Moraes.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.025
  16. J Int Med Res. 2026 Jul;54(7): 3000605261467202
    The long road to a rare diagnosis: A Malaysian case of childhood-onset progressive myoclonus, ataxia, and retinal dystrophy with biopsy features suggestive of mitochondrial dysfunction.
    Kishwen Kanna Yoga Ratnam, Jun Fai Yap.
      ObjectiveMyoclonus is a hyperkinetic movement disorder characterized by sudden, involuntary jerks due to muscle contraction or brief lapses of muscular activity and may arise from diverse conditions. When accompanied by cerebellar dysfunction and retinal involvement, it suggests a heterogeneous spectrum of disorders, including mitochondrial, repeat-expansion, and other inherited neurogenetic disorders. In Malaysia, the diagnosis of rare diseases remains challenging because of phenotypic overlap and resource limitations. We illustrate the diagnostic dilemma of a possible mitochondrial disorder when definitive testing is not readily accessible.MethodsWe describe a woman in her early 40s with childhood-onset myoclonic jerks, progressive gait instability, cerebellar signs, and cognitive decline.ResultsOphthalmic assessment showed reduced visual acuity, optic disc pallor, and electroretinographic findings consistent with cone-rod dystrophy. Audiometry demonstrated bilateral sensorineural hearing loss. Brain computed tomography showed cerebral and cerebellar atrophy. Muscle biopsy revealed preserved architecture without ragged-red fibers, but oxidative enzyme histochemistry showed subsarcolemmal mitochondrial aggregates suggestive of mitochondrial dysfunction. Whole-exome sequencing did not identify a causative variant. Given the combination of cerebellar features and retinal dystrophy, a repeat-expansion disorder, particularly spinocerebellar ataxia type 7, remained a key differential diagnosis. Targeted repeat-expansion testing and mitochondrial deoxyribonucleic acid analysis were not performed because of patient-centered considerations. Despite disease progression, multidisciplinary follow-up was maintained, including structured physiotherapy and annual ophthalmologic surveillance.ConclusionThis case highlights the importance of pragmatic care planning in resource-limited settings and maintaining comprehensive care for patients without a definitive molecular diagnosis. It also emphasizes the need to strengthen rare disease diagnostic pathways to support shared decision making.
    Keywords:  Case report; cerebellar ataxia; cone-rod dystrophy; mitochondrial dysfunction; rare disease
    DOI:  https://doi.org/10.1177/03000605261467202
  17. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00473-9. [Epub ahead of print]
    Distinct sources and effects of mitochondrial reactive oxygen species.
    Daniel Barnett, Caroline Booraem, Anna G Orr, Adam L Orr.
      Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.
    Keywords:  cell metabolism; cell signaling pathways; complex I; complex III; disease mechanisms; electron leak; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.009
  18. Nat Commun. 2026 Jul 21. pii: 6128. [Epub ahead of print]17(1):
    Mitochondrial translation termination, recycling, reinitiation, and rescue for in-frame and out-of-frame contexts.
    Taisei Wakigawa, Mari Mito, Qi Fang, Yuzuru Itoh, Yoichi Shinkai, Shintaro Iwasaki.
      Because mitochondria diverged from a bacterial ancestor during evolution, the mitochondrial protein synthesis system includes both mRNAs and translation factors with unique characteristics. However, the molecular mechanisms underlying translation termination, recycling, and quality control remain unclear. Here, via high-resolution mitochondrial Ribo-Seq and Disome-Seq, we reveal: the specificity of release factors for different kinds of stop codons; the role of mtRF1 in vertebrates, which do not have noncanonical stop codons in their main translons; the recycling-coupled translation of internal translons; and the rescue of mitoribosomes in the early elongation stage. mtRF1L recognizes all stop codons, whereas mtRF1 recognizes only AGA/AGG noncanonical stop codons. Additionally, mtRF1 terminates the translation of out-of-frame translons that end with AGA/AGG. We also found that mtRRF and mtIF3 are required for mitoribosome recycling on stop codons and for the reinitiation of internal translon translation. Mitoribosomes that stall at the start codons and/or at the early elongation phase are major substrates of the rescue factors ICT1, mtRF-R, and mtRES1. Moreover, HEMK1-mediated methylation of release factors enhances the termination reaction on stop codons. Our results provide insights into the mitoribosome dynamics that are associated with the completion of protein synthesis.
    DOI:  https://doi.org/10.1038/s41467-026-75248-6
  19. iScience. 2026 Jul 17. 29(7): 116442
    Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism.
    Esther Paulo, Yuanyuan Wu, Biao Wang.
      Mitochondrial respiration is essential for Ucp1-mediated thermogenesis in brown adipocytes, where heat production depends on oxygen-driven mitochondrial activity. To define the role of complex IV, we generated brown-adipocyte-specific Cox10-knockout mice (Cox10BKO), as Cox10 is required for cytochrome c oxidase assembly. Cox10-deficient brown adipocytes exhibited markedly reduced complex IV activity and impaired Ucp1-dependent thermogenesis. Although ATF4 signaling was strongly induced, the alternative ATF4-dependent thermogenic pathway failed due to suppression of global protein synthesis, consistent with severe mitochondrial stress and reduced ribosomal gene expression. Unexpectedly, Cox10BKO mice housed at room temperature or thermoneutrality were protected against high-fat-diet-induced obesity and insulin resistance. These findings demonstrate that brown adipocytes regulate systemic metabolic homeostasis independently of canonical thermogenic function and suggest that respiration-deficient brown fat may promote metabolic fitness through endocrine or metabolic signaling mechanisms.
    Keywords:  human metabolism; metabolic flux analysis; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116442
  20. Science. 2026 Jul 23. 393(6809): eady6893
    Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure.
    Yang Xie, Luca Tucciarone, Elie N Farah, Lei Chang, Qian Yang, Thirupura S Shankar, Weston Elison, Shaina Tran, Jovina Djulamsah, Audrey Lie, Timothy Loe, Alyssa R Holman, Sierra Corban, Justin Buchanan, Sainath Mamde, Haowen Zhou, Ruth M Elgamal, Eleni Tseliou, Vincent Huang, Zhaoning Wang, Jeffrey Huey-Chuan Chiu, Rebecca Melton, Emily Griffin, Qingquan Zhang, Jacinta Lucero, Sutip Navankasattusas, Daofeng Li, Chanrung Seng, Eugin Destici, Craig H Selzman, Agnieszka D'Antonio-Chronowska, Ting Wang, Allen Wang, Stavros G Drakos, Kyle J Gaulton, Bing Ren, Neil C Chi.
      Heart failure is a leading cause of morbidity and mortality, yet gene-regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications, and chromatin organization of 13 nonfailing and 23 failing human hearts across all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene-regulatory programs, and chromatin organization, particularly in cardiomyocytes and fibroblasts. Mapping cell type-specific enhancer-gene interactions from these analyses enabled the illumination of likely causal genetic contributors to heart failure from genetic association data. Together, these findings provide multimodal gene-regulatory maps of the human heart in health and disease, offering a framework for designing precise, cell type-targeted therapies for treating heart failure.
    DOI:  https://doi.org/10.1126/science.ady6893
  21. MethodsX. 2026 Dec;17 104021
    Cellular thermal shift assay of subcellular isolates to evaluate drug-membrane target interactions.
    Sahiba K Dogra, Varunya Kattunga, Shona A Mookerjee, Anand Rane, Manish Chamoli, Julie K Andersen.
      The cellular thermal shift assay (CETSA) is a tool for target identification and validation in drug discovery. It relies on thermal melting curves to indicate drug binding and is performed in cells, cell lysates, or purified protein. These approaches can disrupt the structural integrity of membrane proteins, hindering drug-target engagement. We describe the first application of CETSA in isolated mitochondria and show the effects of this approach on the analysis of the compound UK5099 and its known binding target, the mitochondrial pyruvate carrier (MPC), a mitochondrial inner membrane-localized protein complex. Our analysis supports a model in which the MPC must remain structurally intact for UK5099 binding. We demonstrate that the binding of UK5099 to the MPC is disrupted in cells and cell lysates, whereas isolating mitochondria maintains the binding interaction between drug and target observable using CETSA. These data suggest that isolating membrane-bound organelles through subcellular CETSA stabilizes membrane-bound proteins in their native conformation, allowing the identification of membrane-localized drug binding targets that might otherwise be missed.•CETSA on subcellular isolates preserves membrane target in native conformation.•UK5099-MPC binding is preserved in mitochondrial isolates but not cells or lysates.•This approach validates direct-binding interaction of membrane proteins.
    Keywords:  Drug discovery; Membrane protein target validation; Mitochondrial pyruvate carrier (MPC); Subcellular compartment isolation
    DOI:  https://doi.org/10.1016/j.mex.2026.104021
  22. Cell Rep. 2026 Jul 22. pii: S2211-1247(26)00792-8. [Epub ahead of print]45(7): 117714
    3D nanoscale reconstruction of human airway multiciliogenesis reveals cellular architecture remodeling and cilia-mitochondria link via rootlets.
    Cell Map Project Team
      A central challenge in single-cell biology is understanding how molecular programs drive changes in cellular architecture that enable specialized function. A striking example of cellular remodeling is the differentiation of airway stem cells into the respiratory multiciliated epithelium, a protective tissue barrier that clears inhaled pathogens and particulate matter. Here, we present its first three-dimensional nanometer-scale reconstruction, revealing coordinated changes in cellular organization, organelle topology, and inter-organelle contacts during multiciliogenesis. We uncover a structural and functional association between motile cilia and mitochondria mediated by rootlets, striated cytoskeletal fibers that remain poorly characterized in human airway multiciliated cells. Rootlets connect to basal bodies through a multiprotein linker containing the uncharacterized rootletin/CROCC homolog CROCC2, oscillate at frequencies comparable to ciliary beating, promote basal body alignment, and when lost, reduce maximal mitochondrial respiratory capacity. Altogether, this work integrates structural, dynamic, and functional analyses to elucidate mechanisms underlying airway mucociliary defense.
    Keywords:  CP: cell biology; airway respiratory epithelium; cellular organization; cilia; mitochondria; nanoscopy; organelle contacts; rootlets; super-resolution microscopy; volume electron microscopy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117714
  23. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600571123
    Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
    Lin Li, Wenzheng Zou, Yuqing Lv, Yingfei Lu, Jiaqi Liang, Shukui Zhang, Baoyang Hu, Jianwei Jiao.
      Neurogenesis is characterized by dynamic structural changes and functional remodeling of multiple organelles, which interact to form an intricate network that precisely modulates processes including neural progenitor cell self-renewal, neurogenesis, and terminal neuronal development. However, the spatiotemporal dynamics of peroxisomes and their functional contributions within this regulatory network remain incompletely defined during mammalian cortical development. Here, we found that radial glial cells (RGCs) exhibit enriched peroxisome abundance, whereas neural differentiation is associated with reduced peroxisome numbers and increased pexophagy, accompanied by the remodeling of lipid metabolic programs. Acute disruption of peroxisomes by PLAAT3-PEX11 impaired neural differentiation in the embryonic mouse cortex, while PEX7 knockout compromised neurogenic progression in human cortical organoids, supporting a conserved requirement for peroxisomal function during cortical development. Lipidomic and imaging analyses revealed that peroxisome-derived ether lipids were essential for driving neural differentiation and were specifically enriched in mitochondria. Consistently, knockdown of Gnpat, which catalyzes the initial step of ether lipid biosynthesis, reduced neural differentiation, and disrupted mitochondrial structure and function, while batyl alcohol supplementation partially restored these defects. Mechanistically, the ether lipids maintain the structural integrity of mitochondrial cristae and thereby support respiratory chain activity, which in turn promotes oxidative phosphorylation and activates the NAD+ associated signaling. Collectively, this work highlights the precise spatiotemporal regulation of neurogenesis through peroxisomal dynamics and interorganelle crosstalk and identifies ether lipids as a potential therapeutic target for neurodevelopmental disorders.
    Keywords:  ether lipids; mitochondria; neurogenesis; peroxisome
    DOI:  https://doi.org/10.1073/pnas.2600571123
  24. Trends Biotechnol. 2026 Jul 21. pii: S0167-7799(26)00286-6. [Epub ahead of print]
    Mitochondrial engineering strategies in yeast cell factories.
    Shuo Yang, Cong Gao, Guipeng Hu, Xiaomin Li, Liming Liu.
      Yeast is widely used as a microbial chassis for sustainable chemical production, with subcellular organelles helping to organize and regulate biosynthesis. Among these organelles, mitochondria play pivotal roles in yeast cell factories by supplying metabolic resources, maintaining cellular vitality, and providing a favorable biosynthetic microenvironment. Accordingly, this review summarizes mitochondria-centered strategies for improving yeast-based chemical production. These strategies include (i) rewiring mitochondrial metabolic pathways to regulate metabolic resource supply; (ii) maintaining mitochondrial homeostasis to improve cellular vitality; and (iii) optimizing mitochondrial compartmentalization. Current bottlenecks and future opportunities are discussed, providing a framework for optimizing chemical biosynthesis in yeast cell factories.
    Keywords:  chemical biosynthesis; mitochondrial compartmentalization; mitochondrial homeostasis; mitochondrial metabolic rewiring; yeast cell factory
    DOI:  https://doi.org/10.1016/j.tibtech.2026.07.007
  25. Mol Genet Genomic Med. 2026 Jul;14(7): e70274
    A Homozygous Founder ELAC2 Variant in Kuwaiti Infants With Fatal Cardiomyopathy and Refractory Severe Lactic Acidosis: A Retrospective Review of the Clinical, Cardiological and Molecular Findings.
    Hind Alsharhan, Worood Alostad, Alshaymaa A Ali, Mohammad A Ebrahim, Hesham A F Mohammed, Ahmad Alahmad, Hashem Alhashemi, Walid M Hassan, Ahmad E M S Alhaj, Rasha M Alsafi, Buthaina Albash.
       BACKGROUND: Infantile-onset cardiomyopathy due to mitochondrial dysfunction is a severe condition frequently associated with poor prognosis. Biallelic pathogenic variants in ELAC2, an essential mitochondrial tRNA processing gene, have been implicated in this phenotype. This study investigates the clinical and genetic spectrum of ELAC2-related disease in a national cohort from Kuwait.
    METHODS: We conducted a retrospective cohort study using data from the Kuwait Medical Genetics Center registry, including individuals with genetically confirmed or clinically suspected ELAC2-related cardiomyopathy. Clinical, metabolic, and molecular data were reviewed. Exome sequencing or targeted mutation testing was performed in affected individuals and at-risk family members.
    RESULTS: A total of 34 individuals from 23 consanguineous families were identified, of whom 30 were genetically confirmed to harbor the homozygous ELAC2 founder variant c.460T>C; p.(Phe154Leu). All individuals presented in infancy with severe cardiomyopathy and refractory lactic acidosis. Neurological involvement was observed in 39% of cases. The majority exhibited hypertrophic cardiomyopathy, with variable dilated features and pericardial effusion. The disease course was fatal in all, with most patients dying in infancy.
    CONCLUSION: This is the largest single-country cohort reported to date with ELAC2-related mitochondrial cardiomyopathy, raising the global case total to over 70. The uniform presence of the Phe154Leu variant across unrelated Bedouin families highlights a strong founder effect. Given the rapid disease progression and high mortality, we recommend targeted ELAC2 screening in infants with idiopathic cardiomyopathy and persistent lactic acidosis, particularly in consanguineous populations. Premarital carrier testing and early family counseling should be prioritized to support preventive strategies.
    Keywords:   ELAC2 ; Kuwait; consanguinity; dilated cardiomyopathy; founder mutation; hypertrophic cardiomyopathy; lactic acidosis; mitochondrial disease; pericardial effusion
    DOI:  https://doi.org/10.1002/mgg3.70274
  26. Smart Med. 2026 Jun;5(3): e70043
    Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
    Yixiang Zhang, Yawei Du, Shifeng Ling, Hanqi Wang, Jiahao He, Jiahong Li, Kaifeng Huo, Baikun Liu, Qingfeng Li, Jiao Wei, Wenguo Cui.
      Adipose-derived stem cells (ADSCs) are central regulators of adipose tissue homeostasis and regenerative capacity. Accumulating evidence indicates that aging and obesity profoundly impair ADSC function, through progressive mitochondrial dysfunction and disrupted mitochondrial-nuclear communication. Emerging studies reveal that defects in nuclear-mitochondrial crosstalk constitute a key driver of ADSC senescence and adipose tissue aging. In this review, we synthesize recent advances in understanding the mitochondrial mechanisms underlying ADSC aging, with particular emphasis on how mitochondrial dysfunction reshapes stem cell fate decisions, metabolic plasticity, and inflammatory signaling within aged adipose niches. We further highlight mitochondria targeting therapeutic strategies that hold promise for reversing ADSC senescence. Collectively, this framework positions mitochondrial regulation as a unifying axis for ADSC rejuvenation, offering new opportunities to restore adipose tissue homeostasis and mitigate age-related metabolic dysfunction.
    Keywords:  adipose derived stem cell; aging; cellular communication; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/smmd.70043
  27. Reproduction. 2026 Jul 22. pii: xaag090. [Epub ahead of print]
    SMCP Maintains ROS Homeostasis During Sperm Mitochondrial Sheath Assembly.
    Chang Wang, Xun Xia, Yudie Guo, Xi Zhang, Mengting Xie, Qingsong Xie, Juran Li, Mengting Tang, Jiaxin Fang, Chuan Xu, Li Liu, Dan Zhao, Rong Hua.
      Abnormal morphology or function of the sperm mitochondrial sheath is a major cause of asthenozoospermia, yet the mechanisms governing its assembly and functional maturation remain poorly understood. SMCP is a mitochondrial sheath-associated protein, and its regulation at the protein level during late spermiogenesis has attracted substantial interest. Here, we show that SMCP is expressed during mitochondrial sheath assembly in late spermiogenesis. SMCP is initially detected in the cytoplasm of elongating spermatids and, following cytoplasm removal, a fraction is retained in the mitochondrial sheath of mature spermatozoa. SMCP deficiency leads to markedly reduced sperm motility and male infertility without overt alterations in mitochondrial sheath morphology. Integrative proteomic and functional analyses further reveal that SMCP loss impairs mitochondrial respiratory chain function and reduces ATP production. Mechanistically, SMCP associates with GLRX, and SMCP deficiency disrupts GLRX localization, accompanied by elevated ROS levels during mitochondrial sheath assembly and in mature sperm. These redox defects likely contribute to compromised mitochondrial sheath function. Collectively, our findings identify SMCP as a regulator of functional module assembly within the sperm mitochondrial sheath and support the concept that mitochondrial sheath assembly represents not only a morphogenetic process but also a developmental window for functional maturation and redox programming, with the SMCP-GLRX complex serving as a localized antioxidant module during this period.
    Keywords:  GLRX; Mitochondrial sheath assembly; ROS homeostasis; SMCP; oxidative respiratory chain
    DOI:  https://doi.org/10.1093/reprod/xaag090
  28. Enzymes. 2026 ;pii: S1874-6047(26)00007-7. [Epub ahead of print]59 105-130
    Mitochondrial carbonic anhydrases VA and VB: Metabolic roles and clinical significance.
    Stanislav Kalinin, Seppo Parkkila, Ashok Aspatwar.
      Mitochondrial carbonic anhydrases VA and VB (CA VA and CA VB) are localized within the mitochondrial matrix. These zinc-containing enzymes catalyze the reversible hydration of carbon dioxide to bicarbonate and protons, thereby providing bicarbonate for essential mitochondrial metabolic reactions and contributing to intracellular pH balance. CA VA is predominantly expressed in the liver and plays a key role in supplying bicarbonate for pathways such as gluconeogenesis, ureagenesis, and lipogenesis. In contrast, CA VB shows a broader tissue distribution and supports mitochondrial metabolism across multiple organs, although its physiological role is less clearly defined. Mitochondrial CAs are directly linked to metabolic processes required for energy homeostasis. Deficiency of CA VA is associated with metabolic disorders, particularly those involving impaired ammonia detoxification and disruption of intermediary metabolism. This chapter summarizes current knowledge on CA VA and CA VB, including their molecular and structural features, biochemical properties, tissue distribution, and roles in mitochondrial metabolism. In addition, evidence from experimental models, clinical findings related to CA5A mutations, and emerging therapeutic perspectives are discussed.
    Keywords:  Bicarbonate metabolism; CA VA; CA VB; Gluconeogenesis; Metabolic disorders; Mitochondrial carbonic anhydrase; Mitochondrial metabolism; Ureagenesis
    DOI:  https://doi.org/10.1016/bs.enz.2026.05.002
  29. Bull Math Biol. 2026 Jul 23. pii: 142. [Epub ahead of print]88(8):
    Mathematical Modelling of the Mitochondrial Dicarboxylate Carrier (SLC25A10).
    Ramin Nashebi, Yingying Lyu, Elías Vera-Sigüenza, Daniel A Tennant, Fabian Spill.
      The mitochondrial dicarboxylate carrier SLC25A10 mediates reversible exchange among succinate, malate, and phosphate, contributing to mitochondrial metabolic regulation. Structural studies establish a ping-pong mechanism, but most mathematical models still assume sequential binding, lacking mechanistic justification and overlooking the alternation of a single binding site. Here, we present the first mechanistically derived and thermodynamically consistent model of SLC25A10 based on a ping-pong framework. The model incorporates competitive binding of succinate, malate, and phosphate, heteroexchange, reversibility, and electroneutrality, and is calibrated using experimental datasets from intact mitochondria and reconstituted proteoliposomes. To estimate kinetic parameters and quantify their uncertainty, we employed Bayesian inference, enabling statistically rigorous calibration to uptake and competition assays. The model introduces new terms that quantify which substrate and from which side of the membrane is most likely to start the transport cycle. Beyond reproducing experimentally observed exchange kinetics, the model resolves non-equilibrium transport dynamics that are difficult to access directly in classical uptake assays. In particular, the simulations reveal a two-phase response in which an initial phosphate-driven high-flux uptake regime for malate and succinate is followed by a slower redistribution phase in which the two dicarboxylates continue to readjust primarily against each other. The model also predicts that mitochondrial morphology modulates early transport behaviour, with matrix swelling increasing and matrix condensation decreasing the initial SLC25A10 flux magnitude. More broadly, the framework provides a quantitative basis for studying how substrate competition, thermodynamic driving forces, and compartment geometry shape SLC25A10-mediated exchange, and it offers a transferable modelling strategy for other carriers in the SLC25 family.
    Keywords:  Bayesian Inference; Kinetic Modeling; MCMC; Mitochondrial Dicarboxylate Carrier (SLC25A10); Ping–Pong Mechanism
    DOI:  https://doi.org/10.1007/s11538-026-01709-0
  30. Cardiovasc Res. 2026 Jul 21. pii: cvag163. [Epub ahead of print]
    LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy.
    Magali Seguret, Charlène Jouve, Andrea Ruiz-Velasco, Lucille Deshayes, Zoheir Guesmia, Céline Pereira, Valentine Ragot, Clara Castelli, Karim Wahbi, Jérémy Fauconnier, Gisèle Bonne, Antoine Muchir, Jean-Sébastien Hulot.
       AIMS: Mutations in the LMNA gene, which encodes lamin A/C, cause a variety of diseases known as laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy and heart failure, but the genotype-phenotype relationship and underlying mechanisms are unclear.
    METHODS AND RESULTS: Induced pluripotent stem cells (hiPSCs) from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro) and a CRISPR/Cas9 corrected isogenic control hiPSCs clones were differentiated into cardiomyocytes (hiPSC-CMs), with no difference in the differentiation yield and in sarcomere organisation between the two cell lines. However, 3D cardiac organoids generated with LMNA p.H222P hiPSC-CMs showed an impaired contractility compared to control organoids. Calcium transient recordings in LMNA p.H222P mutant cardiomyocytes showed a significantly higher calcium transient amplitude with a significantly slower calcium re-uptake. Transcriptomic analyses suggested a global mitochondrial dysfunction and in particular an impaired mitochondrial calcium uptake with a significantly decreased expression of the mitochondrial calcium uniporter (MCU). This decrease in MCU expression was confirmed by western blot and was accompanied by an increased MICU1:MCU ratio, as well as an increased PDH Ser232 and PDH Ser300 phosphorylation, indicating an altered mitochondrial calcium uptake in the LMNA mutant hiPSC-CMs. Consistently, lower mitochondrial respiration and ATP levels were found in LMNA p.H222P hiPSC-CMs as compared to isogenic controls. Strikingly, treatment with the MCU activator amorolfine restored mitochondrial calcium uptake and improved contractility in LMNA mutant hiPSC-CMs.
    CONCLUSIONS: Our results establish a direct mechanistic link between nuclear envelope dysfunction and impaired mitochondrial function, and highlight the MCU complex as a potential therapeutic target in LMNA-related cardiomyopathy. More broadly, this work provides a paradigm for connecting gene-specific nuclear defects to mitochondrial dysfunction in inherited cardiomyopathies.
    Keywords:  Calcium; Heart failure; Laminopathy; Mitochondria; iPS-derived cardiomyocytes
    DOI:  https://doi.org/10.1093/cvr/cvag163
  31. Redox Biol. 2026 Jul 14. pii: S2213-2317(26)00303-4. [Epub ahead of print]96 104304
    Aglycemia triggers alternative electron transport to sustain mesenchymal stem cell survival under anoxia.
    Alice Refeyton, Nivea Dias Amoedo, Veronique Labat, Thibaut Vignane, Corinne Buré, Benoit Pinson, Seyta Ley-Ngardigal, Christelle Debeissat, Biljana Bursac, Stéphane Claverol, Radia Khelifi, Laura Rodriguez, Philippe Brunet de la Grange, Rodrigue Rossignol, Milos R Filipovic, Zoran Ivanovic, Marija Vlaski-Lafarge.
      Adult stem cells, including mesenchymal stem cells (MSC), display marked metabolic flexibility, functioning across anaerobic to microaerophilic conditions. While their survival under energy-restrictive environments is known, the underlying metabolic mechanisms remain incompletely defined. Here, combining functional assays, omics, and multiparametric energetic profiling, we elucidate the adaptations that enable MSC, unlike differentiated cells, to endure prolonged anoxia or anoxia/aglycemia (ischemia-like) conditions. We show that MSC proliferation under anoxia and normal glycemia depends mainly on lactate fermentation, whereas survival under combined anoxia and aglycemia relies on a specific mitochondrial reprogramming. Notably, anaerobic mitochondrial activity including Krebs cycle turnover and sulfide oxidation can proceed through a canonical electron transport chain using an alternative electron acceptor. This anaerobiosis-stemness link positions stem cells as living molecular fossils, preserving features of primordial eukaryotic bioenergetics and illuminating the evolutionary depth of mitochondrial plasticity.
    Keywords:  Aglycemia; Anoxia; Hydrogen sulfide; Mesenchymal stem cells; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.redox.2026.104304
  32. Mitochondrion. 2026 Jul 22. pii: S1567-7249(26)00084-X. [Epub ahead of print]91 102194
    Mito-interpreter: An online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of mitochondrial DNA variants.
    Ning Zhang, Yang Yang, Haoyu He, Qihan Wang, Dongmei Ji.
      Mito-interpreter is an online tool developed to implement the ACMG/AMP standards and guidelines for mitochondrial DNA (mtDNA) variant interpretation. Manually applying these specialized guidelines is time-consuming and error-prone due to mtDNA complexities. This tool streamlines the process by systematically organizing evidence categories and integrating key data sources, including population frequencies from MITOMAP and Helix, as well as pre-computed scores from the APOGEE and expert-validated evidence from ClinGen. By automating data aggregation and rule-based logic, Mito-interpreter enables clinicians and researchers to focus on evidence evaluation, thereby enhancing efficiency and accuracy in clinical diagnostics and research. The tool is freely available at https://www.mtdna-interpreter.com.
    DOI:  https://doi.org/10.1016/j.mito.2026.102194
  33. Mol Biol Rep. 2026 Jul 22. pii: 1236. [Epub ahead of print]53(1):
    ER-mitochondria contact sites and organelle stress in asthma.
    Sihao Zhu, Xinxin Xing, Jia Zheng, Hai Wang.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.
    Keywords:  Asthma; ER–mitochondria contact sites; Mitochondria-associated endoplasmic reticulum membranes; NLRP3 inflammasome; Organelle stress
    DOI:  https://doi.org/10.1007/s11033-026-12441-2
  34. Nucleic Acids Res. 2026 Jul 17. pii: gkag736. [Epub ahead of print]54(14):
    Toward a comprehensive modification landscape of yeast mitochondrial tRNAs using Nanopore direct RNA sequencing and dihydrouridine sequencing.
    Julia L Reinsch, David M Garcia.
      Saccharomyces cerevisiae is an invaluable model in the study of mitochondrial tRNA biology. Yet the positions of modified bases in all yeast mitochondrially encoded tRNAs (mt-tRNAs) are still not fully mapped. We performed Nanopore direct RNA sequencing (DRS) on tRNAs from the crude mitochondrial fraction of yeast to map base modifications across all 24 mt-tRNA isoacceptors. Additionally, we adapted the "D-seq" method to detect dihydrouridine sites in tRNAs, where chemical reduction of dihydrouridine causes disruptions to reverse transcription. We mapped dihydrouridine, pseudouridine, and N2-dimethylguanosine sites in mt-tRNAs using DRS, tRNA-D-seq, and knockouts of five conserved tRNA-modifying enzymes. Our results establish Dus1 and Dus2 as the enzymes responsible for D14, D16, D17, D17a, and D20 formation in S. cerevisiae mt-tRNAs. We provide evidence of interactions between Dus1, Dus2, and Trm1-catalyzed modifications, and the influence of Ψ55 promoting m5U54 in mt-tRNAs. These findings expand our understanding of mt-tRNA base modifications and their interdependence, and advance opportunities for the yeast model to investigate defects in human mt-tRNA function.
    DOI:  https://doi.org/10.1093/nar/gkag736
  35. Nat Commun. 2026 Jul 22. pii: 6813. [Epub ahead of print]17(1):
    Tubulin autoregulation tunes microtubule dynamics to support multicellular architecture and viability.
    Ana C Almeida, Chahrazed Lacheheub, Ivana Gasic.
      Alpha- and beta-tubulin heterodimers dynamically assemble into microtubules, key cytoskeletal elements involved in intracellular trafficking, cell adhesion, and division. The availability of free tubulins regulates the synthesis of new subunits. In response to excessive soluble αβ-tubulins, tetratricopeptide protein 5 (TTC5) selectively recognizes nascent tubulins at the ribosome, recruiting downstream effectors that degrade their encoding messenger RNAs, in a process known as tubulin autoregulation. Despite its well-characterized molecular framework, the biological relevance of this regulatory pathway remains unknown. Here, using human 3D cellular models, advanced optics, and genetic perturbation of tubulin biosynthesis, we reveal that loss of TTC5-dependent tubulin autoregulation elevates soluble tubulin levels, increasing microtubule stability and disrupting cytoskeletal organization. These defects impair the localization of adhesion molecules at cell-cell junctions and extracellular matrix interfaces, compromising tissue architecture and reducing overall cell viability. Our findings establish tubulin autoregulation as a critical mechanism that tunes microtubule dynamics to sustain cellular integrity and tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-75341-w
  36. Genome Med. 2026 Jul 22.
    Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.
    Christy W LaFlamme, Chris Clarkson, Kristina Ibañez, Jin-Yuan Wang, Soham Sengupta, Jenny Lord, Virginia Valentine, Emily S Bonkowski, Edith P Almanza Fuerte, Athena R Olszewski, Sourav Ghosh, Bharati Jadhav, Taralynn Mack, Jiadong Lin, Sophia B Gibson, Johanna M van Hagen, Mariëlle Alders, Alexandra Martin-Geary, Bida Gu, Mira Kharbanda, Siddharth Banka, Helen M Stuart, Andrew R Webster, Akimoto Hosokawa, Harriet Dashnow, Richa Bajpai, Shondra M Pruett-Miller, Mark J P Chaisson, Danny E Miller, Nicola Whiffin, Evan E Eichler, Sanjay M Sisodiya, Henry Houlden, Andrew J Sharp, Bekim Sadikovic, Marc Valentine, Lynette G Sadleir, Arianna Tucci, Heather C Mefford.
       BACKGROUND: Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders.
    METHODS: We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076).
    RESULTS: Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions.
    CONCLUSIONS: CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.
    Keywords:   BCLAF3 ; DNA methylation; Repeat expansions
    DOI:  https://doi.org/10.1186/s13073-026-01729-4
  37. JACC Basic Transl Sci. 2026 Jul 23. pii: S2452-302X(26)00144-0. [Epub ahead of print]11(8): 101625
    Disrupted Mitochondrial Quality Control in Atherosclerotic Disease: Mitophagy and Dynamics in Focus.
    Taylor Wilcox, Julie Hansen, Andrew Blanker, Michael E Widlansky.
      Mitochondrial health is essential for maintaining cardiac function, and mitophagy-the selective degradation of damaged mitochondria-is central to maintenance of mitochondrial quality. In this review, we focus on the role of mitophagy in atherosclerotic disease, exploring both canonical and noncanonical pathways. We aim to highlight how proper regulation of mitophagy supports cardiac health, while imbalances in this process can contribute to the onset and progression of cardiovascular conditions. In addition, we examine the cardioprotective potential of mitophagy in the context of disease and discuss its close relationship with mitochondrial dynamics, particularly as they relate to both macrovascular and microvascular dysfunction. Finally, we identify current gaps in knowledge and outline key questions that remain for the field to address, with the goal of guiding future research in this critical area of cardiovascular biology.
    Keywords:  atherosclerotic disease; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1016/j.jacbts.2026.101625
  38. Front Immunol. 2026 ;17 1848626
    SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair.
    Xin Li, Xiaofei Luo, Zeng Zhang, Linya Tang, Xiudong Meng.
      Myocardial infarction (MI) remains a leading cause of cardiovascular mortality worldwide. Despite significant advances in reperfusion strategies and pharmacotherapy, persistent inflammation and adverse ventricular remodeling continue to underlie poor long-term clinical outcomes. Macrophages serve as central orchestrators of post-MI healing, coordinating the clearance of necrotic debris, resolution of inflammation, remodeling of the extracellular matrix, and maturation of the fibrotic scar. However, the conventional M1/M2 dichotomy fails to fully capture the dynamic, phenotypically heterogeneous, and metabolically constrained macrophage states that emerge during infarct healing. In this review, we synthesize current evidence supporting a trajectory-based framework for macrophage reprogramming following MI and emphasize mitochondrial fitness as a critical determinant governing the transition from sustained inflammation to reparative resolution. We summarize key metabolic checkpoints regulating this functional shift-including glycolytic rewiring, tricarboxylic acid (TCA) cycle remodeling, mitochondrial reactive oxygen species (mtROS) accumulation, efferocytosis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and mitochondrial quality control. Furthermore, we advance the hypothesis that SIRT3-the principal mitochondrial NAD+-dependent deacetylase-may act as a central regulatory node linking mitochondrial protein acetylation to macrophage state transitions after MI. Specifically, we outline a staged dual-axis working model, generated from convergent but largely indirect evidence, in which the SOD2-mtROS axis is more closely linked to early nonresolving inflammation, whereas the PDHA1-metabolic flexibility axis may be more relevant to efferocytosis-associated reparative transition. We further highlight NAD+ availability as an upstream limiting factor that may constrain SIRT3 activity in macrophages under ischemic-inflammatory stress. Finally, we critically evaluate the current evidence hierarchy, human translatability, therapeutic strategies, and key translational challenges-emphasizing considerations of timing, cellular specificity, delivery modalities, and target engagement. Although macrophage-specific causal evidence in myocardial infarction (MI) remains sparse, this framework is intended as a mechanistically coherent and experimentally tractable working hypothesis to guide future investigations into macrophage immunometabolism and mitochondrial-targeted interventions in post-infarction cardiac repair. Accordingly, the proposed framework should be viewed as a testable working hypothesis rather than a settled causal model of macrophage fate control in MI.
    Keywords:  NAD+; SIRT3; efferocytosis; immunometabolism; inflammation resolution; macrophage reprogramming; mitochondrial fitness; myocardial infarction
    DOI:  https://doi.org/10.3389/fimmu.2026.1848626
  39. Kidney Int. 2026 Aug;pii: S0085-2538(26)00427-8. [Epub ahead of print]110(2): 291-293
    Mitochondria poor but capacity rich? The paradox of podocyte respiration.
    Antonio S Novaes, Ilse S Daehn.
      Campbell et al. show that podocyte mitochondria, isolated using a cell-specific MITO-Tag approach, possess high intrinsic respiratory capacity despite their low abundance. The study demonstrates that conventional culture conditions suppress mitochondrial respiration and increase oxidative stress, suggesting that current experimental systems may underestimate mitochondrial function in podocytes. The authors provide evidence that mitochondrial respiratory capacity in podocytes declines in male mice with aging, indicating that mitochondria could play a role in age-associated glomerular injury.
    DOI:  https://doi.org/10.1016/j.kint.2026.05.008
  40. J Child Neurol. 2026 Jul 24. 8830738261467625
    A Case of Paroxysmal Exercise-Induced Dyskinesia Expands the Phenotypic spectrum of NAXE-Related Encephalopathy.
    Mert Altıntaş, Miraç Yıldırım, Ömer Bektaş, Eda Eyduran, Batuhan Ergin, Halil Gürhan Karabulut, Engin Köse, Fatma Tuba Eminoğlu, Tanıl Kendirli, Serap Teber.
      Progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is a rare neurodegenerative disorder caused by pathogenic variants in NAXE gene. Movement disorders are among the clinical features of PEBEL1; however, no case presenting with paroxysmal exercise-induced dyskinesia (PED) has been reported. We reported the case of a 14-year-old girl who presented with PED episodes. Six months after the onset of episodes, she developed encephalopathy and focal status epilepticus. Exome sequencing analysis identified a homozygous pathogenic variant in NAXE gene, and she was diagnosed with PEBEL1. She was started on mitochondrial cocktail and multiple antiseizure medications; however, no response was observed. With the ketogenic diet (KD), seizure control was achieved and improvement in cognitive functions was observed. PED is a clinical feature not previously reported in PEBEL1 cases, and our case expands the phenotypic spectrum of this disorder. Additionally, our case highlights that KD may be a treatment option in PEBEL1.
    Keywords:  dystonia; ketogenic diet; mitochondrial disorder; status epilepticus
    DOI:  https://doi.org/10.1177/08830738261467625
  41. BMC Pediatr. 2026 Jul 21.
    TOP3A pathogenic variants presenting as dilated cardiomyopathy and heart failure in three pediatric cases.
    Yipu Zhang, Jiayi Xu, Wenxiu Chan, Hao Chen, Jinjin Wu, Ying Guo, Ru-En Yao, Lijun Fu.
      Dilated cardiomyopathy (DCM) is the most prevalent form of cardiomyopathy in children, characterized by left ventricle dilation and impaired systolic function. The etiology critically influences clinical trajectory and prognosis. Mitochondrial disorders represent a rare but increasingly recognized cause of DCM. Herein, we report three pediatric patients, diagnosed with early-onset DCM at ages of 8, 9, and 8, who progressed rapidly to end stage heart failure, resulting in two fatalities and one cardiac transplantation. Whole exome sequencing (WES) analysis identified compound heterozygous TOP3A pathogenic variants in all three cases, accompanied by reduced mitochondrial DNA copy number. Therefore, this report expands the recognized etiologies of childhood DCM and delineates a severe cardiac phenotype within the TOP3A pathogenic variant spectrum. Trial Registration: Registered at Chinese Clinical Trial Registry (ChiCTR2600117173). Registered 20/01/2026. Retrospectively registered.
    Keywords:   TOP3A gene; Dilated cardiomyopathy (DCM); heart failure; mtDNA deletion; mtTopIIIα
    DOI:  https://doi.org/10.1186/s12887-026-07361-w
  42. J Neurol. 2026 Jul 20. pii: 475. [Epub ahead of print]273(8):
    Systematic reanalysis of next-generation sequencing data in 101 neuromuscular disorder families enhances diagnostic yield, reveals intronic variants, and identifies a novel disease gene.
    Sivasankar Malaichamy, Kiran Polavarapu, Rachel Thompson, Romane Idoux, Sally Spendiff, Veronika Karcagi, Agnes Herczegfalvi, Momen Almomen, Rosana Herminia Scola, Paulo José Lorenzoni, Edmar Zanoteli, Antonio Alberto Zambon, Clara Gontijo Camelo, Eduardo de Paula Estephan, Thenral S Geetha, Vedam L Ramprasad, Seena Vengalil, Saraswati Nashi, Muddassu Keerthipriya, Dipti Baskar, Veeramani Preethish-Kumar, Ananthapadmanabha Kotambail, David Muhmann, Ulrike Schara-Schmidt, Steven Laurie, Leslie Matalonga, Sergi Beltran, Andreas Roos, Ivo Barić, Atchayaram Nalini, Hanns Lochmüller.
       BACKGROUND: Neuromuscular disorders (NMDs) affect approximately 1 in 1,000 individuals and are clinically and genetically heterogeneous. Despite advances in genomic diagnostics, many cases remain unsolved after initial sequencing. Bioinformatic reanalysis approaches provide opportunities to identify missed variants and establish novel disease genes.
    METHODS: Preexisting next-generation sequencing datasets from 101 undiagnosed NMD families were reanalyzed using the RD-Connect Genome-Phenome Analysis Platform. The data comprised clinical exome sequencing (45 families), whole exome sequencing (31 families), and whole genome sequencing (25 families). Variant prioritization incorporated population frequency, Human Phenotype Ontology terms, in silico predictions, and genotype-phenotype correlation.
    RESULTS: Reanalysis identified causative variants in 17 out of 101 previously unsolved families (16.83% diagnostic yield). Eight cases harbored coding variants in known NMD genes (RYR1, AGRN, SCN4A, TTN, MYH2, GOLGA2) consistent with the observed phenotype. In five cases, intronic variants in known NMD genes (COL6A3, SGCA, DOK7, DYSF, CHRND) were considered causative following in silico predictions and careful correlation with the phenotype. One case had an extended phenotype (PTPN11), and one case had a dual diagnosis (MYH2, KIF21A). A novel ATP2A2 missense variant was identified in two unrelated families, establishing ATP2A2 as a new NMD gene.
    CONCLUSION: Research-based reanalysis of preexisting NGS data improved diagnostic yield of previously unsolved cases consistent with previous literature, reinforcing the utility of in-depth, phenotype-driven reanalysis with expert review. Our study provided 17 families with unsolved NMDs with a diagnosis after having waited for a decade. This supports the routine reanalysis of unsolved NGS data, highlighting its potential to reclassify variants of unknown significance and reveal novel genes and pathomechanisms in NMDs.
    Keywords:  Diagnostics; Gene discovery; NGS; Neuromuscular disorders; Reanalysis
    DOI:  https://doi.org/10.1007/s00415-026-13994-9
  43. Stem Cell Res Ther. 2026 Jul 20.
    Miro1-mediated mitochondrial transfer boosts stem cell therapy for muscle atrophy via restoring mitochondrial homeostasis.
    Fangling Zhao, Jingxin Fu, Linli Gao, Mengting Zhou, Yuhui Xia, Zexian Zhao, MengNa Yang, Jiahui He, Wei Zhu, Mengxiong Pan, Kaiming Liu.
      Mitochondrial dysfunction underlies the major defect in muscle atrophy (characterized by the loss of skeletal muscle mass and function). Mesenchymal stem cells (MSCs), which can mediate mitochondrial transfer (MT) via tunneling nanotubes (TNTs), have been shown to exert therapeutic effects, yet the underlying mechanism remains unclear. Mitochondrial Rho GTPase 1 (Miro1) is crucial for regulating mitochondrial homeostasis; in this study, we aimed to investigate the roles of Miro1 and Milton in MSC-based therapy for muscle atrophy. Dexamethasone (DEX)-induced C2C12 cells and chronically aged mice were used as in vitro cellular and in vivo muscle atrophy models, respectively. In vitro experiments demonstrated that overexpression of Milton alone failed to enhance MT in DEX-induced C2C12 cells. Although Milton could promote the formation of TNTs, it was unable to drive mitochondrial movement along microtubules in the absence of Miro1.In contrast, Miro1 knockdown (MSCmiro1Lo) significantly reduced MT in vivo, while Miro1 overexpression (MSCmiro1Hi) improved mitochondrial morphology, increased muscle fiber count and cross-sectional area, upregulated the expression of type I/III collagen, and downregulated the expression of Atrogin1 and MURF1. Additionally, Miro1 overexpression ameliorated functional outcomes such as grip strength, running distance, and physical activity, and elevated the levels of proteins related to mitochondrial fusion, mitophagy, and biogenesis in damaged muscle cells. These findings indicate that Miro1 is a critical driver of MT, and Miro1-enhanced MT confers substantial in vivo therapeutic benefits. This study provides robust evidence supporting Miro1 as a potential target for the treatment of muscle atrophy-related disorders.
    Keywords:  Miro1; Mitochondrial homeostasis; Mitochondrial transfer; Muscle atrophy; Stem cells
    DOI:  https://doi.org/10.1186/s13287-026-05191-2
  44. Nature. 2026 Jul 22.
    Fly neurons carry a molecular 'timestamp' that encodes their birth order.
      
    Keywords:  Developmental biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-02240-x
  45. Nat Rev Genet. 2026 Jul 23.
    Human genetics across levels of biological organization.
    Diederik S Laman Trip, Pedro Beltrao.
      Genetic variation influences human physiology across biological scales from molecules to cells, tissues, organs and the whole organism. Unravelling how variants and their genetic effects propagate across these levels, through molecular interactions, cellular programmes and tissue architectures, to shape phenotypes remains a central challenge in human genetics. Resolving this challenge requires deciphering the genetic architecture of each biological layer and developing systems-level analyses that aim to integrate across scales. Network-based and computational approaches, including artificial intelligence, offer opportunities to move beyond statistical associations towards a context-aware, mechanistic understanding of the genetics underlying human traits and disease, although integration across layers remains limited. Here we review recent advances in mapping genetic effects across biological scales, from intracellular networks that capture molecular interactions, through single-cell and spatial omics approaches that define cellular and tissue contexts, to population-scale imaging genomics that links genetic variation to organ-level and organismal phenotypes. We discuss emerging strategies and remaining challenges for integrating these layers into mechanistic models of genotype-phenotype relationships.
    DOI:  https://doi.org/10.1038/s41576-026-00991-x
  46. Biochim Biophys Acta Mol Cell Res. 2026 Jul 20. pii: S0167-4889(26)00093-5. [Epub ahead of print]1873(7): 120194
    Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
    Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.
      Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.
    Keywords:  Evolution; Gene expression; Mitochondria; Mitoribosomes; Translation initiation; Translational activators; Translational regulation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120194
  47. Adv Sci (Weinh). 2026 Jul 24. e76582
    Large-scale Whole-Exome Sequencing Defines the Protein-Coding Architecture of Retinal Structure, Visual Function, and Major Blinding Diseases.
    Jianqing Li, Yijun Ge, Jingxiao Du, Liu Yang, Bangsheng Wu, Chenyue Hang, Mengxi Shen, Yimin Mao, Ting Zhang, Qiyu Bo, Tianyuan Zhao, Yutian Jiao, Yazhi Wang, Shunxiang Gao, Jieqiong Chen, Junran Sun, Tong Li, Huixun Jia, Yang Dou, Wei Cheng, Xiaoling Wan, Jintai Yu, Xiaodong Sun, Bai Lu.
      The retina is an accessible extension of the central nervous system, yet the protein-coding architecture linking retinal structure, visual function, and major blinding diseases remains poorly defined. Here, using large-scale whole-exome sequencing data from 356,982 UK Biobank participants, exome-wide gene-based tests of rare coding variants and single-variant analyses of common coding variants are performed. A total of 22 significant rare-variant gene-based associations involving 16 genes are identified, including 12 novel genes, 10 of which are independently supported in the All of Us cohort (N = 245,388). Single-variant analyses identify 243 independent common coding variants in 126 genes, including 24 novel genes. CFI, C3, and RIOX1 show associations across retinal structure, visual function, and disease phenotypes, supporting cross-domain pleiotropy. Among the disease-associated genes, the novel gene FYB2 is prioritized for experimental validation, supported by retinal pigment epithelium (RPE)-related expression evidence and clinical relevance in Cox analyses. FYB2 knockdown aggravates barrier dysfunction in human induced RPE (iRPE) cells, supporting a potential role in diabetic retinopathy. These findings define the protein-coding architecture of retinal phenotypes, and support shared genetic links across retinal structure, visual function, and disease. The identified genes provide candidate targets for mechanistic investigation in blinding retinal disorders.
    Keywords:  genetic pleiotropy; protein‐coding variation; rare coding variants; retinal phenotypes; whole‐exome sequencing
    DOI:  https://doi.org/10.1002/advs.76582
  48. Mol Ther. 2026 Jul 23. pii: S1525-0016(26)00595-2. [Epub ahead of print]
    Evaluating cases of possible insertional mutagenesis after AAV gene therapy.
    Lindsey A George, Rebecca C Ahrens-Nicklas, Frederic D Bushman.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.026
  49. Nat Rev Mol Cell Biol. 2026 Jul 24.
    Mitochondrial tRNA biogenesis, modifications and disease relevance.
    Wen-Yu Zhu, Ilias Skeparnias, Athanasios-Nasir Shaukat, Jinwei Zhang, Ru-Juan Liu.
      The biogenesis, modifications and function of mitochondrial transfer RNAs (mt-tRNAs) reflect the symbiotic relationship and coordinated evolution between the domesticated organelle and the outer cell. Through evolution, mt-tRNA structures have been severely degenerated, and mt-tRNA-associated proteomes have acquired additional domains and interfaces, leveraging post-transcriptional modifications to maintain functional affinity and specificity. Considerable progress has been made in the past decade in elucidating mt-tRNA structure, biogenesis, modifications and functions. In this Review, we outline how mt-tRNAs are excised from polycistronic transcripts and mature through coordinated actions of mitochondrial processing enzymes. We then examine how mitochondrial aminoacyl-tRNA synthetases and mitoribosomes have coevolved to recognize degenerated mt-tRNAs and support a streamlined genetic code. The roles of post-transcriptional modifications in mt-tRNA structure stabilization, mt-tRNA decoding and the coupling of metabolism to translation are also discussed. Moreover, we review mt-tRNA-associated pathologies and emerging therapeutic strategies, highlighting unifying principles that inform efforts to restore coherence of mitochondrial translation.
    DOI:  https://doi.org/10.1038/s41580-026-00999-5
  50. Nature. 2026 Jul 24.
    Personalized gene therapy relieves severe epilepsy in two boys.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-026-02267-0
  51. Eur J Hum Genet. 2026 Jul 20.
    Unraveling missing variants through target capture-based long-read sequencing in autosomal recessive disorders.
    Jee-Soo Lee, Kyeong Seon Ryu, Hyesu Lee, Hara Lim, Seonhoo Youn, Hansol Lim, Seung Won Chae, Hobin Sung, Sung Im Cho, Yeseul Kim, Joo Won Jang, Hoyeon Lee, Jin Sook Lee, Jung Min Ko, Jong-Hee Chae, Moon-Woo Seong.
      Short-read sequencing (SRS)-based disease-targeted NGS gene panels have revolutionized rare disease diagnostics but often leave autosomal recessive cases unsolved when only one pathogenic allele is detected. Missing variants may reside in deep intronic regions or involve structural variants (SVs) undetectable by SRS. To improve diagnostic yield, we implemented a cost-effective target capture-based long-read sequencing (LRS) assay covering 56 genes and retrospectively analyzed 78 patients suspected of autosomal recessive disorders who remained undiagnosed after SRS. Functional validation using reverse transcription PCR (RT-PCR) and minigene assays was performed to further determine pathogenicity. Target capture-based LRS solved 25.6% (20/78) of cases by identifying 10 SVs, 3 deep intronic variants experimentally confirmed to cause aberrant splicing, and 7 cases in which haplotype phasing confirmed that variants were in trans with the known pathogenic variant, leading to reclassification of the VUS as likely pathogenic. This study demonstrates that target capture-based LRS effectively detects diverse types of variants missed by SRS. Integrating this assay into stepwise diagnostic workflows offers a practical and cost-effective strategy to enhance diagnostic yield in autosomal recessive diseases. However, because this cohort was retrospectively defined based on a prior single-allele detection by SRS, this 25.6% (20/78) diagnostic yield reflects performance within a highly enriched population and should not be directly extrapolated to unselected rare disease cohorts.
    DOI:  https://doi.org/10.1038/s41431-026-02197-5
  52. Cureus. 2026 Jul;18(7): e112906
    CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to Nicotinamide Mononucleotide (NMN)-Induced Expression Rescue in Metabolic Tissues.
    Ngo Cheung.
      Age-related decline in mitochondrial function and disruption of epigenetic regulation are two closely connected features of biological aging. In neurons, age-associated remodeling of repressive H3K27me3 chromatin may constrain genes needed for metabolic, synaptic, and stress-adaptive maintenance. In parallel, nicotinamide mononucleotide (NMN), an NAD+ precursor, has been reported to mitigate age-associated physiological and transcriptional changes in peripheral metabolic tissues. However, direct links between neuronal epigenetic aging programs and NMN-responsive transcriptional rescue remain unclear. Here, we performed a secondary integrative analysis of two public datasets: GSE190102, focused on age-associated neuronal H3K27me3 targets mapped through an activity-by-contact-style region-gene framework, and GSE85718, a long-term NMN transcriptomic dataset from skeletal muscle, liver, and white adipose tissue in mice. The analysis identified 23 genes shared between 21,155 aging H3K27me3-associated targets and 35 robust NMN-rescue genes. Because the aging target set was extremely broad, gene-level overlap was not statistically persuasive, and pathway-level convergence was absent. Under repressive-mark direction logic, 14 of the 23 shared genes were concordant, meaning that the NMN expression effect opposed the expected consequence of age-associated H3K27me3 remodeling. Objectives were to quantify overlap between neuronal age-associated H3K27me3 targets and robust NMN-responsive genes in peripheral metabolic tissues, classify shared genes by directional concordance under repressive chromatin logic, and identify high-priority mechanistic candidates. The analysis supports limited global convergence and nominates CPT2 as the leading convergent node for targeted validation. CPT2 emerged as the leading candidate. It showed age-associated H3K27me3 gain, a large K27me3 log-fold change of +3.504, NMN-induced expression increase in old animals, a positive NMN interaction coefficient of +0.201, and membership in the mitochondrial fatty-acid oxidation pathway. Within the downstream shared-gene mitochondrial analysis, CPT2 was the only mitochondrial-core gene, with nominal enrichment only. These findings do not support a broad reversal of neuronal epigenetic aging by NMN. Instead, they identify CPT2 as a biologically coherent and experimentally tractable candidate linking age-related repressive chromatin remodeling to NMN-responsive mitochondrial metabolism.
    Keywords:  cpt2; geroscience; h3k27me3; mitochondrial fatty acid oxidation; nad+ metabolism; neuronal epigenetic aging; nmn; polycomb repression; secondary data analysis; transcriptional rescue
    DOI:  https://doi.org/10.7759/cureus.112906
  53. MedComm (2020). 2026 Aug;7(8): e70879
    Reprogramming Glial Cell Metabolism via a tRNA Fragment Preserves Vision in Retinal Neurodegeneration.
    Yuke Ji, Sha Liu, Ying Zhang, Junya Zhu, Chang Huang, Ya Zhao, Jiao Xia, Wan Mu, Jin Yao, Biao Yan.
      Retinal neurodegeneration leads to progressive and irreversible vision loss driven by retinal ganglion cell (RGC) death, yet effective neuroprotective therapies remain lacking. Recent studies suggest that small non-coding RNAs play key roles in central nervous system injury, but their relevance to retinal neurodegeneration remains incompletely understood. Here, we identify a significant increase in 5'tiRNA-His-GTG, an ANG-generated tRNA-derived fragment, in mouse models of retinal neurodegeneration. Functionally, elevated 5'tiRNA-His-GTG promotes reactive gliosis and contributes to RGC degeneration through Müller cell-RGC crosstalk. Conversely, inhibition of 5'tiRNA-His-GTG attenuates glial activation, preserves RGC survival, and improves visual function and vision-dependent behaviors. Mechanistically, 5'tiRNA-His-GTG induces neurodegenerative changes by suppressing the LPCAT1-mediated phosphatidylcholine (PC) biosynthetic pathway and perturbing glycerophospholipid metabolism. Notably, restoration of LPCAT1 expression or PC levels reverses 5'tiRNA-His-GTG-induced neurodegeneration both in vitro and in vivo. These findings uncover a previously unrecognized 5'tiRNA-His-GTG-LPCAT1-PC regulatory pathway that contributes to retinal neurodegeneration. Collectively, our study identifies 5'tiRNA-His-GTG as a critical mediator of glial-driven neuroinflammation and neuronal loss, and highlights this signaling axis as a potential therapeutic target for retinal neurodegeneration.
    Keywords:  glycerophospholipid metabolism; reactive gliosis; retinal ganglion cell; retinal neurodegeneration
    DOI:  https://doi.org/10.1002/mco2.70879
  54. Hum Cell. 2026 Jul 19. pii: 111. [Epub ahead of print]39(8):
    SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.
    Chunmeng Rong, Ruixiu Chen, Hanqi Lou, Yongming Xia, Shiwei Duan.
      Acute myeloid leukemia (AML) remains a highly lethal hematologic malignancy characterized by metabolic reprogramming, therapeutic resistance, and poor survival, particularly in older patients. Nicotinamide adenine dinucleotide (NAD⁺) metabolism has emerged as a central driver of AML progression, and recent studies have identified solute carrier family 25 member 51 (SLC25A51) as the primary mitochondrial NAD⁺ transporter in mammalian cells. SLC25A51 regulates mitochondrial redox balance, oxidative phosphorylation, and tricarboxylic acid (TCA) cycle activity, thereby sustaining leukemic proliferation and survival. Structural studies have elucidated its six-transmembrane helix architecture, salt-bridge-mediated transport mechanism, and stabilization by cardiolipin binding. Functional investigations demonstrate that SLC25A51 overexpression correlates with poor prognosis, while its depletion disrupts mitochondrial metabolism, induces apoptosis, and suppresses AML progression in vivo. Therapeutically, pharmacologic inhibition of SLC25A51 with fludarabine, or its combination with hypomethylating agents, such as 5-azacytidine, enhances antileukemic efficacy by perturbing metabolic and epigenetic regulation. Moreover, SLC25A51 expression may serve as a predictive biomarker for mitochondrial-targeted therapies, such as complex I inhibitors. Future translational research should focus on developing selective inhibitors, optimizing combination strategies with demethylating agents and BCL-2 inhibitors, and validating its prognostic significance in clinical cohorts. Collectively, SLC25A51 represents a promising metabolic target with potential to overcome therapeutic resistance and improve patient outcomes in AML. Furthermore, this review discusses its potential implications across distinct genetic subtypes of AML (e.g., mutations in TP53, NPM1, and RAS), thereby highlighting key directions for future translational research.
    Keywords:  Acute myeloid leukemia (AML); Metabolic reprogramming; Mitochondrial NAD⁺ transport; SLC25A51; Targeted therapy
    DOI:  https://doi.org/10.1007/s13577-026-01428-7
  55. Mol Biomed. 2026 Jul 22. pii: 117. [Epub ahead of print]7(1):
    SelO-mediated NAD+ hydrolysis safeguards mitochondrial homeostasis.
    Tong Yao, Shuai Wang, Fangfang Zhou.
      
    DOI:  https://doi.org/10.1186/s43556-026-00509-1
  56. Arch Med Res. 2026 Jul 24. pii: S0188-4409(26)00114-1. [Epub ahead of print]57(8): 103492
    Variant Curation and Classification in Rare Disease Genomics: Standards and Emerging Tools for Single-Nucleotide Variant Analysis.
    Jimena Barraza García, Marta García, Leire Echepare Olivera, Carlos Iván Rivera Pedroza, Víctor Del Nogal Soler.
      The widespread adoption of next-generation sequencing (NGS) for rare disease diagnosis has transformed clinical genomics. Multiple approaches have been proposed to standardize and improve the analysis, classification, interpretation, and reporting of genetic variants in clinical settings. This review provides a focused, practical overview of variant curation and current classification frameworks, particularly for single-nucleotide variants (SNVs) and small insertions/deletions within coding regions. These variant types remain the most frequent findings in clinical sequencing and are the primary targets of existing classification guidelines. While highly relevant, other variant types and analytical approaches fall outside the scope of this focused review and are addressed elsewhere in the literature and within this special issue. We distinguish between three related yet conceptually distinct processes: variant curation, defined as the systematic collection and evaluation of evidence; variant classification, defined as the standardized assignment of pathogenicity categories according to established guidelines; and clinical interpretation, which contextualizes a classified variant within an individual patient's phenotype to inform medical decision-making. We will examine advances in the field of variant classification that contribute to improving molecular diagnosis of rare diseases, highlighting the achievements, limitations, and challenges present in each aspect addressed. Key developments in variant classification are reviewed, including the 2015 guidelines and subsequent refinements, population databases, computational predictors, multiplexed functional studies, reanalysis efforts, and collaborative initiatives. Many challenges remain to be addressed, such as the interpretation of non-coding variants, the transition to updated classification frameworks, the diversity in population databases, and the development of new predictors, among others.
    Keywords:  ACMG/AMP guidelines; Pathogenicity predictors; Rare diseases; Variant classification
    DOI:  https://doi.org/10.1016/j.arcmed.2026.103492
  57. Cell Signal. 2026 Jul 24. pii: S0898-6568(26)00420-1. [Epub ahead of print] 112763
    Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.
    Mia Simons Weston, Marta Dominguez Prieto, Nicoleta Moisoi.
      Cellular senescence is a hallmark of ageing and age-related disease and is closely associated with mitochondrial dysfunction and the accumulation of DNA damage. However, the contribution of mitochondria-nucleus communication, mitochondrial quality control (mtQC) and stress signalling to senescence remains incompletely understood. Here, we investigated the interplay between mtQC pathways and cellular stress responses in DNA damage-induced senescence using mouse embryonic fibroblasts (MEFs). MEFs deficient in the mitochondrial protease HtrA2 (proteostasis), the transcription factor Chop (integrated stress response; ISR) or the mitophagy regulator Pink1 were exposed to three mechanistically distinct DNA-damaging agents: bleomycin, etoposide and doxorubicin. Senescence was characterised using multiple complementary markers, including the proportion of high senescence-associated β-galactosidase-positive cells, nuclear size, total and nuclear p21 abundance, and transcriptional analysis of p16, p21 and genes associated with cell-cycle regulation and stress signalling. Mitochondrial dysfunction through mtQC impairment enhanced sensitivity to senescence with HtrA2 and Pink1 loss promoting increased senescence under DNA damage. Although DNA damage response (DDR) was activated as seen by changes in p21 homeostasis, this did not always correlate with senescence levels, which indicates that DDR alone cannot account for all senescence characteristics. The ISR played a modulatory role in the senescence induction, with Chop loss of function reducing senescence induction following DNA damage despite DDR activation. The different DNA damaging drugs produced different senescence outcomes, thus highlighting the importance of the stressor context in addition to the cellular homeostasis mechanisms in the overall senescence profile. This approach allowed, for the first time, to identify senescence subtypes dependent of mtQC and ISR integrity in the context of genotoxic stress.
    Keywords:  Genotoxic stress; Integrated stress response; Mitochondria quality control; Senescence subtypes
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112763
  58. Sci Rep. 2026 Jul 20.
    Numerical simulation of mitochondrial systems for ATP generation and membrane transport.
    Takashi Sato, Tsuyoshi Osawa.
      Simulating intracellular biochemical reactions remains a significant challenge in mathematical modeling because of the complex interactions among diverse molecular species. The natural number simulation (NNS) framework offers a dynamic approach to simulating these reactions using a novel algorithm based on reaction equations. In this study, we developed a computational cell model incorporating mitochondria to examine key metabolic processes, including glucose uptake, glycolysis, the tricarboxylic acid cycle, and ATP synthesis via the electron transport chain. Substrate transport mediated by membrane proteins, such as pyruvate and nicotinamide adenine dinucleotide transporters, and the electron transport chain, was replicated using simplified reaction equations. The simulation results showed that, with appropriately chosen rate constants, the ATP production rate reached approximately 155 molecules s- 1 per ATP synthase. Sensitivity analysis indicated that the number of mitochondrial phosphate transporters and the rate of phosphate transport into mitochondria strongly influence ATP production. The model also showed that intermittent glucose supply has a minimal impact on ATP production and that the framework is capable of incorporating the effects of deuterium-containing water on ATP synthesis. This framework provides a foundation for future efforts in simulating more detailed metabolic pathways and integrating experimental data.
    Keywords:  Glycolysis; Membrane transport proteins; Metabolic modeling; Mitochondrial ATP synthesis; Natural number simulation; Tricarboxylic acid cycle; stoichiometric equations
    DOI:  https://doi.org/10.1038/s41598-026-61463-0
  59. Cell Metab. 2026 Jul 21. pii: S1550-4131(26)00274-3. [Epub ahead of print]
    Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
    Daniel R Weilandt, Won Dong Lee, Michael R MacArthur, Lingfan Liang, Corey D Holman, Qingwei Chu, Alexis J Cowan, Joseph A Baur, Ned S Wingreen, Joshua D Rabinowitz.
      Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, lactate, free fatty acids, and ketones. Yet how the simultaneous homeostasis of these nutrients is achieved remains unclear. Here, we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation ("competitive catabolism"). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes insulin resistance: increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose and thus insulin, which acts to restore proper lipid catabolic flux. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.
    Keywords:  competitive catabolism; differential equation modeling; hyperinsulinemia; insulin regulation; insulin resistance; mass action kinetics; metabolic homeostasis; nutrient competition; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.001
  60. Science. 2026 Jul 23. 393(6809): eadt8307
    Epigenetic and 3D genome reprogramming during the aging of the human hippocampus.
    Nathan R Zemke, Seoyeon Lee, Sainath Mamde, Bing Yang, Nicole Berchtold, B Maximiliano Garduño, Hannah S Indralingam, Weronika M Bartosik, Pik Ki Lau, Keyi Dong, Emily Hsu, Amanda Yang, Yasmine Tani, Chumo Chen, Qiurui Zeng, Varun Ajith, Liqi Tong, Chanrung Seng, Daofeng Li, Ting Wang, Jingtian Zhou, Joseph R Ecker, Christopher K Glass, Carl W Cotman, Xiangmin Xu, Bing Ren.
      Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. To unravel these complexities, we analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin architecture from human hippocampal tissues spanning the adult lifespan. We identified both linear and nonlinear dynamic gene regulatory programs during aging. Between the ages of 50 to 75, embryonic yolk sac-derived microglia were depleted and replaced by cells resembling peripheral blood monocyte-derived microglia. Hippocampal astrocytes decreased substantially with age, including those regulating synaptic transmission. Across cell types, 3D genome architecture underwent global erosion. Our analysis provides insights for how altered gene regulatory programs promote cell type-specific aging phenotypes in the human brain.
    DOI:  https://doi.org/10.1126/science.adt8307
  61. Am J Physiol Cell Physiol. 2026 Jul 21.
    Microbiome-associated metabolites, valerobetaine and homocarnitine, inhibit carnitine transport via OCTN2.
    Jaclyn Weinberg, Jennifer Jeon, William J Crandall, Choon-Myung Lee, Zachery R Jarrell, Gahyun Lim, Ho Young Lee, Young-Mi Go, Dean P Jones.
      The intestinal microbiome-derived metabolite, valerobetaine (δ-valerobetaine), promotes obesity, hepatic steatosis, and impaired cognition in mice and is associated with obesity, fatty liver disease, diabetes, and cardiovascular disease in humans. Mechanistic studies show that valerobetaine decreases systemic carnitine and inhibits mitochondrial fatty acid oxidation. Valerobetaine and its mammalian hydroxylation product, homocarnitine, share close structural homology with carnitine, which is mainly transported by the organic cation transporter OCTN2. To determine whether reductions in systemic carnitine induced by valerobetaine and homocarnitine result from interactions with OCTN2, we performed in vitro uptake studies using HEK293 cells overexpressing human OCTN2 coupled with metabolite measurement by mass spectrometry. OCTN2 overexpression increased the uptake rates of both homocarnitine and valerobetaine relative to control cells. Meldonium, an OCTN2 substrate and inhibitor, reduced uptake of both metabolites in a concentration-dependent manner. Saturating uptake kinetics were observed for valerobetaine whereas homocarnitine exhibited linear uptake across the concentration range tested (1-100 μM). Both metabolites exhibited lower transport efficiency compared to the carnitine precursor γ-butyrobetaine and showed relatively lower potency in inhibition of carnitine uptake. Together, these findings identify homocarnitine and valerobetaine as modulators of carnitine transport and provide a mechanistic basis by which these microbiome-derived metabolites lower systemic carnitine levels and impair mitochondrial fatty acid oxidation.
    Keywords:  OCTN2; carnitine; microbiome; transporter; valerobetaine
    DOI:  https://doi.org/10.1152/ajpcell.00317.2026
  62. STAR Protoc. 2026 Jul 23. pii: S2666-1667(26)00380-1. [Epub ahead of print]7(3): 104727
    A scalable plate reader-based protocol to measure mitochondrial respiration in embryonic hearts.
    Chiemela Ohanele, Jennifer Q Kwong.
      Mitochondrial function is central to embryonic development, yet its assessment in the embryonic heart is hampered by limited tissue availability. Here, we present a protocol to measure mitochondrial oxygen consumption rates directly from embryonic mouse hearts using a fluorescence-based plate reader assay. We describe steps for heart isolation, plate setup, and acquisition of signal profiles. We then detail procedures for normalization and rate conversion. This protocol enables real-time readings with a low input requirement of one heart.
    Keywords:  Cell Biology; Developmental biology; Metabolism; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2026.104727
  63. Nat Aging. 2026 Jul 24.
    Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
    Mariah F Calubag, Ismail Ademi, Cara L Green, Dulmalika N H Manchanayake, Hashan S M Jayarathne, Ryan N Marshall, Sandra M Le, Penelope Lialios, Lucia E Breuer, Shoshana Yakar, Reji Babygirija, Michelle M Sonsalla, Isaac Grunow, Chung-Yang Yeh, Yang Liu, Bailey A Knopf, Sarah Yandell, Charles I Opara, William A Ricke, Teresa T Liu, Mark P Keller, Alan D Attie, Marianna Sadagurski, Dudley W Lamming.
      Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s43587-026-01169-0
  64. Cell Oncol (Dordr). 2026 Jul 20.
    Mitochondrial stress-induced cuproptosis: a metabolic bridge to reprogramming the GBM immune microenvironment.
    Wenyang Li, Yaqing Lv, Guanrong Wang, Xiaolei Lan, Leina Ren, Hai Zhao.
      Glioblastoma (GBM) remains the most lethal primary brain malignancy, characterized by profound metabolic heterogeneity and an immunosuppressive tumor immune microenvironment (TIME) that severely limits the efficacy of immune checkpoint blockade. While cuproptosis has recently been defined as a distinct form of regulated cell death driven by copper-induced mitochondrial proteotoxicity, its non-cell-autonomous roles in remodeling the immune landscape remain poorly understood. This review synthesizes emerging evidence to position cuproptosis not merely as a metabolic collapse, but as a potent driver of immunogenic cell death (ICD). We propose a potential "metabolic-immune" signaling axis wherein copper-triggered aggregation of lipoylated TCA cycle enzymes leads to mitochondrial membrane rupture and the subsequent leakage of mitochondrial DNA (mtDNA) into the cytosol. This danger signal is sensed by the cyclic GMP-AMP synthase (cGAS), activating the STING pathway to stimulate type I interferon production. We discuss how this cascade orchestrates a systemic immune response, including the recruitment of cytotoxic CD8 + T cells and the repolarization of tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Furthermore, we highlight the translational potential of copper ionophores and bioengineered nanomedicines as next generation immunomodulators. By integrating copper metabolism with innate immunity, this review provides a strategic roadmap for exploiting mitochondrial stress to reverse immune exclusion and overcome therapy resistance in GBM.
    Keywords:  Cuproptosis; GBM; Immunotherapy; Mitochondrial Stress; Tumor Immune Microenvironment; cGAS-STING
    DOI:  https://doi.org/10.1007/s13402-026-01254-x
  65. Aging Cell. 2026 Aug;25(8): e70638
    The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.
    Aino Heikkinen, Liina Uusitalo-Kylmälä, Ida Blom, Jørn Wulff Helge, Linn Gillberg, Robert Seaborne, Steen Larsen, Macsue Jacques, Robin Grolaux, Sari Aaltonen, Jaakko Kaprio, Birgitta W van der Kolk, Sini Heinonen, Nir Eynon, Kirsi H Pietiläinen, Riikka Kivelä, Eija Pirinen, Miina Ollikainen.
      Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD+, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4-6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.
    Keywords:  epigenetic aging; high‐intensity interval training; mitochondria; nicotinamide riboside; skeletal muscle; twins
    DOI:  https://doi.org/10.1111/acel.70638
  66. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261469197
    Patients' lived experience of thymidine kinase 2 deficiency: the online survey-based assessment of TK2d patient perspectives study.
    Amel Karaa, Asha Hareendran, Katie Waller, Philip Yeske, Alexandra Morrison, Marnie Ross, Cristy Balcells.
       Background: Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial disease characterized by progressive myopathy.
    Objectives: To understand patient experiences and the impact of TK2d on patient quality of life (QoL), and to explore support needs.
    Design: A cross-sectional international online survey.
    Methods: The survey for the Assessment of TK2d Patient Perspectives (ATP) study, co-created with patient advocates, included multiple-choice questions, verbal rating scales, and open free-text questions. Patients of all ages with a self-reported genetic diagnosis of TK2d were eligible to participate, either directly or through a caregiver proxy. The patient, caregiver proxy, or bereaved caregiver proxy answered questions on demographics, signs/symptoms, impacts on health-related QoL (HRQoL), support needs, healthcare resource use, and overall experience of living with TK2d. Quantitative data were summarized with descriptive statistics. Qualitative data were analyzed using inductive thematic analysis.
    Results: Responses for 32 patients (24 patient and 8 caregiver proxy responses) were collected between September 2023 and February 2024. All patients experienced myopathic symptoms. The most frequently reported impact of TK2d was on patients' ability to perform basic activities of daily living (26/32), including difficulties in walking (22/32), eating/swallowing (19/32), and breathing (25/32). The proportions of patients reporting a moderate or severe impact of breathing and walking difficulties on HRQoL, and the proportions requiring medical devices, were higher for those with an earlier age of TK2d symptom onset (⩽2, vs >2 to ⩽12, or >12 years). For most patients, TK2d also had a negative impact on mood, social and leisure activities, and employment/education. Progressive loss of abilities, increasing dependency on others, and medical equipment use contributed to mental and emotional burdens.
    Conclusion: These quantitative and qualitative analyses of patients' lived experiences highlight the substantial, progressive, and wide-ranging burden of TK2d.
    Keywords:  burden; patient experience; quality of life; thymidine kinase 2 deficiency
    DOI:  https://doi.org/10.1177/26330040261469197
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒26 at 10:07.