bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–08–02
eighty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
  2. Ribosome-associated chaperones integrate co-translational mitochondrial protein import, stress signaling and proteostasis in Saccharomyces cerevisiae.
  3. MSeqDR PMD-VR: An Expert-Curated Virtual Registry of 11,000 Mitochondrial Disease Cases Established Through Literature Mining and Generative AI Augmentation.
  4. Mitochondrial Genetic Diseases and Ophthalmic Manifestations: Molecular Pathophysiology, Genetics, and Clinical Management.
  5. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  6. Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.
  7. A coupled TOM-TIM22 supercomplex in human mitochondrial protein import.
  8. Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes.
  9. Mechanistic Modeling of MCUx Gatekeeping, Ca2+ Transport, and Coupled Cytosolic-Mitochondrial Ca2+ Dynamics.
  10. MSTO1 functions as a TRiC assembly factor linking cytosolic proteostasis to mitochondrial function.
  11. Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
  12. Non-Mammalian Models for Mitochondria Research in CNS Disorders.
  13. Lighting up mitochondrial membranes: Reading and writing the physical state of the inner mitochondrial membrane.
  14. Systematic review of Leber's hereditary optic neuropathy - Clinical diagnosis, genetics overview and current concepts of treatment.
  15. Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
  16. Trans-Mitochondrial Cybrid Generation from mtDNA Patient Platelets: An Efficient Protocol Optimizing Colony Selection and Functional Validation.
  17. ATL2 Recruits TRAK1 to Promote Mitochondrial Transport at ER-Mitochondria Contact Sites.
  18. Sustained loss of Pptc7 triggers variable skeletal muscle dysfunction and diminished body mass through dysregulation of BNIP3.
  19. Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.
  20. The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.
  21. Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites.
  22. Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.
  23. Mitochondrial metabolism and epigenetic crosstalk drive SASP.
  24. Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
  25. MTERF1 loss buffers against pathogenic mtDNA deletions through transcriptional regulation.
  26. Spaceflight-relevant microgravity triggers a sublethal Parkinson's-like dopaminergic decline in human neurons and organoids.
  27. The nuanced role of mitochondrial ROS in modulating aging and aging hallmarks.
  28. Mitochondrial uncoupling therapy reduces established atherosclerosis in mice.
  29. Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
  30. An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
  31. Restoring Parkin Function: An AAV Gene Therapy Approach for Early-Onset Parkinson's Disease.
  32. In vivo changes in zebrafish anesthetic sensitivity in response to the loss of kif5Aa are associated with the alteration of mitochondrial motility.
  33. Digital Cognitive Testing in Mitochondrial Disease: Validity and Challenges for Clinical Trial Use.
  34. Resolving the subcellular redox landscape of Coenzyme Q.
  35. The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
  36. Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
  37. Molecular diagnostic platforms for mitochondrial diseases by conventional and long-read sequencing: Missing pieces.
  38. Integrative structure determination of a human mitochondrial contact site and cristae organizing system (MICOS) sub-assembly.
  39. Molecular Diagnosis to Individualized Therapies in Rare Genetic Diseases: New Approach Methodologies, RNA Therapeutics, and the Case for a Human-First Filter.
  40. Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
  41. STING Goes Mitochondrial: A Metabolic Regulator in Diabetic Cardiomyopathy.
  42. Oxygen-stable streptolysin O variant enables mitochondrial ATP synthesis analysis in minimal cells blood and tissues.
  43. Phenotypic Variations in a Large Family with Dominant Optic Atrophy Related to a Novel OPA1 Deletion.
  44. Nanoscale biointerfaces in inter-organelle communication: membrane contact sites, organelle trafficking, and cell fate control.
  45. Targeted modulation of IGFBP5/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma.
  46. Optimized Isolation and Cryopreservation of Functional Mitochondria for Transplantation and Therapeutic Applications.
  47. Ckmm-Cre transgenic mice maintain phenotypic and cardiac mitochondrial homeostasis during ketogenic feeding.
  48. COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating.
  49. Lineage-Tailored Vesicles from Human Retinal Ganglion-Like Cells Drive Metabolic Homeostasis and Bioenergetic Recovery in Glaucoma.
  50. To help children with rare diseases, we must solve drug delivery.
  51. A C. elegans-to-Mouse Discovery Framework for Prioritizing Sarcopenia Interventions.
  52. The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.
  53. Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.
  54. Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression.
  55. Multi-generational mitochondrial complex V deficiency due to the recurrent ATP5F1A c.620G>A (p.Arg207His) pathogenic variant: A novel family and a review of the literature.
  56. The Impact of Ageing on Skeletal Muscle: Roles of Mitochondrial Dysregulation, Systemic Communication, and Exercise.
  57. TRF2 couples muscle stem cell identity to regenerative repair.
  58. Fertility clinics are offering young mitochondria in controversial fertility technique.
  59. In-cell cryo-electron tomography reveals differential effects of type I and type II kinase inhibitors on LRRK2 filament formation and microtubule association.
  60. Running towards induced pluripotent stem cells.
  61. Super-resolution live imaging reveals spatiotemporal uncoupling of mitochondria-ER contacts and mitochondrial fission in stem cell aging.
  62. Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
  63. Mitochondrial Dysfunction in Circulating Blood Cells and Biological Aging: A Review of Mechanisms and Evidence.
  64. Mitochondrial UQCRC2 as a Redox-Regulatory Node in Metabolic and Cardiometabolic Diseases.
  65. Preparation and Characterization of Neutrophil Membrane-Fused Mitochondria (nMITO).
  66. Matrix polyamines regulate bidirectional calcium flux through MCU.
  67. Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.
  68. Mitochondria-to-plasma-membrane H2O2 signaling induced by branched-chain keto acid oxidation essentially stimulates insulin secretion in pancreatic β-cells.
  69. PhenoSS: phenotype semantic similarity-based approach for rare disease prediction and patient clustering.
  70. Spontaneous and indefinite blinking in upconverting nanoparticles for ångström-precision multicolour super-resolution imaging.
  71. cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.
  72. A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies.
  73. Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
  74. Futile cycles in metabolic flexibility: The energetic cost of regulatory precision.
  75. Distributed clonal deletion prevents autoimmune disease progression.
  76. Mapping the chaperonin TRiC/CCT interactome in mouse photoreceptors reveals functional significance for energy metabolism.
  77. DRP lyase deficient DNA polymerase beta impairs mitochondrial electron transport chain and compromise mitochondrial DNA integrity.
  78. Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.
  79. Turritopsis nutricula-Inspired Engineered Biomimetic Skin Promoting Aged Wound Repair via DAZAP1 Phase Separation-Related Mitochondrial Metabolism Reprogramming.
  80. Olduvai Domains Downregulate Mitochondrial Pathways to Promote Human Brain Evolution and Neoteny.
  1. Sci Adv. 2026 Jul 31. 12(31): eaef0140
    Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
    Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.
      Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.aef0140
  2. Genetics. 2026 Aug 01. pii: iyag200. [Epub ahead of print]
    Ribosome-associated chaperones integrate co-translational mitochondrial protein import, stress signaling and proteostasis in Saccharomyces cerevisiae.
    J Ernesto Bravo-Arévalo, Ariann E Mendoza-Martínez, Teresa Ballado, Ericka Moreno-Méndez, Alexander DeLuna, Soledad Funes.
      Mitochondrial biogenesis requires the coordinated synthesis, targeting, and import of nuclear-encoded mitochondrial precursor proteins. Although ribosome-associated chaperones support co-translational protein folding, their genetic contributions to mitochondrial protein import and cellular homeostasis remain incompletely defined. Here, we investigate the roles of the nascent polypeptide-associated complex (NAC) and the ribosome-associated Hsp70 system Ssb1/2 in Saccharomyces cerevisiae. We show that NAC and Ssb1/2 have distinct yet partially overlapping functions in the handling of mitochondrial precursor proteins. Loss of NAC activates the mitochondrial retrograde pathway and enhances growth on ethanol as a non-fermentable carbon source without compromising respiratory competence, indicating metabolic adaptation rather than overt mitochondrial dysfunction. In contrast, Ssb1/2 deficiency disrupts cytosolic proteostasis, sensitizes cells to TORC1 inhibition, and impairs autophagy and mitophagy. Using a TEV protease-based import reporter, we show that Ssb1/2 promotes efficient co-translational distribution of precursor proteins, whereas NAC limits the accumulation of misfolded proteins at the mitochondrial surface. Biochemical analyses further reveal that Ssb1/2 supports the association of translating cytosolic ribosomes with the mitochondrial outer membrane, while NAC loss partially restores this interaction in the absence of Ssb1/2. Together, these findings establish NAC and Ssb1/2 as key components of an integrated network linking co-translational targeting, mitochondrial signaling, and cellular homeostasis.
    Keywords:   Saccharomyces cerevisiae ; Ribosome-associated chaperones; TORC1 signaling; co-translational targeting; mitochondrial protein import; proteostasis; retrograde signaling
    DOI:  https://doi.org/10.1093/genetics/iyag200
  3. Genes (Basel). 2026 Jun 30. pii: 757. [Epub ahead of print]17(7):
    MSeqDR PMD-VR: An Expert-Curated Virtual Registry of 11,000 Mitochondrial Disease Cases Established Through Literature Mining and Generative AI Augmentation.
    Lishuang Shen, Marie T Lott, Elizabeth M Mccormick, Colleen C Muraresku, Kierstin Keller, Douglas C Wallace, Zarazuela Zolkipli-Cunningham, Shamima Rahman, Marni J Falk, Xiaowu Gai.
      Background/Objectives: Patient registries are essential for rare disease research, yet the extensive genetic and phenotypic heterogeneity of primary mitochondrial diseases (PMDs) makes traditional registry development slow and resource-intensive. We established the MSeqDR PMD virtual registry (PMD-VR) to address this gap through systematic literature mining and semi-automated data harmonization. Methods: The PMD-VR captures, standardizes, and harmonizes published case-level PMD data using a semi-automated curation pipeline. A data transformation framework maps heterogeneous raw data terms to standardized common data elements (CDEs). A generative AI (GenAI) platform leveraging large language models (LLMs), augmented by Human Phenotype Ontology (HPO) and external biomedical knowledge sources, accelerates data transformation and generates simulated clinical reports. Results: Currently, PMD-VR contains approximately 11,000 de-identified literature-derived cases, including over 2300 Leigh syndrome spectrum (LSS), 278 MELAS, and 300 CPEO cases. The pipeline mapped 872 heterogeneous terms to 102 standardized CDEs. Pathogenicity assessments were captured for variants in over 7900 cases, including 3800 with mtDNA pathogenic or likely pathogenic variants. Modes of inheritance were inferred for 5212 cases. PMD-VR has supported ClinGen Mitochondrial Diseases Gene Curation Expert Panel (Mito-GCEP) efforts, providing phenotyped evidence for 440 curated LSS cases across 113 PMD genes. Conclusions: PMD-VR is among the largest single PMD registries, offering a scalable, web-accessible platform for generating analysis-ready cohorts from the published literature. It represents a rich resource enabling comprehensive PMD characterization with unprecedented breadth of genetic and phenotypic knowledge.
    Keywords:  Generative AI (GenAI); Leigh syndrome spectrum (LSS); human phenotype ontology (HPO); large language model; literature mining; mitochondrial disease; rare disease
    DOI:  https://doi.org/10.3390/genes17070757
  4. Int J Mol Sci. 2026 Jul 09. pii: 6128. [Epub ahead of print]27(14):
    Mitochondrial Genetic Diseases and Ophthalmic Manifestations: Molecular Pathophysiology, Genetics, and Clinical Management.
    Khaled K Abu-Amero.
      Mitochondrial genetic disorders compromise oxidative phosphorylation (OXPHOS) and cellular energy supply, and the eye is among the first organs to feel the deficit. Photoreceptors and retinal ganglion cells (RGCs) sustain among the highest metabolic rates in the body, so ophthalmic features often dominate the clinical picture and arrive before systemic disease is recognized. More than half of all patients with confirmed mitochondrial disease develop sight-threatening complications. This review integrates mtDNA and nuclear genetics; ophthalmic and extraocular phenotypes; the bioenergetic and apoptotic mechanisms that drive vision loss; the clinical examination and investigations that delineate the problem; the differential diagnoses that must be excluded; the contribution of common mtDNA haplogroup variation to age-related retinal disease; and the diagnostic, therapeutic, and counseling approaches that turn a molecular result into useful care. Recurring themes are heteroplasmy, the threshold effect, and the selective vulnerability of RGCs and extraocular muscle across genetically distinct disorders. Treatment remains largely supportive, but idebenone, gene therapy, mitophagy modulation, and targeted antioxidants now offer mechanism-based intervention for several ophthalmic manifestations.
    Keywords:  clinical management; diseases; genetics; mitochondria; ophthalmology; oxidative stress
    DOI:  https://doi.org/10.3390/ijms27146128
  5. Res Sq. 2026 Jul 22. pii: rs.3.rs-10117408. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia Liu, Catherine Kelly, Ke Bo, Tor Wager, Eugene Mosharov, Martin Picard.
      Mitochondria power brain function and cognition, yet no label-free, non-invasive method has existed to explore their relationship to ageing, disease, and cognition in humans. The MitoBrainMap framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here we tested whether it captures meaningful age- and disease-related variation across individuals. MR-predicted mitochondrial density and tissue respiratory capacity declined with age, whereas intrinsic mitochondrial respiratory capacity was relatively preserved. Correlations among predicted features matched known mitochondrial biology, supporting preliminary construct validity. In patients with genetically confirmed mitochondrial diseases, predicted maps revealed region-specific alterations, notably the expected compensatory upregulation of nuclear- encoded complex II. Predicted features were further associated with the energetic stress marker GDF15 and with cognitive performance, linking brain mitochondrial estimates to systemic physiology and behavior. These findings introduce a first-generation, label-free neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.21203/rs.3.rs-10117408/v1
  6. FEBS Lett. 2026 Jul 29.
    Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.
    Yoshihito Kishita, Manabu Tsuda, Yukiko Sato-Miyata, Satomi Takeo, Toshiro Aigaki.
      Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes involved in central metabolism. In humans, mutations in the lipoyl transferase LIPT2 impair mitochondrial protein lipoylation and cause severe metabolic disease. Here, we investigated the Drosophila homolog, lipT2, in vivo. lipT2 mutants exhibited locomotor defects and shortened lifespan, accompanied by markedly reduced lipoylation of pyruvate dehydrogenase (PDH) and 2-oxoglutarate dehydrogenase (OGDH). Loss of lipT2 impaired glucose oxidation and disrupted tricarboxylic acid (TCA) cycle activity, leading to reduced mitochondrial energy production. Metabolomic analysis revealed altered amino acid homeostasis, including a marked reduction in aspartate, a key TCA cycle-derived metabolite. These findings demonstrate that defective lipoylation disrupts central metabolic processes and energy homeostasis.
    Keywords:  Drosophila melanogaster; LipT2; carbon flux; energy metabolism; metabolic homeostasis; mitochondrial protein lipoylation
    DOI:  https://doi.org/10.1002/1873-3468.70422
  7. Nat Struct Mol Biol. 2026 Jul 31.
    A coupled TOM-TIM22 supercomplex in human mitochondrial protein import.
    Doron Rapaport, Johannes M Herrmann.
      
    DOI:  https://doi.org/10.1038/s41594-026-01852-1
  8. Front Immunol. 2026 ;17 1758569
    Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes.
    Maija Corey, Mahati Rayadurgam, Mousa Vatanmakanian, Alicia Gibbons, Carolina Altbaum, Jeamin Jung, Neha Reddy, Priyanka Saminathan, Kiyokazu Kakugawa, Sonia Sharma.
       Introduction: Mitochondrial DNA depletion syndromes (MDS) caused by deoxyguanosine kinase (DGUOK) deficiency are classically attributed to impaired mitochondrial DNA (mtDNA) maintenance. However, many patients develop hepatic steatosis and inflammation despite preserved mtDNA content, suggesting that additional pathogenic mechanisms contribute to disease. DGUOK is a key enzyme in the mitochondrial purine salvage pathway, but its role in coordinating purine metabolism with lipid homeostasis and innate immune signaling remains poorly understood.
    Methods: Acute DGUOK deficiency was induced in human hepatocellular carcinoma (HepG2) hepatocytes by siRNA-mediated knockdown. Mitochondrial integrity was assessed by mtDNA quantification, mitochondrial morphology, and oxidative phosphorylation (OXPHOS) protein expression. Lipid accumulation was evaluated by BODIPY staining, and transcriptomic changes were analyzed by bulk RNA sequencing. Purine imbalance was modeled by treatment of wild-type cells with 2'-deoxyadenosine, followed by assessment of DNA methylation, interferon signaling, and lipid accumulation.
    Results: Acute DGUOK depletion induced a 2.9-fold increase in intracellular lipid droplet accumulation and activation of a type I interferon (IFN) transcriptional program despite preserved mtDNA copy number, mitochondrial morphology, and OXPHOS complex expression. Bulk RNA sequencing revealed induction of human endogenous retroviruses (HERVs) and interferon-stimulated genes (ISGs), together with suppression of lipid metabolic pathways and remodeling of purine-, methionine-, and methylation-associated networks. Consistent with these transcriptional changes, DGUOK-deficient cells exhibited an approximately 40% reduction in global DNA methylation, accompanied by hypomethylation of CpG-rich region within the ISG15 and ISG20 promoters. Perturbation of purine homeostasis with exogenous 2'-deoxyadenosine phenocopied DGUOK deficiency, driving DNA hypomethylation, activation of viral mimicry pathways, and lipid accumulation.a.
    Discussion: These findings demonstrate that acute DGUOK deficiency promotes innate immune activation and metabolic reprogramming through a purine-dependent mechanism that precedes mtDNA depletion and overt mitochondrial dysfunction. By linking disrupted mitochondrial purine salvage to HERV and ISG derepression, interferon signaling, epigenetic remodeling, and steatosis, this study provides a mechanistic framework for the immunometabolic pathology of DGUOK deficiency and identifies mitochondrial purine metabolism as an important regulator of hepatic immune and metabolic homeostasis.
    Keywords:  deoxyguanosine kinase deficiency; hepatic steatosis; human endogenous retroviral elements; immunometabolism; purine metabolism; type I interferon
    DOI:  https://doi.org/10.3389/fimmu.2026.1758569
  9. Am J Physiol Cell Physiol. 2026 Jul 29.
    Mechanistic Modeling of MCUx Gatekeeping, Ca2+ Transport, and Coupled Cytosolic-Mitochondrial Ca2+ Dynamics.
    Yisak D Asefa, Devanshi D Dave, Said H Audi, Dexuan Xie, Xiaowen Bai, Allen W Cowley, Ranjan K Dash.
      Mitochondrial Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUx), in which MICU1/2 serve as cytosolic Ca2+-sensing gatekeepers that set a Ca2+-dependent activation threshold. Coordinated control of MCUx activity is critical because mitochondrial Ca2+ uptake couples cytosolic Ca2+ signals to metabolic activation and must be regulated to prevent mitochondrial Ca2+ overload and bioenergetic dysfunction. We developed a mechanistic model that incorporates explicit MICU1/2-dependent MCUx gatekeeping and a thermodynamically constrained Ca2+ transport formulation that accounts for Mg2+ inhibition and membrane potential dependence. Cytosolic and mitochondrial Ca2+ dynamics were simulated by integrating the MCUx model into a mitochondrial cation-handling model under multiple Ca2+ stimulation protocols. Because matrix-side Ca2+ regulation of MCUx remains controversial, we also evaluated a putative matrix-side regulatory mechanism by comparing simulations with and without an added matrix-side regulatory module, rather than assuming such regulation as a required feature of the MCUx model. The model reproduces key experimental behaviors across genotypes. In wild-type mitochondria, MCUx-mediated Ca²⁺ uptake is negligible below a cytosolic Ca2+ threshold (~0.2 µM), whereas MICU1-knockout mitochondria show constitutive uptake and MICU2-knockout mitochondria exhibit an intermediate, lowered threshold. Inclusion of matrix-side MCUx regulation transiently attenuated MCUx-mediated Ca²⁺ uptake over an intermediate mitochondrial Ca2+ range, producing higher transient cytosolic Ca2+ and lower transient mitochondrial Ca2+, while both cases approached similar steady states. In addition, cytosolic Mg2+ acts as a graded inhibitor of MCUx-mediated Ca2+ uptake, limiting mitochondrial Ca2+ loading. These results provide a quantitative framework for coupled cytosolic-mitochondrial Ca²⁺ dynamics across diverse conditions.
    Keywords:  Cytosolic-mitochondrial Ca2+ dynamics; MCUx gating; MICU1/2 regulation; Mitochondrial Ca2+ uptake; Mitochondrial calcium uniporter complex (MCUx)
    DOI:  https://doi.org/10.1152/ajpcell.00204.2026
  10. bioRxiv. 2026 Jul 23. pii: 2026.07.21.739937. [Epub ahead of print]
    MSTO1 functions as a TRiC assembly factor linking cytosolic proteostasis to mitochondrial function.
    Amy M Bounds, Chloe Higuchi, Suzanne Hoppins.
      Bi-allelic mutations in MSTO1 are linked to clinical disease phenotypes characteristic of mitochondrial dysfunction, including ataxia and muscular dystrophy. Consistent with this, MSTO1 patient-derived fibroblasts have fragmented mitochondria and a striking loss of mtDNA. Although MSTO1 has been implicated in regulating mitochondrial fusion, the molecular function of this cytosolic protein in vertebrate cells remains unclear. Using the auxin-inducible degradation (AID) system we demonstrate that MSTO1-FLAG-AID protein is rapidly depleted to almost undetectable levels. Importantly, these cells recapitulate the fragmented mitochondrial phenotype observed in patients and thus are a valuable model of disease. Surprisingly, prior to any changes in mitochondria, we show that MSTO1-depleted cells have a significant decrease in TRiC levels, an essential cytosolic ATP-dependent chaperone required to fold diverse substrates, including actin and tubulin. We reveal that TRiC is also reduced in MSTO1 patient-derived fibroblasts, indicating that loss of TRiC may contribute to disease pathophysiology. We further demonstrate that knockdown of TRiC leads to a decrease in MSTO1 protein levels and remarkably, was sufficient to induce a fragmented mitochondrial phenotype, independent of changes in tubulin or actin. This reveals a previously unrecognized connection between TRiC and mitochondrial homeostasis. Using co-immunoprecipitation we found that MSTO1 interacts with the TRiC chaperone. We also observe accumulation of early TRiC assembly subcomplexes in the absence of MSTO1 suggesting that MSTO1 facilitates assembly of TRiC. Together, our findings identify MSTO1 as a TRiC assembly factor and connect mitochondrial defects caused by MSTO1-depletion to the loss of TRiC.
    Significance: MSTO1, a protein linked to myopathy and ataxia, has been thought to control mitochondrial fusion, although the molecular mechanism is unknown. Using rapid depletion of MSTO1, we found that mitochondrial fragmentation appears only after six days. Significantly, the levels of the essential cytosolic chaperonin TRiC are reduced within two days of MSTO1 depletion. Directly depleting TRiC reproduces the fragmented mitochondrial phenotype seen with loss of MSTO1, consistent with a model where mitochondrial dysfunction is a downstream consequence of impaired protein folding rather than a direct effect of MSTO1 loss. We show that MSTO1 is required for assembly of TRiC, identifying it as a long-sought assembly factor for this macromolecular protein complex.
    DOI:  https://doi.org/10.64898/2026.07.21.739937
  11. Signal Transduct Target Ther. 2026 Jul 29. pii: 295. [Epub ahead of print]11(1):
    Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
    Agustina Creus, Shrestha Mohapatra, Leonardo Ortega, David Sebastián.
      Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.
    DOI:  https://doi.org/10.1038/s41392-026-02813-2
  12. Biomolecules. 2026 Jul 22. pii: 1072. [Epub ahead of print]16(7):
    Non-Mammalian Models for Mitochondria Research in CNS Disorders.
    Dubravka Svob Strac, Vedrana Filic, Ana Filosevic Vujnovic, Ivana Vrhovac Madunic, Josip Madunic, Ana Cipak Gasparovic, Ana Havelka Mestrovic, Rozi Andretic Waldowski.
      Mitochondrial dysfunction is increasingly recognized as a major contributor to central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Animal models are essential for elucidating disease mechanisms and supporting the development of new therapeutic strategies. Among these models, non-mammalian organisms offer distinct advantages, including low cost, rapid life cycles, genetic tractability, and suitability for large-scale, high-throughput studies. Organisms such as Saccharomyces cerevisiae, Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio have substantially advanced the understanding of mitochondrial processes relevant to CNS pathology. Studies using these models have revealed conserved mechanisms involving mitophagy, mitochondrial quality control, respiratory function, bioenergetic signaling, and neurodegenerative pathways. Their strengths, including scalability, live imaging capacity, and efficient genetic manipulation, have accelerated disease modeling and therapeutic discovery. However, simplified physiology, evolutionary distance from humans, and the incomplete representation of complex CNS organization limit their translational relevance and often require validation in higher-order organisms. Nevertheless, integrating these models into CNS research, particularly alongside emerging technologies, provides a powerful strategy for linking fundamental mitochondrial biology with translational neuroscience. This review summarizes the use of non-mammalian models in neuroscience research, with an emphasis on mitochondrial dysfunction in CNS disorders and their potential to support future therapeutic advances.
    Keywords:  CNS disorders; Caenorhabditis elegans; Danio rerio; Dictyostelium discoideum; Drosophila melanogaster; Saccharomyces cerevisiae; mitochondria; non-mammalian models
    DOI:  https://doi.org/10.3390/biom16071072
  13. Curr Opin Chem Biol. 2026 Jul 25. pii: S1367-5931(26)00083-9. [Epub ahead of print]94 102734
    Lighting up mitochondrial membranes: Reading and writing the physical state of the inner mitochondrial membrane.
    Gaurav Singh, Sunil Laxman.
      The mitochondrial inner membrane (IMM) is depicted as a scaffold housing the enzymes of the electron transport chain, allowing electron transfer and generation of the electrochemical gradient that drives respiration and adenosine triphosphate (ATP) synthesis. However, evidence from imaging, structural biology, and novel chemical probes reveals that the IMM is not a mere passive backdrop: its physical properties change with the metabolic state, and together these changes influence mitochondrial function. Here, we summarize how IMM microviscosity, lipid packing, and mesoscale organization might shape electron transfer kinetics, reactive oxygen species (ROS) production, and mitochondrial form/function. We discuss new chemical probes that reveal IMM organization, alongside novel chemical/genetic approaches to alter IMM organization and mitochondrial function. Finally, we outline current challenges in measuring or modulating the state of the IMM, suggesting approaches required to address how the IMM state is coupled with electron entry routes, ROS dynamics, and mitochondrial morphology.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102734
  14. Indian J Ophthalmol. 2026 Aug 01. 74(8): 1151-1161
    Systematic review of Leber's hereditary optic neuropathy - Clinical diagnosis, genetics overview and current concepts of treatment.
    Selvakumar Ambika, Sundaramurthy Srilekha.
      Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, typically causing substantial, often permanent, central vision loss in young adults. It manifests as a subacute optic neuropathy, frequently progressing sequentially in both eyes, due to selective degeneration of retinal ganglion cells (RGCs). The condition is primarily associated with three mitochondrial DNA (mtDNA) point mutations-m.11778G>A, m.14484T>C, and m.3460G>A-located in complex I of the mitochondrial respiratory chain. These mutations impair oxidative phosphorylation, elevate reactive oxygen species (ROS), and trigger apoptosis of RGCs. Although historically considered untreatable, emerging therapies provide new prospects. Idebenone, a synthetic CoQ10 analog, is the first pharmacologic agent approved in Europe, demonstrating partial visual recovery in patients treated early by improving mitochondrial electron transport and reducing oxidative stress. Gene therapy using allotopic expression of ND4 via adeno-associated viral vectors (rAAV2/2-ND4) has shown improvement in both eyes even after unilateral injection. Advanced gene-editing techniques, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), offer potential approaches for correcting heteroplasmic mutations. High-throughput genetic testing, including whole-genome sequencing and clinical exome analysis, enables precise identification of nuclear modifiers that influence LHON phenotypes, facilitating early diagnosis and intervention. Current clinical trials, including RESTORE and REFLECT, emphasize the importance of prompt treatment to optimize visual outcomes.
    Keywords:  Allotopic expression; gene therapy; idebenone; mitochondrial inheritance; mitochondrial mutation; mutation-specific/nonspecific treatment; oxidative stress
    DOI:  https://doi.org/10.4103/IJO.IJO_1696_25
  15. Autophagy. 2026 Jul 31.
    Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
    Laura Kristine Rasmussen, Diana Gomes Moreira, Justyna Okarmus, Anne Simonsen, Morten Meyer.
      Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.
    Keywords:  Autophagy receptors; E3 ubiquitin ligases; PINK-PRKN/parkin pathway; PRKN-independent mitophagy; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neurodegeneration; therapeutic targets
    DOI:  https://doi.org/10.1080/15548627.2026.2711596
  16. J Vis Exp. 2026 Jul 10.
    Trans-Mitochondrial Cybrid Generation from mtDNA Patient Platelets: An Efficient Protocol Optimizing Colony Selection and Functional Validation.
    Donna M Iadarola, Jarelis Cabrera, Eiko Nakamaru-Ogiso, Marni J Falk.
      Trans-mitochondrial cybrid cell line generation represents the gold-standard method for determining pathogenicity by enabling biochemical analyses of a specific mitochondrial DNA (mtDNA) variant of interest at high and low percentages (heteroplasmy levels) within an otherwise identical mtDNA and nuclear genome background. Historically, the cybrid generation process has been tedious and poorly efficient. Here, we describe a highly efficient and effective protocol for generating trans-mitochondrial cybrid cell lines by fusing human platelets with a standard osteosarcoma 143B cell line to provide an isogenic nuclear background depleted of mtDNA (Rho0 cells). Cell isolates capture a given mtDNA genome of interest to establish stable cell lines harboring different degrees of heteroplasmy, or to compare divergent effects of distinct mitochondrial haplogroups. Because cybrids from mitochondrial patients may be more difficult to establish with standard protocols, this current methodology focuses on isolating mtDNA variants where the electron transport chain activity is affected. We here demonstrate that colony selection techniques reduce time and improve the yield of generating high-level heteroplasmy mtDNA mutant cybrid lines. A case study is provided of cybrid generation for a variant of unknown significance in MT-ND1, m.3985G>A (p.E227K). We analyze the efficiency of the cybrid generation process using this protocol and run functional studies performed by high-resolution respirometry. High-level heteroplasmy MT-ND1 m.3985G>A cybrid mutants generated by this protocol are shown to have impaired complex I-dependent mitochondrial respiration relative to wild-type control, demonstrating m.3985G>A is likely pathogenic.
    DOI:  https://doi.org/10.3791/71632
  17. Adv Sci (Weinh). 2026 Jul 30. e76972
    ATL2 Recruits TRAK1 to Promote Mitochondrial Transport at ER-Mitochondria Contact Sites.
    Yiru Cheng, Peiyuan Chai, Xiayuhe Pei, Yiwen Chen, Xiaoshuai Huang, Bei Liu, Yiqian Wu, Junlin Teng, Pengli Zheng, Jianguo Chen.
      Mitochondrial transport and distribution are crucial for cellular homeostasis, yet whether and how they are regulated by endoplasmic reticulum (ER)-mitochondria contact sites remains unclear. Here, we demonstrate that the ER protein atlastin-2 (ATL2) orchestrates mitochondrial transport and distribution by promoting assembly of the transport machinery at ER-mitochondria contact sites. Mechanistically, ATL2 recruits the adaptor trafficking kinesin-binding protein 1 (TRAK1) to the ER membrane, strengthening the interaction of TRAK1 with the mitochondrial transport adaptor MIRO1 to promote anterograde mitochondrial transport. Loss of ATL2 disrupts this process, leading to perinuclear mitochondrial clustering. We further find that ATL2 stabilizes ER-mitochondria contact sites by interacting with MFN2, providing a platform for mitochondrial transport complex assembly. Moreover, in hypoxia, ATL2 is ubiquitinated at lysine 567 by the E3 ligase SYVN1, leading to its degradation and a resulting defect in mitochondrial distribution. Our findings elucidate a novel ER-mediated mechanism for mitochondrial transport.
    Keywords:  ATL2; ER–mitochondria contact sites; TRAK1; hypoxia; mitochondrial transport
    DOI:  https://doi.org/10.1002/advs.76972
  18. bioRxiv. 2026 Jul 18. pii: 2026.07.13.738264. [Epub ahead of print]
    Sustained loss of Pptc7 triggers variable skeletal muscle dysfunction and diminished body mass through dysregulation of BNIP3.
    Tessa M Lochetto, Thiago N Menezes, Kevin Cho, Srikar Vegesna, Michaela M Morhaus, Jeremie L A Ferey, Merima Forny, Leah P Shriver, Gretchen A Meyer, Gary J Patti, Natalie M Niemi.
      The mitochondrial phosphatase PPTC7 is required to sustain mammalian metabolism, as its global knockout (KO) triggers hypoketotic hypoglycemia and perinatal lethality in mice. However, the extent to which the loss of Pptc7 manifests pathology beyond the perinatal transition is unknown. Furthermore, PPTC7 was recently identified as dual functional, regulating mitochondrial protein phosphorylation and receptor mediated mitophagy, rendering it unclear which function(s) may influence in vivo physiology. Here, we find that sustained, inducible Pptc7 KO decreased lean mass, compromised whole body oxygen consumption, and altered circulating metabolites in adult male mice. We hypothesized that these phenotypes stemmed from skeletal muscle dysfunction and found lower mass and fiber cross-sectional area with shifts in fiber type distribution in select muscles of the hindlimb in Pptc7 KO animals. Loss of PPTC7 increased BNIP3 protein levels and decreased mitochondrial content in skeletal muscle, suggesting elevated mitophagy may drive pathology. Consistently, KO of Bnip3 rescued the lower body weight and lean mass seen in inducible Pptc7 KO adult animals and partially rescued perinatal lethality in global Pptc7 KO mice. These data demonstrate that loss of PPTC7 incites surprisingly variable dysfunction across physiological contexts that at least partially stems from dysregulated BNIP3.
    DOI:  https://doi.org/10.64898/2026.07.13.738264
  19. Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00845-4. [Epub ahead of print]45(8): 117767
    Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.
    Arijita Ghosh, David Weaver, Chi Li, Gyӧrgy Hajnóczky.
      Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP3 receptor Ca2+ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca2+ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca2+ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca2+ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy of ER-mitochondrial Ca2+ transfer without changing ER Ca2+ release, despite attenuating mitochondrial Ca2+ uptake. We find interaction between Bcl-xL and each IP3R isoform occurring at the mitochondria and a complex formed by OMM-localized Bcl-xL and IP3Rs. OMM Bcl-xL interacts with IP3Rs in trans at ER-mitochondrial contacts to optimize local Ca2+ signal propagation into the mitochondria.
    Keywords:  Bcl-xL; CP: cell biology; CP: metabolism; ERMC; IP3R; calcium signaling; endoplasmic reticulum; local Ca(2+) transfer; mitochondria; organellar crosstalk
    DOI:  https://doi.org/10.1016/j.celrep.2026.117767
  20. bioRxiv. 2026 Jul 17. pii: 2026.07.16.738975. [Epub ahead of print]
    The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.
    Brandon R Desousa, Yohei Abe, Martin Kampmann, Isha H Jain.
      Complex I (CI) is the largest and most disease-associated component of the mitochondrial electron transport chain. While many diseases are linked to defects in specific CI subunits, the extent to which non-mitochondrial proteins contribute to CI function or disease is less clear. Here, we perform genome-wide CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively. These screens identify THAP12 as a previously unrecognized transcriptional regulator of CI biogenesis. THAP12 loss selectively destabilizes CI and impairs oxidative ATP production. Mechanistically, THAP12 functions in the nucleus as a DNA-binding factor that directly activates genes required for CI assembly and iron-sulfur cluster maintenance, including NDUFAF3, NDUFAF4 and BOLA3. Patient-derived fibroblasts carrying THAP12 mutations exhibit conserved transcriptional defects and profound CI deficiency, establishing THAP12-associated neurodevelopmental disorder as a secondary mitochondrial CI disease. Finally, hypoxia rescues growth defects in THAP12-deficient cells, nominating low-oxygen therapy as a potential treatment strategy. Together, these findings identify THAP12 as a dedicated regulator of CI assembly and expand the genetic landscape of CI disease.
    DOI:  https://doi.org/10.64898/2026.07.16.738975
  21. bioRxiv. 2026 Jul 24. pii: 2026.07.23.740218. [Epub ahead of print]
    Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites.
    Sahana Mitra, Giulia Burrone, Surya Rubarajan, Christophe Klein, Tyler Kwok, Suchit Gutta, Keyu Chloe Li, Elizaveta Berson, Joseph Orofino, Maria Dafne Cardamone, Michael Blower, Valentina Perissi.
      Mitochondria relay their functional state to the nucleus via retrograde signaling, yet whether the spatial organization of the mitochondrial network plays a role in this process remains unclear. Here, we show that stress-induced clustering of mitochondria around the nucleus is a crucial part of the retrograde response. Perinuclear clustering facilitates the formation of mitochondria- nucleus contact sites (MNCS) and the nuclear entry of GPS2, a key mediator of mitochondrial retrograde signaling essential for activating nuclear-encoded mitochondrial and stress-response genes in response to various mitochondrial stressors. Unexpectedly, TSPO-driven MNCS are dispensable for GPS2-based retrograde signaling. Instead, we identify the mitochondrial import receptor TOMM70 and the nucleoporin RanBP2/NUP358 as components of a stress-induced nuclear pore-associated tethering complex required for promoting GPS2 nuclear translocation and activation of downstream programs. These findings establish MNCS as a functional gateway for mitochondrial retrograde signaling, highlighting that organelle positioning and tethering at the nuclear pore provide an unexpected layer of stress regulation.
    DOI:  https://doi.org/10.64898/2026.07.23.740218
  22. Metabolites. 2026 Jul 11. pii: 489. [Epub ahead of print]16(7):
    Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.
    Jin Jin, Yang Cheng.
       BACKGROUND/OBJECTIVES: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted.
    METHODS: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies.
    RESULTS: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis.
    CONCLUSIONS: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature.
    Keywords:  MASH; MASLD; fibrosis; insulin resistance; metabolic syndrome; metabolomics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/metabo16070489
  23. Nature. 2026 Jul 29.
    Mitochondrial metabolism and epigenetic crosstalk drive SASP.
    Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.
      Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.
    DOI:  https://doi.org/10.1038/s41586-026-10791-2
  24. Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2602775123
    Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
    Wasi Iqbal, Ben Zucker, Xiaoying Liu, Ruiru Wang, Hongfei Zhu, Sijie Chen, Renjie Zhou, Xingguo Liu, Michael M Kozlov, Liting Duan.
      Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.
    Keywords:  membrane elasticity; membrane pearling; membrane tension; mitochondria; mitochondrial fission
    DOI:  https://doi.org/10.1073/pnas.2602775123
  25. bioRxiv. 2026 Jul 17. pii: 2026.07.16.738964. [Epub ahead of print]
    MTERF1 loss buffers against pathogenic mtDNA deletions through transcriptional regulation.
    Tamar Kavlashvili, Elim Choi, Ruobing Cui, Juan C Landoni, Simon Zhang, Stefan Isaac, Stirling Churchman, Suliana Manley, Craig Thompson, Agnel Sfeir.
      Large-scale mitochondrial DNA (mtDNA) deletions cripple oxidative phosphorylation once they exceed a critical heteroplasmy threshold, causing incurable mitochondrial pathologies. Using a genome-wide CRISPR/Cas9 screen in an engineered human cell line carrying a large-scale mtDNA deletion at high heteroplasmy, we identified mitochondrial transcription termination factor 1 (MTERF1) as a suppressor of the heteroplasmy burden. Loss of MTERF1 restored mitochondrial function and increased cellular proliferation in cells with a mtDNA deletion burden exceeding the pathogenic threshold, without altering heteroplasmy or mtDNA copy number. MTERF1 binds wild-type and deletion-bearing mitochondrial genomes indiscriminately at a site downstream of the ribosomal RNA genes and curbs transcription. Relieving this constraint broadly increased OXPHOS transcripts, thereby eliciting more respiratory output from the residual wild-type genomes. Notably, the buffering effect of MTERF1 loss extended beyond mtDNA deletions. In a counter-screen, MTERF1 loss could also restore respiratory growth in cells depleted of nuclear-encoded mitochondrial genes such as OPA1 and COX5A . Together, these findings indicate that by relieving a transcriptional constraint, MTERF1 loss compensates for reduced genome dosage, defining a strategy to enhance residual mitochondrial function in mtDNA deletion disorders and related conditions.
    DOI:  https://doi.org/10.64898/2026.07.16.738964
  26. bioRxiv. 2026 Jul 15. pii: 2026.07.09.737494. [Epub ahead of print]
    Spaceflight-relevant microgravity triggers a sublethal Parkinson's-like dopaminergic decline in human neurons and organoids.
    Nilufar Ali, Shehbeel Arif, Max-Florian Mortimer, Matthew Brandner, Joshua Baldridge, Ruben Ferreira Paiva, Mukta S Sane, Shin Pu, Luke Woodbury, Gunes Uzer, Cheryl Jorcyk, Greg Hampikian, Masihhur Laskar, Julia Oxford.
      Spaceflight stressors may increase Parkinson's disease (PD) risk, but microgravity's specific contribution to human dopaminergic (DA) vulnerability remains undefined. Here, we exposed human iPSC-derived midbrain DA organoids and differentiated SH-SY5Y neurons to simulated microgravity for 72 hours. This exposure reduced neurite outgrowth, eroded DA identity, and activated familial-PD mitochondrial kinases without depleting extracellular dopamine. We observed severe mitochondrial dysfunction-including membrane potential loss and respiratory suppression-coupled with global translational repression. Furthermore, a sublethal, pre-degenerative state emerged, characterized by the selective release of mitochondrial cell-free DNA without apoptotic activation. Proteomic profiling revealed striking convergence with human PD transcriptomes and astronaut blood, highlighting shared suppression of mitochondrial metabolism, ribosomal translation, and altered RNA splicing. Together, these findings establish simulated microgravity as a sufficient, non-toxin trigger of early PD-like DA dysfunction, providing a robust human model for investigating prodromal neurodegeneration.
    Keywords:  Parkinson’s disease; iPSC organoids; mitochondrial dysfunction; neurodegeneration; simulated microgravity
    DOI:  https://doi.org/10.64898/2026.07.09.737494
  27. Redox Biol. 2026 Jul 24. pii: S2213-2317(26)00318-6. [Epub ahead of print]96 104319
    The nuanced role of mitochondrial ROS in modulating aging and aging hallmarks.
    Annika Müller-Eigner, Elena Morin, Katherine S Morton, Andrew P Wojtovich.
      Aging is characterized by a progressive decline in cellular integrity and function, making it a major risk factor for numerous disease pathologies. Mitochondrial dysfunction and oxidative stress have long been recognized as contributors to the aging phenotype. The loss of mitochondrial function and the overproduction of reactive oxygen species (ROS) are linked to many hallmarks of aging and are associated with a wide range of diseases; however, their role in the aging process is nuanced. Mitochondria produce ROS as harmful respiratory byproducts, but ROS can also act as a signaling molecule with emerging functions linked to variables such as location, timing, and quantity. Similarly, mitochondrial dysfunction is often broadly categorized, overlooking its multifaceted nature and diverse contributions to aging. Due to this complexity, our understanding of how mitochondrial ROS production shapes disease processes and aging hallmarks remains limited. This review aims to clarify the complex and nuanced role of mitochondrial ROS in aging by focusing on ROS production within mitochondria, especially complexes I, II and III, and exploring how these localized ROS influence various hallmarks of aging to contribute to the aging phenotype.
    Keywords:  Aging; And complex III; Complex I; Complex II; Hallmarks of aging; Mitochondria; Mitochondrial ROS; Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2026.104319
  28. Nat Rev Cardiol. 2026 Jul 28.
    Mitochondrial uncoupling therapy reduces established atherosclerosis in mice.
    Irene Fernández-Ruiz.
      
    DOI:  https://doi.org/10.1038/s41569-026-01330-7
  29. Bio Protoc. 2026 Jul 20. 16(14): e5746
    Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
    Katie G Vineall, Danielle L Schmitt.
      Phosphatase and tensin homolog-induced kinase 1 (PINK1) is a serine/threonine kinase that plays a key role in mitophagy initiation. Loss-of-function autosomal recessive mutations in PINK1 cause early onset Parkinson's disease (EOPD). Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity or provide an indirect readout of PINK1 activity. Here, we present a protocol using our newly developed phase separation-based PINK1 biosensor (PINK1-SPARK) to observe real-time activity of endogenous PINK1 in single cells. Following transfection of live cells with PINK1-SPARK, cells are treated with mitochondrial depolarizing agents and visualized using widefield or confocal fluorescence microscopy, either following the same cells over time for time-lapse imaging of PINK1 activity or end-point measurements. Thus, PINK1-SPARK is a new tool that enables the measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function. Key features • Detailed protocol for use of PINK1-SPARK, a new PINK1 biosensor introduced in Vineall et al. [1]. • PINK1-SPARK, based on phase separation, has a high signal-to-noise, enabling robust detection of PINK1 activity in multiple cell types under multiple activating conditions. • Enables measurement of real-time endogenous PINK1 activation at the single-cell level.
    Keywords:  Biosensor; Fluorescence microscopy; Functional imaging; Kinase activity reporter; Mitophagy; PINK1
    DOI:  https://doi.org/10.21769/BioProtoc.5746
  30. Science. 2026 Jul 30. 393(6810): eads5397
    An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
    Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Dean R Campagna, Mark D Fleming, Sarah Ducamp, Julia R Kardon.
      Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
    DOI:  https://doi.org/10.1126/science.ads5397
  31. bioRxiv. 2026 Jul 13. pii: 2026.07.09.737487. [Epub ahead of print]
    Restoring Parkin Function: An AAV Gene Therapy Approach for Early-Onset Parkinson's Disease.
    Sambuddha Basu, Tyler G Demarest, Nicholas J Gattone, Alexandra J Gilsrud, Brittany Wicks, Apeksha Khatiwada, Mohammad Nayal, Renee Gentzel, Daniel Cohen, Eric W Kostuk, Derek P Narendra, Pedro Gonzalez-Alegre, Maria-Grazia Biferi, Elizabeth A Ramsburg.
       Background: Biallelic loss-of-function mutations in PRKN gene (encoding Parkin protein) cause early-onset Parkinson's disease (EOPD). Parkin is a crucial component of PINK1-Parkin pathway, which marks damaged mitochondria for degradation via mitophagy. Without functional Parkin, damaged mitochondria accumulate, causing oxidative stress and neurodegeneration.
    Objective: Investigate Parkin gene replacement via AAV gene therapy as a potential treatment for Parkin-dependent EOPD.
    Methods: We initially validated phosphorylated ubiquitin Ser65 (pUb Ser65 ) as an indicator of Parkin-mediated mitophagy initiation. We evaluated AAV-mediated PRKN replacement (hereafter, AAV-Parkin) in a Parkin knockout neuroblastoma cell line (SH-SY5Y cells) and feasibility of delivery in mouse and rat models.
    Results: Our research showed pUb Ser65 signal was reduced in Parkin-KO SH-SY5Y cells when compared to wild-type cells after mitochondrial stress, indicating deficiency in initiation of mitophagy. AAV-mediated human PRKN gene replacement successfully restored these pUb Ser65 levels in knockout cells. We saw restoration in patient-derived fibroblasts following AAV-Parkin overexpression. We developed a translatable gene therapy approach using rodents. We demonstrated the feasibility of delivering AAV-Parkin directly into the substantia nigra (SN) of wild-type rats. Using an AAV1 capsid with Ef1a promoter, we achieved dose-dependent Parkin expression and identified a well-tolerated dose. We also evaluated multiple promoters in a proprietary Spark100 capsid, finding Ef1a and Synapsin1 (Syn1) were most effective for transducing dopaminergic neurons in the SN of mice without causing adverse effects. These findings established a well-tolerated vector dose and an optimal capsid-promoter combination.
    Conclusions: Our results support the potential of AAV-Parkin gene therapy as a disease-modifying approach for Parkin-deficient EOPD.
    DOI:  https://doi.org/10.64898/2026.07.09.737487
  32. PLoS One. 2026 ;21(7): e0316959
    In vivo changes in zebrafish anesthetic sensitivity in response to the loss of kif5Aa are associated with the alteration of mitochondrial motility.
    Priya Dubey, Roshni Datta, Roderic G Eckenhoff, Victoria M Bedell.
      Anesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the motor domain of a neuronal mitochondrial transport kinesin, kif5A. Here, we used zebrafish wild type (WT) and kif5Aa knockout (KO) larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alterations in mitochondrial motility. We found that the loss of kif5Aa increases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast, kif5Aa KO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT and kif5Aa KO larvae responded similarly to the behavioral effects of ketamine. Propofol inhibited the anterograde motility of mitochondria in WT zebrafish neurons, while etomidate inhibited mitochondrial motility in both anterograde and retrograde directions; neither drug altered mitochondrial motility in the kif5Aa knockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT and kif5Aa KO animals. Finally, ketamine had little significant effect on mitochondrial motility in either mutant or WT animals. These data demonstrate that each anesthetic/sedative drug affects the motor protein machinery uniquely and is associated with unique changes in behavior. Understanding how different anesthetic compounds alter neuron motor proteins will be important in defining how anesthetics alter neuronal signaling and energetic dynamics.
    DOI:  https://doi.org/10.1371/journal.pone.0316959
  33. Ann Clin Transl Neurol. 2026 Jul 31.
    Digital Cognitive Testing in Mitochondrial Disease: Validity and Challenges for Clinical Trial Use.
    Oksana Pogoryelova, Jan Smeitink, Herma Renkema, Rosabeth White, Frankie Barton, Rachel Lyon, Jane Newman, Aye Moe, Yi Shiau Ng, Grainne Siobhan Gorman.
       BACKGROUND: Primary mitochondrial disease is a group of genetic disorders caused by pathogenic variants in nuclear or mitochondrial DNA, often resulting in progressive neurodegeneration and cognitive decline. Current management is primarily supportive, though recent research offers hope for disease-modifying treatments in the future. Selecting appropriate therapeutic outcomes for clinical trials in mitochondrial diseases is challenging due to limited sensitivity to changes, small sample sizes, and the burden of study related activities. This study aims to identify an efficient choice of cognitive endpoints for translational research.
    METHODS: This study compared digital cognitive assessments with traditional paper-based tools. It included two cohorts: the Newcastle cohort of 45 patients recruited from the mitochondrial clinic Newcastle upon Tyne (UK) and the KHENERGYZE clinical trial cohort of 27 patients recruited from four European countries. Patients in the Newcastle cohort underwent two conventional cognitive assessments (Addenbrooke's Cognitive Examination and Montreal Cognitive Assessment), along with two computerized tests (Cogstate and Test of Attentional Performance). Potential confounding factors were also assessed.
    RESULTS: Both cohorts showed a high prevalence of moderate to severe perceived fatigue. Over 50% of patients showed reduced reaction times. Strong correlations were found between conventional and digital assessments. Several confounding factors such as education and employment were identified as influencing cognitive performance.
    CONCLUSIONS: The findings support the understanding of mitochondrial disease as a slowly progressive condition, where impaired cognitive function is evident even in patients in the absence of devastating CNS manifestations such as stroke-like episodes. Observed variability in cognitive performance may help detect meaningful changes over time.
    Keywords:  minimal clinically important differences; neurocognitive assessments; neurodegeneration; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/acn3.70463
  34. Cell Chem Biol. 2026 Jul 30. pii: S2451-9456(26)00243-6. [Epub ahead of print]
    Resolving the subcellular redox landscape of Coenzyme Q.
    Tae Ha Kim, Chi Thi Ngoc Nguyen, Dahee Jang, Sae Bom Lee, Yun Jae Cha, Seon Min Kim, Yun Ji Lim, Tae Hwan Choi, Taeryeong Kim, Jae-Young Lee, Eun-Woo Lee, Sung Eun Kim, Tong-Shin Chang, You Jeong Lee, Maria Fedorova, Derek A Pratt, Marcus Conrad, Sung Won Kwon, Yun Pyo Kang.
      Coenzyme Q (CoQ) is an essential electron carrier and lipophilic antioxidant whose biological functions depend on its redox state. However, accurate measurement of reduced and oxidized CoQ is hindered by rapid ex vivo oxidation during sample preparation and analysis. Here, we develop a dual-isotope-based oxidation-correction LC-MS/MS platform that enables accurate quantification of CoQ redox status across diverse biological matrices. Coupled with rapid subcellular fractionation, this approach resolves cytosolic and mitochondrial CoQ pools and reveals that the CoQ10H2/CoQ10 ratio is substantially higher in the cytosol than in mitochondria. During ferroptosis, compartment-specific remodeling of CoQ redox status is observed, consistent with distinct roles for CoQ in plasma membrane and mitochondrial biology. The platform also enables robust analysis of plasma CoQ redox status in mouse and human samples. These advances provide a broadly applicable approach for studying redox biology, ferroptosis, mitochondrial metabolism, and biomarker discovery.
    Keywords:  CoQ; clinical biomarker; dual-isotope-based oxidation correction; ferroptosis; mass spectrometry; redox biochemistry; subcellular fractionation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.001
  35. J Cell Sci. 2026 Jul 15. pii: jcs265083. [Epub ahead of print]139(14):
    The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
    Rebecca Morrison, Simeon R Mihaylov, Chak Hon Luk, Cyril Lemerle, Angela Rodgers, Natalia Athanasiadi, Huw R Morris, Enrica Pellegrino, Sila K Ultanir, Maximiliano G Gutierrez.
      Variants in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, yet how these variants alter immune cell function remains unclear. Because LRRK2 is activated by lysosomal damage in macrophages, we investigated how the pathogenic G2019S variant affects macrophage responses to lysosomal damage. Here, we show that LRRK2 G2019S has an effect during lysosomal damage through kinase-dependent and kinase-independent mechanisms. Phosphoproteomic analysis revealed that lysosomal damage induces selective rewiring of LRRK2-dependent Rab GTPase phosphorylation, characterised by increased Rab12 phosphorylation and reduced Rab35 phosphorylation without global kinase hyperactivation. Strikingly, LRRK2 G2019S macrophages showed increased susceptibility to apoptosis following lysosomal damage. This increase in cell death occurred independently of the kinase activity, indicating a distinct kinase-independent role of LRRK2 in regulating cell survival. We generated isogenic induced pluripotent stem cells from patients carrying the LRRK2 G2019S variant and confirmed that LRRK2 G2019S macrophages are more susceptible to cell death in a kinase-independent manner. Together, our findings support a model in which the LRRK2 G2019S variant selectively changes the phosphorylation of Rab GTPases in macrophages and increases cell death after lysosomal damage in macrophages.
    Keywords:  Apoptosis; LRRK2; Lysosomal damage; Macrophage; Parkinson's disease; Rab GTPase
    DOI:  https://doi.org/10.1242/jcs.265083
  36. Curr Issues Mol Biol. 2026 Jun 23. pii: 645. [Epub ahead of print]48(7):
    Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
    Xiaobing Zhang, Huiyu Li, Jiaxin Zhao, Jiawen Tang, Xiaoqing Li, Pengjing Li, Qingyun Zhao, Qi Wang, Wei Zou.
      The second most prevalent neurodegenerative illness in the world, Parkinson's disease (PD), currently has no viable treatments. Although it is yet unknown if mitochondrial dysfunction is an initial event or evolves as a result of neurodegeneration, it is thought to be a crucial component of Parkinson's disease etiology. From the perspective of mitochondrial quality control (MQC), which includes PINK1/Parkin-mediated mitophagy, mitochondrial dynamics, and mitochondrial proteostasis, this article examines mitochondrial dysfunction. Together, these processes preserve mitochondrial homeostasis and prevent the buildup of damaged mitochondria. Dysfunctional mitochondria gradually build up and cause oxidative stress and aberrant cellular signaling when mitochondrial quality control is compromised. According to available data, mitochondrial reactive oxygen species (mtROS) primarily worsen pre-existing mitochondrial damage by encouraging α-synuclein aggregation, cardiolipin remodeling, and dopamine oxidation. In addition, innate immune pathways like cGAS-STING and TLR9 signaling can be triggered by mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial DNA, which can lead to long-term neuroinflammatory reactions in PD. While new research suggests that m6A RNA modification may be involved in the regulation of mitochondrial stress, the PINK1/Parkin pathway is crucial for maintaining mitochondrial homeostasis. Therapeutic approaches that target mitophagy augmentation, neuroinflammatory signaling, and mitochondrial protection have garnered increasing attention. In an attempt to improve mitochondrial function and lessen persistent neuroinflammatory activation, future research will probably need to concentrate on combination treatment techniques.
    Keywords:  PINK1/Parkin pathway; Parkinson’s disease; m6A modification; mitochondrial malfunction; neuroinflammation; oxidative stress; therapeutic target
    DOI:  https://doi.org/10.3390/cimb48070645
  37. Biomed J. 2026 Jul 25. pii: S2319-4170(26)00048-X. [Epub ahead of print]49(4): 100992
    Molecular diagnostic platforms for mitochondrial diseases by conventional and long-read sequencing: Missing pieces.
    Kok-Siong Poon, Karen Mei-Ling Tan, Nor Azian Abdul Murad.
      
    DOI:  https://doi.org/10.1016/j.bj.2026.100992
  38. bioRxiv. 2026 Jul 22. pii: 2026.07.19.739404. [Epub ahead of print]
    Integrative structure determination of a human mitochondrial contact site and cristae organizing system (MICOS) sub-assembly.
    Muskaan Jindal, Rakesh Mahato, Sreemoyee Das, Arko Guha, Kartik Majila, Shreyas Arvindekar, Anand T Vaidya, Shruthi Viswanath.
      The Mi tochondrial contact site and C ristae O rganizing S ystem (MICOS) complex is an inner mitochondrial membrane (IMM) assembly present at the cristae junction. It is responsible for regulating cristae formation and remodeling. However, its structure is not known. We applied Bayesian integrative structure determination to characterize the structure of the Mic60, Mic19, Mic10, and Mic13-containing MICOS complex combining AlphaFold predictions with data from crosslinking mass spectrometry, biochemical assays, electron tomography, homology modeling, and sequence alignments. The integrative structure revealed novel mutual interfaces among Mic10 N,C , Mic60 LBS1,LBS2,mitofilin , and Mic13 central,C , which were experimentally validated. Several likely-pathogenic missense mutations also localize to these novel interfaces, highlighting their importance. Our results indicate that Mic13 likely facilitates MICOS assembly by binding Mic10 in the IMM-proximal region and Mic60 in the intermembrane space. Taken together, our integrative approach sheds light on the structure and assembly of the MICOS complex.
    DOI:  https://doi.org/10.64898/2026.07.19.739404
  39. Genes (Basel). 2026 Jul 03. pii: 780. [Epub ahead of print]17(7):
    Molecular Diagnosis to Individualized Therapies in Rare Genetic Diseases: New Approach Methodologies, RNA Therapeutics, and the Case for a Human-First Filter.
    Saeed Anwar, Toshifumi Yokota.
      Rare genetic diseases are heterogeneous across mechanisms, trajectories, and treatment responses. To date, approved therapies remain available for only a small proportion of rare genetic diseases. Oligonucleotide-based RNA therapeutics, particularly antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), offer a promising therapeutic avenue for rare genetic diseases with sequence-level precision. However, traditional preclinical paths may mis-predict human outcomes when disease biology diverges from animal models. New approach methodologies (NAMs), including patient-derived induced pluripotent stem cells (iPSCs), organoid models, and clinical-trials-in-a-dish (CTiD), aim to bring human biology earlier into the translational pipeline. NAMs enable variant-to-function studies, efficacy screening, and safety triage at clinically relevant speed and scale. While critics argue that NAMs are unvalidated and cannot replace preclinical animal models, proponents report that they are increasingly able to recapitulate human phenotypes and predict clinical liabilities, although their predictive validity remains context-dependent. Here, a front-loaded human filter refers to the use of human-derived systems early in development to support mechanistic interpretation, candidate prioritization, and early liability assessment before broader nonclinical evaluation. Recent studies pairing NAMs with ASOs support rapid, patient-specific preclinical screening in selected settings, while also showing the need for broader evidence on delivery, pharmacology, safety, and clinical relevance. This review places these developments within the translational realities of oligonucleotide-based therapeutics, including model fidelity, ASO chemistry and optimization, delivery challenges, pharmacology, regulatory pathways for individualized ASOs, and accessibility. We also propose a pragmatic validation framework to assess the scientific and translational credibility of NAMs across rare genetic diseases.
    Keywords:  RNA therapeutics; antisense oligonucleotides (ASOs); clinical-trials-in-a-dish (CTiD); engineered tissues; induced pluripotent stem cells (iPSCs); microphysiological systems; new approach methodologies (NAMs); pharmacokinetics/pharmacodynamics (PK/PD); rare genetic diseases; small interfering RNAs (siRNAs)
    DOI:  https://doi.org/10.3390/genes17070780
  40. Cell Rep. 2026 Jul 31. pii: S2211-1247(26)00921-6. [Epub ahead of print]45(8): 117843
    Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
    Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.117843
  41. Circ Res. 2026 Jul 31. 139(4): e329116
    STING Goes Mitochondrial: A Metabolic Regulator in Diabetic Cardiomyopathy.
    Giulia Guerra, Alessandra Ghigo.
      
    Keywords:  Editorials; diabetic cardiomyopathies; heart failure; immunity, innate; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329116
  42. iScience. 2026 Aug 21. 29(8): 116788
    Oxygen-stable streptolysin O variant enables mitochondrial ATP synthesis analysis in minimal cells blood and tissues.
    Makoto Fujikawa, Natsuhiko Yamada, Shuhei Yasuda, Tsutomu Tanabe, Kenta Maruyama.
      Quantifying mitochondrial ATP synthesis remains inaccessible in rare cells, blood, and microdissected tissues because of the biochemical instability of streptolysin O (SLO)-based permeabilization. Here, we introduce an oxygen-stable SLO variant, streptolysin O tolerant (SLOT), and an improved mitochondrial ATP synthesis capacity (iMASC) assay to enable sensitive analysis across diverse samples. SLOT combines non-essential N-terminal deletion (Δ1-77) with a C530A substitution, conferring reductant-independent activity and long-term stability. Temperature-controlled activation restricts permeabilization to the plasma membrane, preserving mitochondrial function. iMASC assay supports continuous measurement for more than 1 h from 10 to 20 cells and applies to adherent and suspension cells, whole blood, and microdissected tissues. Using this platform, we identify platelets as dominant contributors to glycerol-3-phosphate-driven ATP synthesis in murine blood and enable sequential dissection of respiratory chain and ATP synthase activities within single tissues. This framework establishes a broadly applicable approach for mitochondrial metabolism analysis.
    Keywords:  SLOT; iMASC assay; improved mitochondrial ATP synthesis capacity assay; mitochondrial ATP synthesis; mitochondrial metabolism; rare and complex biological samples; respiratory chain complexes; streptolysin O tolerant; temperature-controlled permeabilization; whole blood
    DOI:  https://doi.org/10.1016/j.isci.2026.116788
  43. Ophthalmol Sci. 2026 Aug;6(8): 101286
    Phenotypic Variations in a Large Family with Dominant Optic Atrophy Related to a Novel OPA1 Deletion.
    Aymane Bouzidi, Patrizia Amati-Bonneau, Valérie Desquiret-Dumas, Cléis Beaulieu, Agnès Guichet, Céline Bris, Béatrice Bocquet, Xavier Dieu, Pascal Reynier, Delphine Mirebeau-Prunier, Clara Houdayer, Marc Planes, Sylvie Odent, Isabelle Meunier, Dominique Bonneau, Majida Charif, Guy Lenaers, Xavier Zanlonghi.
       Purpose: Dominant optic atrophy (DOA) is a rare disease characterized by the chronic loss of retinal ganglion cells that transduce the visual information from the retina to the brain. Dominant optic atrophy shows interfamilial and intrafamilial phenotypic variations and a restricted 35% molecular diagnosis, with half presenting a pathogenic variant in optic atrophy 1 (OPA1), encoding a large mitochondrial GTPase. Here, we describe the largest ever identified DOA family, with 64 nonsyndromic individuals harboring a novel 10-kb OPA1 deletion.
    Design: Retrospective, longitudinal cohort study of a family from the Western part of France.
    Participants: Thirty-nine individuals were included, 34 patients harboring a novel OPA1 10-kb deletion and 5 healthy controls.
    Methods: OPA1 sequencing, multiplex ligation-dependent probe amplification, and copy number variations using single nucleotide polymorphism array identified the genetic variation causing DOA. The relatedness between the different family branches was analyzed by micro-satellite markers. Best-corrected visual acuity (BCVA), Lanthony D-15 desaturated color vision test, retinal nerve fiber layer (RNFL), and macular ganglion cell layer (GCL) thickness were recorded at 2 different time points for longitudinal analyses.
    Main Outcome Measures: Best-corrected visual acuity, RNFL and GCL thickness at first and follow-up examinations. Correlations between morphological and functional measurements.
    Results: We disclosed the largest ever identified DOA family, with 64 nonsyndromic patients for whom we discovered a novel 10-kb deletion encompassing OPA1 exons 30 and 31. Ophthalmic examination revealed a consistent BCVAvariability, ranging from 0 (Snellen equivalent, 20/20) to 1.61 (20/815) logarithm of the minimum angle of resolution (logMAR), strongly correlated to RNFL and GCL thickness, but moderately with age and not with dyschromatopsia. Follow-up of individuals evidenced a significant BCVA loss with a median of 0.018 logMAR per year (0.18 logMAR per decade) and a temporal, superior, and inferior RNFL thickness loss of 1.13, 0.70, and 0.50 μm/yr, respectively, whereas the nasal quadrant did not evolve.
    Conclusion: The identification of a large OPA1 deletion in this DOA family illustrates the critical importance of screening for large genomic rearrangements in DOA genes and confirms the high intrafamilial phenotypic variability while correlating BCVA with RNFL and GCL thickness.
    Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.
    Keywords:  Dominant optic atrophy; OPA1; Phenotypic variation; Visual acuity evolution
    DOI:  https://doi.org/10.1016/j.xops.2026.101286
  44. Front Cell Dev Biol. 2026 ;14 1901757
    Nanoscale biointerfaces in inter-organelle communication: membrane contact sites, organelle trafficking, and cell fate control.
    Mohamed R Abdel-Hamed, Sameh Saber, Elsayed A Elmorsy, Basem H Elesawy, Maha M Amer, Abdel-Moneim Hafez Abdel-Moneim, Alaa El-Din L Firgany, Enas A Mohamed, Huda Eltayeb, Ageeb M Hassan, Mohamed El-Sayed, Ahmed Y Kira.
      Cellular and tissue organization depends on the spatial arrangement, ultrastructure, and functional coupling of organelles. This review reframes intracellular nanomaterials as nanoscale tools for interrogating and modulating membrane contact sites (MCSs), rather than simply as delivery systems. We focus on mitochondria, the endoplasmic reticulum, lysosomes, endosomes, and the nucleus because these compartments form dynamic contact networks that regulate metabolism, calcium and redox signaling, membrane trafficking, autophagy, mitophagy, chromatin organization, stress adaptation, and cell fate. Emphasis is placed on morphological and ultrastructural readouts, including mitochondrial cristae organization, fission-fusion balance, membrane-potential-dependent localization, endosomal and lysosomal trafficking, ER-mitochondria and lysosome-mitochondria communication, nuclear-pore access, chromatin organization, and inter-organelle contact-site remodeling. We discuss how particle size, surface charge, geometry, ligand presentation, and stimulus-responsive behavior influence cellular uptake, endosomal escape, organelle localization, and structural consequences within cells and tissues. A central distinction is made between intentional organelle nano-regulation, in which engineered systems are designed to engage defined subcellular mechanisms and organelle interfaces, and incidental stress responses, in which altered morphology or gene expression reflects oxidative, lysosomal, mitochondrial, inflammatory, or genotoxic injury. By organizing current evidence around MCS biology, subcellular compartmentalization, membrane trafficking, organelle dynamics, and tissue-relevant cell fate decisions, this review provides a morphology-centered framework for evaluating intracellular nanomaterials in health, disease, stem-cell biology, and regenerative bioengineering.
    Keywords:  ER–mitochondria crosstalk; cell fate regulation; endolysosomal trafficking; inter-organelle communication; membrane contact sites; organelle-targeted nanomaterials
    DOI:  https://doi.org/10.3389/fcell.2026.1901757
  45. bioRxiv. 2026 Jul 24. pii: 2026.07.20.739625. [Epub ahead of print]
    Targeted modulation of IGFBP5/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma.
    Kelsey Keith, Min Peng, Cristina Remes, Victoria Miranda, Nicholas Wachowski, Melis Kose, Shrikant Dharaskar, Suraiya Haroon, Agustin B Velasco, Priya Sivaramakrishnan, Donna Iadarola, Sundeep Dugar, Marni J Falk.
      Primary mitochondrial diseases (PMD) have limited disease-modifying therapies, currently applicable to only 3 of over 400 discrete gene disorders. Cycloheximide (CHX) is a global cytosolic translation inhibitor we previously reported to rescue PMD preclinical models, although its toxicity precluded clinical development. To identify specific mediators underlying CHX treatment benefit in PMD, SOMAscan-based proteomics was performed in complex I deficient and genetic disease fibroblast cell line models grown in galactose. Thrombopoietin (THPO) and insulin-like growth factor binding protein 5 (IGFBP5) were the only two differentially regulated proteins, together with ERK/MAPK pathway dysregulation, identified upon CHX treatment in PMD versus healthy control cells. THPO inhibition by siRNA or pharmacologic approaches rescued stress-induced viability loss in patient fibroblasts having diverse PMD gene etiologies, and significantly improved mitochondrial stress, linear growth, and neuromuscular function in a classical ndufs2 -/- C. elegans model. IGFBP5 overexpression by lentiviral or mRNA approaches rescued cell viability across distinct PMD gene etiologies, as did IGF1 pharmacologic inhibition across both PMD mutant and C. elegans models. MAPK pharmacologic inhibition rescued multiple distinct complex I disease cells' survival, as well as mitochondrial stress in SLC25A46 -/- C. elegans . Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models. Additionally, single or combined pharmacologic inhibition of THPO or IGF1 significantly enhanced primary and metastatic osteosarcoma cell death. Collectively, targeted small molecule and genetic modulation of THPO, IGF1, or MAPK recapitulated the significant therapeutic benefit of CHX in PMD, while avoiding global translation inhibition. These novel PMD therapies likely confer benefit by attenuating MAPK-driven autophagy and potentially promoting noncanonical glucose uptake, improving cellular energy balance. Overall, these glucose signaling cellular pathway targets hold broad therapeutic promise for PMD patients, warranting further clinical research development.
    DOI:  https://doi.org/10.64898/2026.07.20.739625
  46. Cells. 2026 Jul 16. pii: 1279. [Epub ahead of print]15(14):
    Optimized Isolation and Cryopreservation of Functional Mitochondria for Transplantation and Therapeutic Applications.
    Vikky Awasthi, Aasthika Das, Meriem Bkhache, Abeer Alshambky, Glenn S Gerhard, Karim Bahmed, Timothy Cashman, Rihab Bouchareb.
      Mitochondria play a central role in numerous physiological and pathological processes, and mitochondrial transplantation is emerging as a promising strategy to restore cellular function and mitigate disease. The success of this approach depends critically on the methods used to isolate, preserve, and retrieve intact, functional mitochondria. Objective: To optimize an isolation strategy that preserves mitochondrial integrity, dynamics, and metabolic activity and to evaluate conditions that enable short-term storage for future organelle biobanking applications. Methods: We compared a mitochondria isolation method developed in our laboratory (Protocol A) with a commercially available kit (Protocol B). Donor mitochondria were isolated from proximal tubular cells and transplanted into HEK293T recipient cells. Mitochondrial functionality was assessed following transfer into HEK293T cells by measuring reactive oxygen species (MitoSOX Red), oxygen consumption rate (OCR) using Seahorse XF analysis, and high-resolution imaging of mitochondrial morphology and dynamics. We further evaluated mitochondrial storage at low temperature and subsequent functional recovery. Results: Protocol A enabled faster isolation (~30 min) than Protocol B (~80 min) and yielded mitochondria with higher transplantation efficiency, greater OCR, preserved dynamic morphology, and lower oxidative stress. Mitochondria isolated using Protocol A remained metabolically active after transplantation and continued to exhibit fission and fusion, whereas those isolated using Protocol B showed reduced dynamic behavior. Importantly, mitochondria isolated with Protocol A retained functional integrity after low-temperature storage, supporting their potential for standardized preservation. Conclusions: This study presents a robust, efficient, and reproducible isolation and frozen-storage protocol that yields highly functional mitochondria suitable for transplantation. The ability to preserve mitochondrial function after storage further highlights the potential for developing organelle biobanks to support future research and therapeutic applications.
    Keywords:  cryopreservation of mitochondria; mitochondria isolation; mitochondria transplantation
    DOI:  https://doi.org/10.3390/cells15141279
  47. Mol Cell Biochem. 2026 Jul 29.
    Ckmm-Cre transgenic mice maintain phenotypic and cardiac mitochondrial homeostasis during ketogenic feeding.
    Sukru Anil Dogan.
      Conditional gene targeting using the Cre-loxP system requires validation of each Cre driver line under the specific experimental conditions to be employed, as Cre recombinase expression can cause transgene-associated pathology. The Ckmm-Cre transgenic mouse is widely used for heart- and skeletal muscle-directed conditional gene targeting, yet its phenotypic and cardiac mitochondrial response to ketogenic diet (KD) remains uncharacterized. Here we report that four-week KD feeding did not alter body weight, treadmill endurance, grip strength, locomotor activity, or rotarod performance in young male Ckmm-Cre mice. Cardiac mitochondrial oxygen consumption and hydrogen peroxide production, assessed by high-resolution respirometry, were likewise unchanged. In cardiac tissue lysates, oxidative phosphorylation subunit abundance and VDAC1 levels were maintained, with no major diet-associated changes in mitochondrial protein content. These pilot data establish a baseline reference for future conditional knockout studies employing this Cre driver under ketogenic conditions.
    Keywords:  Cardiac mitochondria; Ckmm-Cre; Cre-loxP; High-resolution respirometry; Ketogenic diet; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11010-026-05672-1
  48. Sci Adv. 2026 Jul 31. 12(31): eaeg1124
    COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating.
    Andrea Gottinger, Marco Malatesta, Callum R Nicoll, Georg Ansari, Mathieu Quinodoz, Karolina Kaminska, Rachael W C Tang, Tien-En Tan, Beau J Fenner, Pilar Barberán-Martínez, Gema García-García, José M Millán, Maximilian Pfau, Natalie E Burbach, Domiziana Cecchini, Carlo Rivolta, Andrea Mattevi.
      Coenzyme Q biosynthesis requires two atypical kinase-like proteins (COQ8A and COQ8B), whose detailed molecular mechanism remains unclear. Here, we show that both paralogs function as adenosine triphosphatases (ATPases) that promote coenzyme Q biosynthetic metabolon activity by engaging in loose protein-protein interactions and delivering insoluble biosynthetic intermediates. Structural bioinformatics and pathological variant-driven mutagenesis identify a previously uncharacterized pocket that selectively recognizes coenzyme Q biosynthetic intermediates via their head groups. X-ray crystallography reveals that access to this pocket is gated by long-range conformational changes controlled by adenosine 5'-triphosphate hydrolysis. Last, excess coenzyme Q suppresses binding of early-stage intermediates and thereby abolishes the promoting effect of COQ8 on the metabolon. Together, these findings support a model in which COQ8 tunes coenzyme Q biosynthesis by coupling ATPase-driven intermediate chaperoning to feedback inhibition by the final product.
    DOI:  https://doi.org/10.1126/sciadv.aeg1124
  49. Mol Ther. 2026 Jul 29. pii: S1525-0016(26)00672-6. [Epub ahead of print]
    Lineage-Tailored Vesicles from Human Retinal Ganglion-Like Cells Drive Metabolic Homeostasis and Bioenergetic Recovery in Glaucoma.
    Sandeep Kumar Vishwakarma, Mallikarjuna Rao Gedda, Stanislav I Tomarev.
      Retinal ganglion cells (RGCs) exhibit high bioenergetic demands, rendering them vulnerable to mitochondrial dysfunction and metabolic collapse during glaucomatous neurodegeneration. Therapeutic strategies capable of restoring mitochondrial homeostasis in human RGCs remain limited. We established a human retinal ganglion-like cell (RGLC) model of mitochondrial injury and evaluated neuroprotective efficacy of small extracellular vesicles (sEVs) derived from either undifferentiated BRN3B-H9 cells or differentiated lineage-tailored RGLCs. RGLC-derived sEVs (RGLC-sEVs) conferred robust neuroprotection, significantly enhancing neuronal survival, preserving neurite architecture, and mitigating mitochondrial stress following injury. These effects were reproducible in mixed retinal cultures and in an ocular hypertension mouse model of glaucoma, with neuroprotective benefits observed throughout the retinal landscape. Mechanistically, untargeted metabolomic profiling revealed extensive metabolic reprogramming involving oxidative phosphorylation, amino acid utilization, lipid metabolism, and redox regulatory pathways. In vitro tracking studies confirmed efficient uptake of sEVs by injured RGLCs, confirming effective vesicular cargo delivery under conditions that promote neuroprotection and metabolic recovery. Functional bioenergetic analysis further validated restoration of mitochondrial-glycolytic coupling and improved cellular energetic resilience. Collectively, our findings establish lineage-tailored RGLC-sEVs as a potent, cell-specific therapeutic candidate capable of reprogramming metabolic networks and restoring bioenergetic homeostasis in glaucomatous neurodegeneration, highlighting their translational potential for neuroprotective intervention in optic neuropathies.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.051
  50. Nature. 2026 Jul;655(8125): S11
    To help children with rare diseases, we must solve drug delivery.
    Shadi Farhangrazi, Seyed Moein Moghimi.
      
    Keywords:  Diseases; Medical research; Nanoparticles; Nanoscience and technology
    DOI:  https://doi.org/10.1038/d41586-026-02182-4
  51. Aging Dis. 2026 Jul 26.
    A C. elegans-to-Mouse Discovery Framework for Prioritizing Sarcopenia Interventions.
    Yejin Cho, Hyo-Deok Seo, Chang Hwa Jung, Jiyun Ahn, Jeong-Hoon Hahm.
      Sarcopenia is a manifestation of musculoskeletal aging, yet no approved therapy is available. A major challenge is not the lack of potential interventions, but the difficulty of efficiently identifying which candidates should advance to aged-mammal validation. Sarcopenia is driven by multiple biological processes, including mitochondrial dysfunction, impaired proteostasis, redox dysregulation, inflammaging, and altered nutrient sensing. Consequently, candidate interventions encompass not only conventional drug candidates but also natural products, dietary compounds, food-derived metabolites, and multi-component formulations. This diversity creates a candidate space that is difficult to systematically evaluate using aged-mouse models alone. Here, we propose a C. elegans-to-mouse discovery framework for sarcopenia intervention development. C. elegans enables rapid organism-level assessment of locomotor function, muscle integrity, toxicity, genetic dependency, and conserved aging mechanisms within a single in vivo system. These features allow large candidate pools, including diverse compounds, doses, and combinations, to be screened and prioritized before resource-intensive mammalian studies. Within this framework, preservation of age-related function serves as the primary selection criterion, whereas conserved biological mechanisms provide additional support for candidate advancement. Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation. Examples including urolithin A, norharmane, and spermidine illustrate how worm-based functional screening can be integrated with mechanistic evidence and aged-mouse validation. Collectively, this review proposes a practical framework that integrates function-centered screening with conserved mechanistic interpretation to improve early-stage prioritization of sarcopenia interventions. This framework provides a conceptual strategy for accelerating the discovery of function-preserving therapeutics for skeletal muscle aging.
    DOI:  https://doi.org/10.14336/AD.2026.0758
  52. Cell Rep. 2026 Jul 27. pii: S2211-1247(26)00804-1. [Epub ahead of print]45(8): 117726
    The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.
    Sahana Mitra, Huai-Wei Huang, Rhihab Faruk, Arissa Low, Adam I Yeo, Hyung Don Ryoo.
      The integrated stress response (ISR) coordinates cellular adaptation to diverse stress conditions. In Drosophila, two bZIP transcription factors, Xrp1 and crc (ATF4 homolog), are induced during ISR. Crc protein can dimerize with two CEBP factors in vitro, but the in vivo relevance of those interactions remained unknown. Here, we report that the CEBPG homolog, Irbp18, is an essential partner of crc during ISR. Specifically, Irbp18 is broadly required for the transcriptional induction of ISR target genes in the photoreceptors of ninaEG69D, a Drosophila model of retinitis pigmentosa. Moreover, CUT&RUN analysis indicates that Irbp18 loss reduces or abolishes crc binding to target DNAs in photoreceptors and impairs crc's ability to induce target transcripts upon overexpression. Functionally, Irbp18 loss causes retinal degeneration and suppresses ISR signaling in parkin mutants, a model of Parkinson's disease. Together, these findings identify Irbp18 as a cofactor for crc, impacting pathological outcomes in Drosophila models of degeneration.
    Keywords:  ATF4; CEBP; CP: molecular biology; CP: neuroscience; ISR; Irbp18; bZIP; dimerization; integrated stress response; parkin; retinal degeneration; transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2026.117726
  53. Antioxidants (Basel). 2026 Jun 25. pii: 793. [Epub ahead of print]15(7):
    Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.
    Hsu-Hung Chang, Phebe Ting Syuan Chang, Chung-Che Tsai, Chan-Yen Kuo.
      Mitochondrial Lon peptidase 1 (LONP1) is an ATP-dependent AAA+ (ATPases associated with diverse cellular activities) protease that has emerged as a key regulator of mitochondrial proteostasis, with functions extending beyond protein quality control. In addition to degrading misfolded and oxidized proteins, LONP1 coordinates mitochondrial DNA maintenance, metabolic remodeling, and stress-responsive signaling. Recent structural and functional advances have expanded the biological significance of LONP1 beyond protein quality control, highlighting its roles in mitochondrial metabolism, genome maintenance, and stress responses. LONP1 dysregulation is increasingly implicated in cancer, metabolic disorders, neurodegeneration, and aging, where it exerts context-dependent effects on cell survival and disease progression. In cancer, LONP1 supports metabolic plasticity, redox adaptation, and therapeutic resistance, whereas in degenerative conditions, its decline contributes to mitochondrial dysfunction and tissue damage. Here, we synthesize recent insights into the structure, mechanisms, and biological functions of LONP1 and discuss their implications for human disease. We further discuss emerging therapeutic strategies and key challenges for targeting LONP1 in human disease.
    Keywords:  LONP1; cancer metabolism; mitochondrial metabolism; mitochondrial proteostasis; stress response
    DOI:  https://doi.org/10.3390/antiox15070793
  54. bioRxiv. 2026 Jul 17. pii: 2026.07.13.737346. [Epub ahead of print]
    Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression.
    Isabella Lin, Michael Sigfrid S Reyes, Abigail S Krall, Neerja Vashist, Suzanne Sarkissian, Nedas Matulionis, Aileen Ning, Linsey Stiles, Bianca E Russell, Paul Mark B Medina, Heather R Christofk, Valerie A Arboleda.
      Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1 ), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined. Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Truncated ASXL1 and BAP1 show aberrant co-occupancy at an H3K4me3-marked intronic regulatory element within MPC2 intron 1, with broadened ASXL1 occupancy extending beyond BRD4-defined regulatory boundaries while BRD4 positioning remains unchanged, consistent with aberrant PR-DUB complex spreading beyond its normally constrained chromatin territory. This altered occupancy is accompanied by modest but significant reduction in MPC2 transcript abundance and a disproportionately larger reduction in MPC1 and MPC2 protein levels, indicating that transcriptional dysregulation at this intronic element is amplified at the protein level through post-transcriptional mechanisms including impaired MPC1/MPC2 heterodimer stability. Pharmacologic MPC inhibition recapitulates both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation increases glycolytic flux without reducing MPC abundance, establishing mitochondrial pyruvate restriction as causally upstream of signaling dysregulation. These findings define a previously unrecognized chromatin-to-metabolism axis connecting gain-of-function ASXL1 truncation to mitochondrial pyruvate transport, identifying MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1 -mutant myeloid malignancy.
    DOI:  https://doi.org/10.64898/2026.07.13.737346
  55. Mol Genet Metab. 2026 Jul 14. pii: S1096-7192(26)00490-7. [Epub ahead of print]149(1-2): 110207
    Multi-generational mitochondrial complex V deficiency due to the recurrent ATP5F1A c.620G>A (p.Arg207His) pathogenic variant: A novel family and a review of the literature.
    Undiagnosed Diseases Network
      ATP5F1A encodes part of the catalytic core of mitochondrial complex V, which is responsible for the majority of ATP production. Mitochondrial complex V deficiency, nuclear type 4A (MC5DN4A; MIM#620358) is due to monoallelic pathogenic variants in ATP5F1A. MC5DN4A is a neonatal-onset disorder with features including growth faltering, developmental delay, epilepsy, and a biochemical phenotype indicative of urea cycle dysfunction. Interestingly, patients who have MC5DN4A due to the recurrent pathogenic ATP5F1A c.620G>A (p.Arg207His) variant appear to demonstrate clinical resolution before 18 months of age. All reported cases of MC5DN4A due to the ATP5F1A c.620G>A (p.Arg207His) variant have been de novo. Here we present a mother and her three children with MC5DN4A harboring the ATP5F1A c.620G>A (p.Arg207His) variant. The oldest child has growth faltering, seizures, autism spectrum disorder, global developmental delay, urea cycle dysfunction, and elevated plasma lactate without full clinical resolution. The two younger children have similar biochemical findings with a more severe clinical phenotype including congenital heart disease, growth faltering, sideroblastic anemia, and hypogammaglobulinemia, however both children are showing signs of spontaneous clinical resolution. Additionally, both younger children have a deletion of the entire coding sequence of NDUFA12, which may be contributing to the more severe presentation. The mother is reportedly asymptomatic. In summary, we present the first known instance of transgenerational transmission of the pathogenic ATP5F1A c.620G>A (p.Arg207His) variant. The presence of congenital heart disease, sideroblastic anemia, and hypogammaglobulinemia in two cases may indicate a phenotypic expansion of MC5DN4A or may suggest a modifying effect of the NDUFA12 deletion on the phenotype.
    Keywords:  ATP5F1A; Congenital heart disease; Hypogammaglobulinemia; Mitochondria; Sideroblastic anemia
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110207
  56. J Cell Physiol. 2026 Aug;241(8): e70212
    The Impact of Ageing on Skeletal Muscle: Roles of Mitochondrial Dysregulation, Systemic Communication, and Exercise.
    Juan Diego Hernández-Camacho, Marielle Saclier.
      Ageing is a major risk factor for degenerative diseases, including sarcopenia, which is characterized by a progressive loss of skeletal muscle mass and function, frailty, and is associated with increased mortality. Skeletal muscle regeneration relies on muscle stem cells and efficient communication with cellular microenvironment. With ageing, skeletal muscle regenerative capacity declines, and sarcopenia results from complex, multitissue dysregulation involving mitochondrial dysfunction, immune ageing, chronic inflammation, senescence, extracellular matrix modification, disruption of neuromuscular junctions and muscle-specific vulnerability. This review summarizes current knowledge contributing to sarcopenia and inefficient muscle repair during ageing from cell-autonomous metabolic dysregulation to age-associated changes in the local and systemic cellular environment. We also explore recent insights into important role of exercise on muscle tissue health. Overall, emerging technologies, including human muscle atlases and spatial transcriptomics, together with exercise-based interventions, will help to identify of novel biomarkers and therapeutic targets to better prevent and treat sarcopenia.
    Keywords:  ageing; cellular communication; exercise; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1002/jcp.70212
  57. Sci Adv. 2026 Jul 31. 12(31): eaei7316
    TRF2 couples muscle stem cell identity to regenerative repair.
    Ji-Hyung Lee, Kiran Kumar Nakka, Ryan P Calhoun, Sarah Hachmer, Adity Gupta, Eric Arreza, Lynn A Megeney, Patrick Seale, Roger A Greenberg, F Jeffrey Dilworth, Foteini Mourkioti.
      Stem cell-mediated regeneration is essential for tissue integrity. In skeletal muscle, tissue repair largely depends on muscle stem cells (MuSCs), which undergo dynamic cell-state transitions through making precise fate decisions during regeneration. However, the molecular regulators of cell-state conversion in MuSCs remain unclear. Here, we identify a previously unrecognized, noncanonical role for TRF2 in MuSC biology. TRF2 is dynamically regulated upon injury and required to preserve stem cell identity, support reparative myogenesis, and sustain self-renewal. MuSC-specific TRF2 disruption exacerbates muscular dystrophy pathology in mice, recapitulating key features of human disease. Mechanistically, TRF2 associates with regulatory regions enriched for DNA G-quadruplex-forming sequences at lineage-specific genes, sustaining their expression. These findings establish TRF2 as a pivotal regulator of adult stem cell function and tissue-specific regenerative responses.
    DOI:  https://doi.org/10.1126/sciadv.aei7316
  58. Nature. 2026 Jul 28.
    Fertility clinics are offering young mitochondria in controversial fertility technique.
    Edward Chen.
      
    DOI:  https://doi.org/10.1038/d41586-026-01935-5
  59. Elife. 2026 Jul 27. pii: RP111075. [Epub ahead of print]15
    In-cell cryo-electron tomography reveals differential effects of type I and type II kinase inhibitors on LRRK2 filament formation and microtubule association.
    Tamar Basiashvili, Joshua Hutchings, Siyu Chen, Eva P Karasmanis, William Alexander Flaherty, Andres E Leschziner, Elizabeth Villa.
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are a leading contributor to developing familial and idiopathic Parkinson's disease (PD). Most PD-causing LRRK2 mutations increase the kinase activity, leading to increased phosphorylation of Rab GTPases, disrupting vesicular trafficking, cytoskeletal dynamics, and autophagy. Under homeostatic conditions, the bulk of WT and PD-mutant LRRK2 is found in the cellular cytosol. However, exogenously expressed LRRK2 can form microtubule-associated filaments that have been shown to affect molecular transport along microtubules in vitro. While the physiological relevance of microtubule binding has not been established yet, inhibitors being designed and tested as therapeutics have been shown to either promote or prevent filament formation of LRRK2. In this study, we examine the localization and resulting molecular organization of hyperactive LRRK2-I2020T, a common PD mutant, in HEK 293FT cells treated with type I (MLi-2) or type II (GZD-824) kinase inhibitors. Treatment with a type I kinase inhibitor results in extensive LRRK2-I2020T decoration around microtubules and microtubule bundling. Stabilization of LRRK2-I2020T filaments by type I inhibitor treatment allowed us to build a full-length closed-kinase model of LRRK2-I2020T in its cellular environment. Conversely, treatment with a type II inhibitor resulted in minimal microtubule decoration by LRRK2-I2020T compared to type I inhibitor-treated cells. This study provides a structural framework for understanding how type I and type II kinase inhibitors differentially modulate LRRK2 filament formation, demonstrating that type I inhibitor treatment promotes a distinct filament architecture, whereas such assemblies are not observed with type II inhibitors.
    Keywords:  LRRK2; Parkinson's disease; cryo-ET; human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.111075
  60. Nat Cell Biol. 2026 Jul 30.
    Running towards induced pluripotent stem cells.
    Yanhong Shi.
      
    DOI:  https://doi.org/10.1038/s41556-026-02029-0
  61. Protein Cell. 2026 Jul 31. pii: pwag054. [Epub ahead of print]
    Super-resolution live imaging reveals spatiotemporal uncoupling of mitochondria-ER contacts and mitochondrial fission in stem cell aging.
    Tianling Cao, Quan Meng, Tiantian Sun, Yaobin Jing, Ping Yang, Zeming Wu, Bin Zhang, Baohu Zhang, Amin Jiang, Shuai Ma, Si Wang, Jing Qu, Dong Li, Guang-Hui Liu.
      
    DOI:  https://doi.org/10.1093/procel/pwag054
  62. Antioxidants (Basel). 2026 Jun 30. pii: 830. [Epub ahead of print]15(7):
    Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
    Jingmin Che, Ye Sun, Fang Wang, Qing Feng, Cuixiang Xu, Xuhui Li.
       BACKGROUND: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders.
    SCOPE OF REVIEW: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging.
    CONCLUSIONS AND IMPLICATIONS: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of "restoring mitochondrial plasticity and removing dysfunctional mitochondria", and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases.
    Keywords:  age-related diseases; cellular senescence; metabolic homeostasis; mitochondrial quality control; mitophagy; therapeutic targets
    DOI:  https://doi.org/10.3390/antiox15070830
  63. Biomolecules. 2026 Jul 01. pii: 972. [Epub ahead of print]16(7):
    Mitochondrial Dysfunction in Circulating Blood Cells and Biological Aging: A Review of Mechanisms and Evidence.
    Abdullah M AlShahrani, S Rehan Ahmad.
      Chronological age tells us how long a person has lived-but not how well. Two individuals of the same age can differ dramatically in their cellular health, disease risk, and functional capacity. This gap between calendar age and biological age has driven growing interest in biomarkers that reflect true cellular aging rather than years lived. Mitochondria sit at the heart of this problem. Far more than cellular power plants, these organelles govern energy production, oxidative stress, immune signaling, and programmed cell death. As the body ages, mitochondria deteriorate in consistent and measurable ways-and crucially, these changes can be detected in circulating blood cells, offering a minimally invasive window into the body's biological age. This narrative review synthesizes two decades of research (2005-2025) on three blood-based mitochondrial markers: mitochondrial DNA copy number (mtDNA-CN) in peripheral blood mononuclear cells, mitochondrial membrane potential (MMP), and cell-free mitochondrial DNA (cf-mtDNA) in plasma. Across 68 carefully selected studies, we evaluate the strength, consistency, and clinical relevance of each marker, alongside their associations with cardiovascular disease, metabolic dysfunction, cognitive decline, and mortality. The evidence is promising but still maturing. Significant methodological variation across studies limits direct comparisons, and robust prospective outcome data remain limited. We propose a four-phase framework for responsible clinical translation and identify specific research investments needed-from measurement standardization to large cohort studies and intervention trials-before these markers can responsibly inform patient care.
    Keywords:  aging biomarkers; biological aging; cell-free mitochondrial DNA; clinical translation; inflammaging; mitochondrial dysfunction; mitochondrial membrane potential; mtDNA copy number; oxidative stress; peripheral blood mononuclear cells
    DOI:  https://doi.org/10.3390/biom16070972
  64. Antioxidants (Basel). 2026 Jun 25. pii: 794. [Epub ahead of print]15(7):
    Mitochondrial UQCRC2 as a Redox-Regulatory Node in Metabolic and Cardiometabolic Diseases.
    Shiyi Chen, Yang Jiao, Wen Shen, Xingru Hu, Guoyue Yuan, Jue Jia.
      Metabolic and cardiometabolic diseases are closely associated with mitochondrial dysfunction and redox imbalance. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2), a non-catalytic structural core subunit of mitochondrial respiratory chain Complex III, is increasingly recognized as a regulator of Complex III integrity, electron transfer, oxidative phosphorylation, and mitochondrial redox homeostasis. Under metabolic stress, reduced expression or functional impairment of UQCRC2 may promote electron leakage, mitochondrial reactive oxygen species (mtROS) generation, lipid peroxidation, impaired antioxidant defense, and disrupted glucose-lipid metabolism. These alterations may contribute to insulin resistance (IR), metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and cardiovascular disease (CVD). This review summarizes current evidence linking UQCRC2 dysfunction to mitochondrial bioenergetic failure, oxidative stress, inflammatory signaling, and cardiometabolic injury. We further discuss redox-regulatory pathways, including Nrf2, AMPK-SIRT1-PGC-1α, glutathione metabolism, and mitophagy, as well as pharmacological agents and natural compounds that may modulate UQCRC2-related mitochondrial responses. Collectively, these findings highlight UQCRC2 as a redox-sensitive mitochondrial node linking Complex III dysfunction to cardiometabolic injury and targeted redox-based interventions.
    Keywords:  UQCRC2; complex III; insulin resistance; mitochondrial ROS; oxidative stress; redox imbalance
    DOI:  https://doi.org/10.3390/antiox15070794
  65. Bio Protoc. 2026 Jul 20. 16(14): e5744
    Preparation and Characterization of Neutrophil Membrane-Fused Mitochondria (nMITO).
    Qing Zhang, Yuqin Yue, Xing Zhou.
      Mitochondrial transplantation is an emerging strategy for cellular repair, yet its efficiency is often limited by poor targeting and environmental instability. This protocol details the fabrication and comprehensive characterization of neutrophil membrane-fused mitochondria (nMITO), a hybrid organelle platform designed to combine the metabolic vigor of natural mitochondria with the targeting and anti-inflammatory properties of neutrophil membranes. We describe an optimized workflow for mouse heart mitochondrial isolation, lipopolysaccharide (LPS)-activated neutrophil membrane (NEM) extraction, and the subsequent sonication-mediated fusion process. Characterization techniques include dynamic light scattering (DLS) for size and zeta potential, transmission electron microscopy (TEM) for ultrastructural integrity, and bioenergetic assays [ATP synthesis and tetramethylrhodamine methyl ester (TMRM)-based membrane potential] to ensure functional preservation. Key features • The protocol provides a methodology for the isolation of neutrophil membranes from mouse bone marrow and mitochondria from the heart. • The protocol provides a methodology for the fabrication of neutrophil membrane-fused mitochondria (nMITO).
    Keywords:  Membrane coating; Mitochondria isolation; Mitochondrial assessment; Neutrophil membranes; nMITO
    DOI:  https://doi.org/10.21769/BioProtoc.5744
  66. Structure. 2026 Jul 27. pii: S0969-2126(26)00212-1. [Epub ahead of print]
    Matrix polyamines regulate bidirectional calcium flux through MCU.
    Qinzhe Wang, Enrique Balderas, Alejandro Jara Ramos, Ashley Nwafor, Jack S McManus, Neeraj K Rai, Yasmin B Masini, David R Eberhardt, Emma C Rekate, Anthony M Balynas, Xue Yin, Tracy Murray Stewart, Erhu Cao, Anna Stary-Weinzinger, Dipayan Chaudhuri.
      Polyamines, well-known regulators of the mitochondrial calcium (Ca2+) uniporter channel, show unexpected effects when binding the channel from within the matrix. Using cryo-EM, molecular dynamics simulations, and mutagenesis experiments, we determine that polyamines achieve such regulation by binding within the pore to a ring of negative residues forming a matrix gate, inhibiting Ca2+ conduction. In whole-mitoplast electrophysiology assays, matrix polyamines cause a gradual increase in Ca2+ currents during prolonged conduction, due to relief of this inhibition. Notably, this electrostatic binding increases 3-fold as the inner membrane depolarizes, preventing Ca2+ efflux. Additionally, we also identify that phospholipids form part of the Ca2+ conduction pathway through MCU. Because we find significant variability in matrix polyamine content across mouse organs, this unexpected mechanism for sculpting the mitochondrial Ca2+ waveform suggests a tissue-specific regulation of metabolism.
    Keywords:  MCU; calcium channels; disinhibition; inward rectification; mitochondrial calcium uptake; polyamine; putrescine; spermidine; spermine
    DOI:  https://doi.org/10.1016/j.str.2026.07.002
  67. Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2608102123
    Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.
    Jingwen Chen, Lili Su, Bangze Pan, Junhao Sang, Linlin Li, Junsong Huang, Zhao-Lan Hu, Lixin Wang, Xiaojie Zhang, Jun Jin.
      Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8+ T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.
    Keywords:  T cell aging; cryo-electron tomography; mitoribosome
    DOI:  https://doi.org/10.1073/pnas.2608102123
  68. Redox Biol. 2026 Jul 16. pii: S2213-2317(26)00308-3. [Epub ahead of print]96 104309
    Mitochondria-to-plasma-membrane H2O2 signaling induced by branched-chain keto acid oxidation essentially stimulates insulin secretion in pancreatic β-cells.
    Eduardo Klöppel, Hana Engstová, Pavla Duspiva, Jan Tauber, Oleksandra Mozheitova, Martin Jabůrek, Petr Ježek.
      Oxidation (β-like) of branched-chain keto acids (BCKAs) α-ketoisocaproate (KIC), α-ketoisovalerate (KIV), and α-ketomethylvalerate (KMV), yields FADH2, NADH (in order of KIC < KMV < KIV), and acetyl-CoA (KIC, KMV) or succinyl-CoA (KIV, KMV). Here, we examined whether BCKA-oxidation contributes to H2O2-dependent redox signaling, studied mechanism(s) of its generation, and investigated whether such H2O2 signal is required for BCKA-stimulated insulin secretion (BCKA-SIS) in pancreatic β-cells and islets. Using Amplex UltraRed, we detected BCKA-induced H2O2 release to the exterior of INS-1E cells and pancreatic islets (PIs) upon BCKA-SIS. This H2O2 signal determined closure of ATP-sensitive K+ channels and enabled Ca2+oscillations. It was inhibited by the mitochondrial antioxidant SkQ1; partially by S1QEL, S3QEL (Complex I, III) superoxide-suppressors and by 80-90% after silencing of electron-transfer flavoprotein (ETF) ubiquinone (Q) oxidoreductase (ETFQOR). The H2O2 (redox) signal is generated i) due to the excessive ETFQOR QH2 input, which retards respiratory chain electron transport, providing surplus superoxide at Complex I site IQ (i.e., reversed electron transfer, representing an effective product inhibition of the Complex I QH2 output) and ii) due to the excessive incoming QH2 to the Complex III site IIIQo (minimum for KIV). 13C-incorporation from U-13C-KIC/KIV into various metabolites confirmed β-like oxidation and characterized auxiliary reactions. A causal dependence of BCKA-SIS in PIs on H2O2 generation was found at both phases, evidenced by non-constant correlations of insulin release vs. H2O2 release rates, similarly to glucose-stimulated insulin secretion. Thus, BCKA-stimulated insulin secretion requires coordinated peri-plasma-membrane elevations of ATP/ADP and H2O2, both arising from mitochondrial BCKA β-like oxidation.
    Keywords:  Branched-chain keto acids/ insulin secretion; Electron-transfer flavoprotein ubiquinone oxidoreductase; Mitochondrial H(2)O(2)signaling; Pancreatic β-cells
    DOI:  https://doi.org/10.1016/j.redox.2026.104309
  69. J Am Med Inform Assoc. 2026 Jul 31. pii: ocag131. [Epub ahead of print]
    PhenoSS: phenotype semantic similarity-based approach for rare disease prediction and patient clustering.
    Shihan Chen, Quan M Nguyen, Yu Hu, Cong Liu, Chunhua Weng, Kai Wang.
       OBJECTIVES: Systematic clinical phenotyping using Human Phenotype Ontology (HPO) is central to rare disease diagnosis. However, current disease prioritization (ranking candidate diseases from HPO for a patient) methods face key challenges: they often fail to account for the hierarchical structure of HPO terms, ignore dependencies among correlated terms, and do not adjust for batch effects arising from systematic differences in phenotype documentation across cohorts, institutions, or clinicians. We aim to develop a scalable and statistically principled framework to address these limitations for rare disease prediction and patient stratification.
    MATERIALS AND METHODS: We developed PhenoSS, a Gaussian copula-based framework that models disease-specific marginal prevalence of HPO terms while capturing their joint dependencies through a multivariate normal distribution. Phenotype frequencies were estimated using external curated resources, including OARD (Open Annotations for Rare Diseases) and HPO annotations. PhenoSS supports both pair-wise phenotype similarity calculation for patient clustering and posterior odds estimation for patient-specific disease prioritization. A batch-effect correction module mitigates systematic phenotyping differences across datasets.
    RESULTS: Across diverse simulation scenarios, PhenoSS demonstrated robust disease-prediction performance and consistently improved accuracy after batch-effect correction. In real electronic health record data, PhenoSS identified clinically meaningful patient clusters and effectively distinguished patients with different rare diseases. In disease prioritization tasks, PhenoSS achieved competitive performance with existing methods, particularly for patients exhibiting sparse or noisy phenotype annotations.
    CONCLUSION: PhenoSS provides a statistically interpretable framework for modeling phenotypic heterogeneity in rare disease research and is adaptable to other structured clinical vocabularies such as SNOMED-CT and ICD codes.
    Keywords:  Human Phenotype Ontology; electronic health record; patient clustering; rare disease; semantic similarity
    DOI:  https://doi.org/10.1093/jamia/ocag131
  70. Nat Nanotechnol. 2026 Jul 27.
    Spontaneous and indefinite blinking in upconverting nanoparticles for ångström-precision multicolour super-resolution imaging.
    Saptarshi Mandal, Harrison W Toll, Kaibo Ma, Irmuun Tommy Altankhuyag, Lidao Li, Wanlin Zhang, João F Shida, Chunte Sam Peng.
      Single-molecule localization microscopy enables high-resolution biological imaging, but its precision is limited by the rapid photobleaching of conventional fluorophores. Multicolour imaging is further constrained by the need for spectrally distinct dyes requiring separate excitations or sequential acquisition. Here we show that small (~10 nm) upconverting nanoparticles can be compositionally tuned to exhibit spontaneous, sustained blinking under single near-infrared excitation without optical or chemical modulation. By adjusting sensitizer (Yb3+)-emitter (Tm3+/Er3+) ratios, we identify a regime with intrinsic ON-OFF switching and low duty cycles (~0.9%) without photobleaching or statistical aging, enabling repeated localizations and sub-ångström precision (0.62 Å over 88,000 localizations) in upconversion-enabled stochastic optical reconstruction microscopy. By elucidating the underlying physical mechanism of this blinking, we engineered blue- and red-emitting probes for multicolour upconversion-enabled stochastic optical reconstruction microscopy. This technique enables the resolution of tightly packed UCNPs and the visualization of epidermal growth factor receptor dimers and multimers on cell membranes at single-protein resolution, all achieved with a simple optical setup without imaging buffers.
    DOI:  https://doi.org/10.1038/s41565-026-02233-x
  71. Nat Neurosci. 2026 Jul 29.
    cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.
    Yige Huang, Li Fan, Man Ying Wong, Zhuofan Lei, Balaji Krishnamachary, Daphne Zhu, Mika P Cadiz, Ravi Kumar Nagiri, Pearly Ye, Kendra Norman, Maitreyee Bhagwat, Young Jae Lee, Hui Li, Jingjie Zhu, Sadaf Amin, Kelli Lauderdale, Hao Chen, Wenjie Luo, Shiaoching Gong, Benjamin L Liechty, Jorge J Palop, Subhash C Sinha, Junfang Wu, Mingrui Zhao, Li Gan.
      Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41593-026-02384-z
  72. bioRxiv. 2026 Jul 13. pii: 2026.07.10.737576. [Epub ahead of print]
    A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies.
    Magdalena Riedl Khursigara, Alissa C Goss, Maria Kost-Alimova, Keith Keller, Christine Danielle De Mata, Ranjithmenon Muraleedharan, Edward Ryan Collantes, Matthew Brown, Elizabeth Grinkevich, Felichi Mae Arines, John Lin, Patrick Byrne, Silvana Bazua Valenti, Elizabeth Morici, Julie Roignot, Jason Zavras, Brianna R Silverman, John Carlos Ignacio, Yoochan Myung, Seulki Kwon, Andrew Nelson, Hyery Yoo, Michelle Melanson, Matthew Racette, Valeria Padovano, Seth L Alper, Dominique Carey, Namrata D Udeshi, Steven A Carr, Moran Dvela-Levitt, Toshio Narimatsu, Gustavo Sakuno, Victor San Martin Carvalho Correa, Nikolaos E Efstathiou, Dimitrios P Ntentakis, Tian Cao, Zhiqian Dong, Kim Thien Nguyen, Carolline Rodrigues Menezes, Ravi Kurumbail, Steven Kazmirski, Le Xiao, Hao Wu, David Liu, Sumaiya Iqbal, Eric S Lander, Demetrios G Vavvas, Krzysztof Palczewski, Juan Lorenzo B Pablo, Anna Greka.
      Severe proteinopathies-such as retinitis pigmentosa, a form of inherited blindness-are driven by genetic mutations that overwhelm the quality control of the post-endoplasmic reticulum (post-ER) secretory pathway, causing toxic protein accumulation. Here, we identify a therapeutic node defined by a hetero-oligomeric cargo receptor complex consisting of TMED7, 2, 9, and 10. This "entrapment complex" anchors structurally and functionally diverse mutant clients within the early secretory pathway via TMED7 binding to the integral Golgi protein GRASP55. Disruption of the entrapment complex results in the clearance of accumulated protein cargoes. In vivo ablation of the entrapment node via inducible genetic deletion or via the small molecule BRD7635 reverses histopathological hallmarks and rescues functional deficits in clinically distinct proteinopathies of the kidney and the eye, including mitigating vision loss in a mouse model of retinitis pigmentosa.
    DOI:  https://doi.org/10.64898/2026.07.10.737576
  73. J Immunother Cancer. 2026 Jul 27. pii: e015462. [Epub ahead of print]14(7):
    Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
    Zhiwei Zhang, Yu-An Xie, Chenglin Mu, Shiying Sheng, Jinyuan Zhang, Jie Han, Jiwen Li, Zhengfu He, Xia Liu.
       BACKGROUND: Mitophagy is a mitochondrial quality control process that maintains cellular homeostasis in cancer, yet whether its dysregulation can be exploited to induce tumor immunogenicity remains unclear.
    METHODS: We integrated pancancer single-cell transcriptomic analyses with genetic perturbation strategies in hepatocellular carcinoma models, including CRISPR/Cas9-mediated gene depletion, in vivo syngeneic tumor systems, and RNA-based lipid nanoparticle delivery. Mechanistic investigations combined mitochondrial functional assays, imaging-based mitophagy analysis, flow cytometry, and transcriptional profiling, together with evaluation of immune checkpoint blockade responses in preclinical and clinical cohorts.
    RESULTS: We identify translocase of the outer mitochondrial membrane 40 (TOMM40) as a mitochondrial import gatekeeper that restrains PINK1-Parkin-dependent mitophagy. Loss of TOMM40 induces catastrophic mitochondrial dysfunction and triggers a lethal form of hyperactivated mitophagy. This process is immunogenic and converts immune-cold tumors into immune-inflamed states characterized by enhanced CD8+ T-cell infiltration and activation. Mechanistically, TOMM40 deficiency leads to intracellular reactive oxygen species accumulation, which activates NF-κB signaling and drives upregulation of major histocompatibility complex class I antigen presentation machinery, thereby increasing tumor visibility to cytotoxic T cells. In parallel, TOMM40 loss induces programmed death-ligand 1 upregulation, establishing an adaptive immune resistance program. Functionally, TOMM40-deficient tumors exhibit markedly increased responsiveness to immune checkpoint blockade and generate systemic antitumor immune protection. Clinically, a TOMM40-loss transcriptional signature is associated with improved immunotherapy outcomes across multiple independent patient cohorts.
    CONCLUSIONS: TOMM40 functions as a mitochondrial immune checkpoint that controls the threshold of immunogenic mitophagy. Its loss reprograms mitochondrial stress into antigen presentation and immune activation, providing a strategy to convert immune-cold tumors into immune-responsive states.
    Keywords:  Antigen Presentation; Immunotherapy; Mitochondria
    DOI:  https://doi.org/10.1136/jitc-2026-015462
  74. Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Jul 27. pii: S1388-1981(26)00048-X. [Epub ahead of print] 159762
    Futile cycles in metabolic flexibility: The energetic cost of regulatory precision.
    Radhika Khandelwal, Lianggong Ding, Anand Kumar Sharma.
      Futile cycles (FCs), also known as substrate cycles, are a pair of opposing biochemical reactions that continually convert a substrate into a product and back. In doing so, FCs waste ATP without producing a tangible metabolic output (thus termed 'futile'). Because ATP hydrolysis is exothermic, recent studies have extensively focused on the thermogenic function of various FCs, particularly in adipose tissue. However, the function of FCs on other target organs and their primary biological functions remain poorly defined. In this forward-looking minireview/perspective, we discuss a few underexplored functions of FCs that underpin metabolic flexibility and systemic metabolic health. We propose an integrative model in which discrete FCs across metabolic organs act in concert to regulate cellular energetics and organismal metabolic physiology. We postulate that FCs sense and integrate metabolic status, redox balance, and metabolite signaling, with mitochondria serving as the central hub where energetic and signaling cues converge to generate a calibrated cellular response. Given the broad regulatory role of FCs, including in metabolic flexibility, future studies should aim to define the wider functions vis-à-vis metabolic homeostasis in health and disease.
    Keywords:  Futile cycles; Lipid metabolism; Metabolic flexibility; Metabolic flux; Mitochondria; Thermogenesis
    DOI:  https://doi.org/10.1016/j.bbalip.2026.159762
  75. Cell Rep. 2026 Jul 25. pii: S2211-1247(26)00801-6. [Epub ahead of print]45(8): 117723
    Distributed clonal deletion prevents autoimmune disease progression.
    Anna M Newen, Uzair A Ansari, Mikala J Simpson, Fiona Flynn, Sukriti Sharma, Michael Ivanov, Ishaan Antani, Dylan Pfannenstiel, Baktiar Karim, Laura Bassel, Brian Capaldo, Qingrong Chen, Daoud Meerzaman, Indu Raman, Chengsong Zhu, Cornelius Y Taabazuing, Hamid Kashkar, Christian T Mayer.
      Self-reactive B cells arise during development and can increase pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that self-tolerance is enforced through temporally distinct mitochondrial outer membrane permeabilization (MOMP) checkpoints. Using conditional Bcl-2 expression to inhibit MOMP either from B cell development or activation, we find that early inhibition permits survival of autoreactive B cells after peripheral egress, expanding the pool available for activation and AID-dependent diversification. This results in broadened class-switched IgG autoreactivity, complement activation, kidney pathology, and drives lethal autoimmune disease. In contrast, post-activation MOMP inhibition promotes autoreactive cell accumulation and autoantibody production but causes limited tissue damage and normal survival. Together, these findings support a Distributed Clonal Deletion Model in which temporally distinct checkpoints cooperate to constrain autoimmune disease progression.
    Keywords:  AID; B cell tolerance; CP: immunology; MOMP; SLE; activation-induced cytidine deaminase; autoimmunity; clonal deletion; germinal center; mitochondrial outer membrane permeabilization; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.celrep.2026.117723
  76. PLoS One. 2026 ;21(7): e0345843
    Mapping the chaperonin TRiC/CCT interactome in mouse photoreceptors reveals functional significance for energy metabolism.
    Celine Brooks, David Salcedo-Tacuma, Isabella Mascari, Mark Eminhizer, Tuan Ngo, Douglas Kolson, Emily Sechrest, Tongju Guan, Neil Billington, Wen-Tao Deng, David Smith, Jianhai Du, Nikolai Skiba, Maxim Sokolov.
      The eukaryotic chaperonin TRiC/CCT is essential for folding a diverse set of proteins, yet its interactome and functional roles in specialized neurons remain incompletely understood. To investigate TRiC-mediated folding in rod photoreceptors, we generated a transgenic mouse line expressing an epitope-tagged Tcp-1α subunit, enabling purification of intact TRiC complexes from retinal tissue. Mass spectrometry identified 226 TRiC-interacting proteins, including known TRiC substrates and co-chaperones as well as numerous novel candidates enriched in RNA processing, cytoskeletal organization, and cell-cycle regulation. Using a TRiC loss-of-function model in which expression of a short splice isoform of phosducin-like protein (PhLPs) competitively inhibits TRiC activity, we observed marked reductions in canonical TRiC substrates, including tubulins, transducin β subunits, and triosephosphate isomerase, as well as secondary alterations in proteins involved in cytoskeletal stability, membrane trafficking, energy metabolism, and phototransduction. Quantitative metabolomic profiling revealed that TRiC deficiency induces a metabolic "energy crisis" characterized by reduced glycolytic- and tricarboxylic acid cycle intermediates, acylcarnitines, ATP, NAD, and NADH, implicating widespread impairment of glucose utilization, mitochondrial bioenergetics, and fatty acid oxidation. Integrative proteomic-metabolomic analysis identified a small subset of proteins, including Rab10 and Anxa1, as potential drivers of these metabolic disruptions, with defective Rab10-dependent GLUT4 trafficking emerging as a plausible mechanism underlying impaired glucose uptake in TRiC-deficient rods. Finally, experiments using a perpetually unfolded Gβ1 mutant and Gγ1-knockout mice demonstrated that substrate overload sequesters TRiC and competitively displaces other clients, exacerbating proteostasis imbalance. Together, our study provides a comprehensive in vivo mapping of the TRiC interactome in mammalian rods, reveals a connection between TRiC-dependent proteostasis and energy metabolism in rods, and indicates a mechanism by which misfolded TRiC substrates exacerbate a proteostasis imbalance that ultimately results in neurodegeneration.
    DOI:  https://doi.org/10.1371/journal.pone.0345843
  77. Res Sq. 2026 Jul 21. pii: rs.3.rs-10361921. [Epub ahead of print]
    DRP lyase deficient DNA polymerase beta impairs mitochondrial electron transport chain and compromise mitochondrial DNA integrity.
    Dawit Kidane, Aashirwad Shahi, Nyima Kinteh, Shengyuan Zhao.
      Endogenous and environmental exposures can induce mitochondrial DNA (mtDNA) damage. Previous studies have shown that mtDNA is particularly vulnerable due to its proximity to mitochondrial reactive oxygen species (ROS) and the absence of histone-like protective proteins, both of which contribute to elevated levels of mtDNA damage. Base excision repair is a critical oxidative DNA damage repair pathway to reverse mitochondria genomic stability. In this work, we examined the impact and repair of ROS-induced DNA damage in the mtDNA due to lose of dRP layse activity of DNA polymerase beta (PolB). We used dRP lyase deficient DNA polymerase beta (PolB-dRP lyase) as a model to uncover the mechanism of mtDNA genomic instability and metabolic dysregulation. We have found that PolB-dRP lyase deficient cells significantly accumulate ROS, decrease mitochondrial encoding antioxidant genes, and low expression of genes involved in electron transport channels (ETC) including respiratory complexes I, II, III and IV. Further PolB-dRP lyase deficient cells exhibit a significant mtDNA damage and replication stress. Moreover, PolB-dRP lyase deficient stomach tissues of mice harbor a significant accumulation of ROS and alter mitochondria signaling pathways. Overall, this work highlights the molecular mechanism associated with PolB-dRP lyase function role in modulating ETC/ROS axis and maintaining mitochondrial DNA integrity.
    DOI:  https://doi.org/10.21203/rs.3.rs-10361921/v1
  78. bioRxiv. 2026 Jul 14. pii: 2026.07.13.738307. [Epub ahead of print]
    Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.
    Arnar Breevoort, Dimitar Ivanov, Liam Horan-Portelance, Alissa Nana, Sarat Vatsavayai, Àlex Tudoras Miravet, Jenelle L Wallace, Jingwen W Ding, Felipe L Pereira, Kristen Fernhoff, Maria Luisa Gorno-Tempini, Salvatore Spina, Jennifer S Yokoyama, Howard J Rosen, Lea T Grinberg, Frank M J Jacobs, Bruce L Miller, William W Seeley, Alex A Pollen.
      Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.
    Keywords:  Single-cell; TDP-43; amyotrophic lateral sclerosis; frontoinsular cortex; frontotemporal dementia; selective vulnerability; single-nucleus; von Economo neurons
    DOI:  https://doi.org/10.64898/2026.07.13.738307
  79. Adv Mater. 2026 Jul 25. e74352
    Turritopsis nutricula-Inspired Engineered Biomimetic Skin Promoting Aged Wound Repair via DAZAP1 Phase Separation-Related Mitochondrial Metabolism Reprogramming.
    Chen Liang, Yu Cheng, Zhuoyuan Li, Ao Zheng, Xiujun Fu, Weian Zhang, Lingyan Cao, Chen Wang.
      Aging-associated wound healing deficiency causes a variety of health complications and makes both economic and psychological burdens on patients greatly, with current therapies failing to address underlying pathophysiology and aging-related impairments. Inspired by Turritopsis nutricula, we directly fabricated biomimetic skin matrix (BSM) from human adipose tissue (AT) by decellularization, then incorporated with amino-functionalized apoptotic bodies (FABs) to construct a biomimetic skin (BSM@FABs). BSM@FABs effectively displayed high fibroblast affinity while reversing cellular senescence, accelerating migration, and stimulating neovascularization in aged wounds. Mechanistically, we identified a pioneering DAZAP1 liquid-liquid phase separation (LLPS) triggered by BSM@FABs. These biomolecular condensates in the LLPS process enhanced tricarboxylic acid (TCA) cycle flux and oxidative phosphorylation (OXPHOS), concomitant with suppressed glycolysis and reduced mitochondrial reactive oxygen species, thereby resolving aging-impaired mitochondrial dysfunction. Our work introduces a novel LLPS-targeted strategy for aged wound treatment by reprogramming mitochondrial energy metabolism.
    Keywords:  apoptotic bodies; biomimetic skin; liquid–liquid phase separation; mitochondrial energy metabolism; skin aging
    DOI:  https://doi.org/10.1002/adma.74352
  80. Res Sq. 2026 Jul 18. pii: rs.3.rs-10345985. [Epub ahead of print]
    Olduvai Domains Downregulate Mitochondrial Pathways to Promote Human Brain Evolution and Neoteny.
    Jonathon G Keeney, David Astling, Vanessa Andries, Karl Vandepoele, Nathan Anderson, Jonathan M Davis, Pamela Lopert, Manisha Patel, Ken Jones, Jonathan Vandenbussche, Kris Gevaert, An Staes, Santos Franco, Natasia Paukovich, Beat Vogeli, Frans van Roy, James M Sikela.
      Olduvai (formerly DUF1220) protein domains, encoded by the NBPF gene family, have undergone the greatest human lineage-specific copy-number expansion of any coding sequence in the genome and strongly correlate with brain size and neuron number across primates. Here we show that Olduvai domains act in a dosage-dependent manner to suppress mitochondrial metabolism. Transcriptomic, proteomic, and live-cell imaging analyses of cells overexpressing NBPF1 (which encodes seven Olduvai domains) reveal pronounced downregulation of mitochondrial pathways, including electron transport chain components and NADH dehydrogenase activity, as well as reduced mitochondrial abundance. By limiting energy availability, this suppression delays cellular maturation and developmental timing. We propose that the resulting prolongation of neurogenesis increases neuron production, providing a mechanistic link between Olduvai copy number expansion and the evolutionary enlargement of the human brain. This dosage-sensitive mitochondrial regulation may also contribute to broader neotenic features of human development, offering a unifying molecular mechanism for brain expansion and the neotenic traits that distinguish humans from other primates.
    DOI:  https://doi.org/10.21203/rs.3.rs-10345985/v1
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