bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–08–09
43 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
  2. Targeting mitochondria for the treatment of neurodegenerative diseases.
  3. Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
  4. Mitochondria with (distinct) personality.
  5. The Plasmodium heme detoxification protein functions in mitochondrial protein synthesis.
  6. Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.
  7. ABHD4-2: a cardiolipin-selective phospholipase of the outer mitochondrial membrane.
  8. Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.
  9. Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
  10. Cancer prevalence in primary mitochondrial disease patients and their families.
  11. Long-read sequencing for neurological disorders: opportunities, challenges, and future directions.
  12. Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
  13. Drug safety in patients with mitochondrial disease: an observational cohort study.
  14. Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.
  15. Asymmetric distribution of mitochondrial Ca2+ regulators specifies compartment-specific mitochondrial function and neuronal development.
  16. Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
  17. Mitochondrial alterations in pellagra-associated central chromatolysis: Comparison with ballooned achromatic neurons of other etiologies.
  18. Piezo1-mitochondrial calcium coupling in mechanotransduction, mitochondrial stress, and cell fate.
  19. Organ-specific mitochondrial heterogeneity: An under-recognized variable in preclinical drug toxicity screening.
  20. Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
  21. Complementary Mitochondrial and α-Synuclein Signatures Refine Biological Stratification of Parkinson's Disease.
  22. An ancient mitochondrial program tunes translation to haem availability.
  23. Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
  24. Quantitative In Vivo Imaging of ATP Dynamics in Drosophila Using the Ratiometric Biosensor QUEEN.
  25. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  26. Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
  27. Cardiac MRI reveals myocardial fibrosis and systolic dysfunction in mitochondrial trifunctional protein-deficient mice.
  28. Timely Diagnosis of Cobalamin C Disease via Rapid Genome Sequencing in a Neonate With Severe Prenatally Detected Biventricular Dysfunction.
  29. Mechanistic basis for calmodulin‑dependent allosteric activation of the neuropathy-associated formin INF2.
  30. LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics.
  31. Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
  32. Multilevel impairment of mitochondrial respiration in inclusion body myositis.
  33. Mitochondria as programmable redox rheostats: Advancing from transplantation to bioengineered organelle therapeutics.
  34. A single-nucleus chromatin accessibility atlas reveals epigenetic dynamics in aging mouse skeletal muscle.
  35. Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling.
  36. Mas receptor activation promotes mitophagy and preserves neuronal function after traumatic brain injury.
  37. Exploring cell-type associations of rare disease phenotypes using non-diseased cell atlases.
  38. Mapping enhancer-gene regulatory interactions from single-cell data.
  39. Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner.
  40. Switching off the FNIP1 gene protects against metabolic disease.
  41. Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis-generating candidate for nephrolithiasis.
  42. The identification of drp1 patient mutations that limit interactions with mff.
  43. Asparagine synthetase deficiency: clinical features and experience with asparagine supplementation.
  1. Science. 2026 Aug 06. 393(6811): 601-606
    A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
    Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.
      The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
    DOI:  https://doi.org/10.1126/science.aeh1475
  2. Front Neurosci. 2026 ;20 1835506
    Targeting mitochondria for the treatment of neurodegenerative diseases.
    Qian Li, Ming You.
      Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.
    Keywords:  blood–brain Barrie; mitochondrial dysfunction; mitochondrial targeting; nanocarrier delivery system; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnins.2026.1835506
  3. J Mol Neurosci. 2026 Aug 05. pii: 124. [Epub ahead of print]76(3):
    Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
    Lishu Guo.
      Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.
    Keywords:  Aging; Mitochondria; Mitochondrial permeability transition; Neurodegeneration; The permeability transition pore
    DOI:  https://doi.org/10.1007/s12031-026-02583-0
  4. Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923
    Mitochondria with (distinct) personality.
    Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.
      Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.044
  5. Nat Commun. 2026 Aug 07. pii: 8002. [Epub ahead of print]17(1):
    The Plasmodium heme detoxification protein functions in mitochondrial protein synthesis.
    Louis Sarrazin, Melissa R Rosenthal, Joachim Kloehn, Tanja Ziesmann, Yasmin Schmitz, Anna-Lena Sandtmann, Robert Domènech-Eres, Katharina Scholz-Höhn, Coralie Boulet, Ute Distler, Daniel E Goldberg, Joachim M Matz.
      Malaria blood-stage parasites digest ~80% of host cell hemoglobin within a degradative vacuole, releasing heme that is detoxified by sequestration into hemozoin crystals. Although essential for survival and a validated drug target, the mechanisms of heme biomineralization remain unclear. Here, we study the parasite's Heme Detoxification Protein (HDP), previously proposed to mediate hemozoin formation, using genetic, microscopic, bioenergetic, and proteomic approaches. Endogenous tagging reveals that HDP localizes to the mitochondrion, not the digestive vacuole. HDP inactivation has no effect on heme biomineralization, but causes mitochondrial depolarization, proguanil hypersensitivity, and developmental arrest, which is rescued by bypassing respiratory-chain-dependent pyrimidine biosynthesis. HDP knockout abolishes mitochondrial electron flow due to loss of complexes III and IV, consistent with impaired mitochondrial protein synthesis. Integration of structural modelling with quantitative proteomics places HDP within the mitoribosomal large subunit. Here, we show that HDP is essential for mitochondrial function and does not contribute to hemozoin formation.
    DOI:  https://doi.org/10.1038/s41467-026-76511-6
  6. J Proteome Res. 2026 Aug 07. 25(8): 3965-3986
    Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.
    Chiranjit Panja, Aneta Wiesyk, Suchismita Masanta, Katarzyna Niedzwiecka, Emilia Baranowska, Dominik Cysewski, Marta Sipko, Anna Anielska-Mazur, Agata Malinowska, Roza Kucharczyk.
      Protein adenylation (AMPylation) is a post-translational modification in which an adenosine monophosphate (AMP) group is covalently attached to target proteins by AMPylases using ATP as a donor. In metazoans, two conserved AMPylase families are known: FIC-domain proteins and SelO. The yeast Saccharomyces cerevisiae lacks a FIC-domain enzyme; its only known AMPylase is the mitochondrial SelO homologue, Fmp40, involved in redox signaling. We conducted the first comprehensive screen for AMPylated proteins in the mitochondrial proteome of S. cerevisiae analyzing both wild-type and fmp40Δ cells using quantitative mass spectrometry. We identified 124 AMPylated mitochondrial proteins in wild-type and 41 in fmp40Δ mitochondria, suggesting the existence of additional AMPylase(s) in yeast. Among the modified targets, seven ATP synthase subunits were AMPylated, many at sites also phosphorylated, underscoring complex PTM regulation of the enzyme. We demonstrated that substitutions of one such residue, serine 29 in the δ subunit (Atp16), to alanine or glutamic acid, altered ATP synthase activity and oxidative phosphorylation coupling under both fermentative and respiratory conditions. This regulation is crucial for maintaining mitochondrial membrane potential. Our study provides the first catalog of AMPylated mitochondrial proteins in yeast, establishing a foundation for future studies on mitochondrial AMPylation.
    Keywords:  AMPylation; ATP synthase; Fmp40; mitochondria; yeast
    DOI:  https://doi.org/10.1021/acs.jproteome.5c01273
  7. J Lipid Res. 2026 Aug 06. pii: S0022-2275(26)00149-5. [Epub ahead of print] 101119
    ABHD4-2: a cardiolipin-selective phospholipase of the outer mitochondrial membrane.
    Raja Narayanasamy, Matthew A Sanders, Huamei Zhang, Marta Moreno-Torres, Vanesa D Ramseyer, Hong-Guang Wei, Nils J Færgeman, Christopher V Kelly, James G Granneman.
      Cardiolipin (CL) is a unique dimeric phospholipid essential for mitochondrial integrity and stress signaling. While most CL is present in the inner mitochondrial membranes (IMM), CL can be exposed to the outer mitochondrial membrane (OMM) under specific physiological and pathological conditions; however, the mechanisms regulating its metabolism at the OMM are poorly defined. Based on its striking structural similarity to Cld1p, a yeast CL hydrolase, we hypothesized that α/β-hydrolase domain-containing protein 4 (ABHD4) functions as a mammalian CL hydrolase. We identified two isoforms of mouse ABHD4 arising from alternative splicing: ABHD4-1 localizes to lipid droplets, whereas ABHD4-2 selectively targets mitochondria and is enriched in oxidative tissues. We demonstrate that ABHD4 selectively hydrolyzes CL in vitro, producing monolysocardiolipin (MLCL) and dilysocardiolipin (DLCL). Site-directed mutagenesis identified catalytic serine residues as essential for enzymatic activity in ABHD4 and its Drosophila homolog, Pummelig. In contrast to Cld1p, which resides in the IMM, topological analyses indicate that ABHD4-2 and Pummelig-2 localize to the cytosolic face of the OMM, a conserved orientation that suggests a function distinct from classic acyl chain remodeling of CL. In brown adipocytes, ABHD4-2 overexpression reduces mitochondrial membrane potential in an activity-dependent manner. In silico analyses further reveal conservation of the catalytic triad across yeast, insect, and mammalian orthologs, supporting an evolutionarily conserved role for this enzyme family in CL metabolism. Together, these findings identify ABHD4-2 as an OMM-localized phospholipase with preferential CL hydrolase activity and define an isoform-specific pathway linking CL metabolism to mitochondrial stress responses.
    Keywords:  ABHD4-2; Cardiolipin; cardiolipin hydrolase; outer mitochondrial membrane; phospholipase activity
    DOI:  https://doi.org/10.1016/j.jlr.2026.101119
  8. Front Neurol. 2026 ;17 1882474
    Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.
    Luigi Del Giudice, Marco Guida, Maria Rosaria Aletta, Paola Pontieri.
      Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.
    Keywords:  Alzheimer's and Parkinson's disease; GEP3; MRPL44; NAM9; mitochondrial disease; mitochondrial genome; nuclear genome; yeast and C. elegans model organisms
    DOI:  https://doi.org/10.3389/fneur.2026.1882474
  9. Mol Cell Biochem. 2026 Aug 07.
    Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
    Paulo Roberto Dos Santos, Joseph Rastegar, Mariana Roesch-Ely.
      Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10- 5 mol.L- 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.
    Keywords:  Coenzyme Q; Hydroxyhydroquinone; Metabolism; Mitochondrial; Ubiquinone
    DOI:  https://doi.org/10.1007/s11010-026-05687-8
  10. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261471914
    Cancer prevalence in primary mitochondrial disease patients and their families.
    Shrey Dalwadi, Nicole M Engelhardt, Colleen C Muraresku, Kelsey Keith, Kathleen D Valverde, Katherine L Nathanson, Marni J Falk.
       Background: While somatic mitochondrial dysfunction occurs in diverse cancers, the association between oncogenesis and germline mitochondrial gene pathogenic variants remains unclear. Further, few clinical observations have been reported of cancer occurring in primary mitochondrial disease (PMD) patients.
    Objectives: To improve understanding of the potential modulating role for PMD gene disorders in cancer prevalence.
    Design: 727 individuals, including 100 with PMD, from 97 unrelated families were retrospectively surveyed to assess their history of individual cancer occurrence.
    Methods: We evaluated survey responses by characterizing the cancer prevalence among the study cohort and comparing to the general U.S. population via the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Odds ratio calculation was performed to determine the association of survey responses and cancer prevalence.
    Results: Although overall cancer prevalence in PMD probands and their families was elevated compared to the NCI SEER rate (8800 vs 5600 cases per 100,000), odds ratio calculation determined that PMD did not significantly increase the likelihood of developing cancer, with a non-significant trend observed toward less cancer occuring in PMD that needs to be explored in further studies. Cancer prevalence was significantly correlated with advanced age. Significantly reduced prevalence of prostate cancer was seen across the entire cohort. Surprisingly, while low absolute prevalence (n = 3), a 9-fold increased odds ratio of cancer was seen in POLG patients relative to those with other causes of PMD.
    Conclusion: No evidence of increased cancer odds was identified in a cohort of PMD patients and their close relatives. Interestingly, a possible inverse association, which did not reach statistical significance, was suggested between mitochondrial disease status and cancer odds. Future prospective investigations in larger PMD kindreds are warranted to validate and evaluate potential mechanistic relations between cancer prevalence and PMD.
    Keywords:  POLG; cancer; mitochondria; primary mitochondrial disease
    DOI:  https://doi.org/10.1177/26330040261471914
  11. Neurol Sci. 2026 Aug 01. pii: 675. [Epub ahead of print]47(8):
    Long-read sequencing for neurological disorders: opportunities, challenges, and future directions.
    Hanabi Geiger, Yutaka Furuta, B Lakshitha A Perera, Russell Stewart, Rory J Tinker, John A Phillips.
       BACKGROUND: Many neurological disorders (NDs) have a genetic basis, yet traditional diagnostic tools such as EEGs, EMGs, and neuroimaging primarily capture downstream manifestations. Although short-read sequencing (SRS) has advanced genetic diagnostics, significant gaps remain. Large repeat expansions, complex structural variants, mitochondrial variants, transcript splicing alterations, and epigenetic changes, all common contributors to NDs, are difficult to resolve with SRS.
    METHODS: This review examines the capabilities of long-read sequencing (LRS) technologies in addressing these limitations. We evaluate studies leveraging LRS for genetic diagnosis in NDs and assess current barriers to clinical adoption, including technological, analytical, cost-related, and ethical considerations.
    RESULTS: By producing read lengths of tens of kilobases or more, LRS enables detection of variant types often inaccessible to SRS. Recent work has demonstrated its power in conditions such as Duchenne muscular dystrophy, fragile X syndrome, spinocerebellar ataxias, and unresolved mitochondrial syndromes. These findings highlight the potential of LRS to substantially increase diagnostic yield in NDs. However, major challenges persist: the need for high-quality DNA, demanding analytic pipelines, limited access outside major research centers, high costs, and ethical concerns including equity and management of incidental findings.
    CONCLUSIONS: LRS offers advantages for identifying complex genomic contributors to NDs and holds promise for improving diagnostic accuracy. Nonetheless, key technical, logistical, and ethical barriers must be addressed before widespread implementation is feasible. This review outlines current strengths, limitations, and emerging applications of LRS to guide clinicians and researchers in understanding how the technology can be applied today and what is needed for broader adoption.
    Keywords:  Clinical genomics; Epigenetic and methylation profiling; Long-read sequencing (LRS); Neurogenetic disorders; Oxford Nanopore Technologies (ONT); Pacific Biosciences HiFi
    DOI:  https://doi.org/10.1007/s10072-026-09283-y
  12. J Transl Med. 2026 Jul 31. pii: 988. [Epub ahead of print]24(1):
    Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
    Anbin Chen, Tsering Yangzom, Gareth John Sullivan, Kristina Xiao Liang.
       BACKGROUND: POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined.
    METHODS: Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how POLG mutations alter mitochondrial and neuronal programs at subtype resolution. We analyzed dopaminergic neuronal populations and ventral midbrain neurons to define disease-associated transcriptional changes. To evaluate therapeutic improvement, POLG organoids were treated chronically with nicotinamide riboside (NR), followed by single-cell transcriptomic profiling and pathway enrichment analysis.
    RESULTS: POLG mutations induced a coordinated downregulation of genes associated with oxidative phosphorylation and synaptic signaling, particularly in terminally differentiated dopaminergic neurons. This transcriptional alteration involved genes encoding respiratory chain complexes I-V, mitochondrial translation machinery, and ATP synthase components, suggesting disruption of mitochondrial bioenergetic programs at the transcriptomic level. Among dopaminergic subtypes, DA2 neurons and ventral midbrain neurons showed the most pronounced transcriptional alterations, indicating maturation-dependent vulnerability. NR treatment was associated with altered expression of genes involved in oxidative phosphorylation, NADH dehydrogenase activity, respiratory chain assembly, and synaptic pathways. Following NR exposure, dopaminergic subpopulations exhibited changes in cell-type proportions and partial normalization of mitochondrial- and synaptic-related transcriptional programs.
    CONCLUSIONS: These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD⁺ metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.
    Keywords:  Dopaminergic vulnerability; Midbrain organoids; NADH-dependent respiration; POLG disease; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12967-026-08706-w
  13. Neurol Sci. 2026 Aug 06. pii: 683. [Epub ahead of print]47(9):
    Drug safety in patients with mitochondrial disease: an observational cohort study.
    Oskar Järvinen, Mika H Martikainen.
       BACKGROUND: Mitochondrial diseases are common inherited neurometabolic disorders and frequently involve the nervous system, yet their multisystem nature often necessitates complex pharmacological management. Many commonly prescribed medications have off-target effects on mitochondrial function, and patients with mitochondrial disease may be particularly vulnerable to such effects due to impaired energy metabolism. However, systematic data on medication safety in this patient group remain scarce.
    METHODS: In this retrospective, single-centre, cohort-based study at Turku University Hospital (Turku, Finland), we reviewed the medication data from all hospital stays and outpatient prescriptions of 44 mostly adult (20 women; mean age 50 years, range 12-83 years) patients with genetically and clinically confirmed mitochondrial disease for years 2010-2022. We used the Anatomical Therapeutic Chemical system for drug classification. Potential drug-drug interactions and potential adverse drug reactions were investigated. Special focus was on potential mitochondrial toxicity of drugs and clinically relevant drug-drug interactions.
    RESULTS: Altogether ~ 1000 individual medication entries were reviewed. We identified several common drugs with potentially adverse effects on mitochondria, including metformin, beta-blockers, statins, ciprofloxacin, fluoxetine, ibuprofen, and certain anti-seizure drugs. Medications generally considered contraindicated in mitochondrial disease were not observed. No high-risk drug interactions were detected. Additional finding of clinical relevance was the frequent use of analgesics.
    CONCLUSIONS: Further research regarding mitochondrial safety of several drug classes is needed for more evidence-based safety evaluations. Pain in the context of mitochondrial disease merits increased attention.
    Keywords:  Drug safety; Medication; Mitochondria; Mitochondrial disease; Pharmacological treatment
    DOI:  https://doi.org/10.1007/s10072-026-09298-5
  14. Life Sci. 2026 Aug 07. pii: S0024-3205(26)00433-9. [Epub ahead of print] 124624
    Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.
    Yiqin Yan, Lupeng Chen.
      Adipose tissue protects metabolic homeostasis by storing excess fatty acids, releasing fuels during energy demand and coordinating endocrine and inflammatory signals. These functions are often described as linear pathways of lipogenesis, lipolysis, fatty acid oxidation and thermogenesis. However, lipid handling in adipocytes is spatially organized by organelle contact sites. The endoplasmic reticulum (ER), lipid droplets (LDs), mitochondria, peroxisomes and lysosomes form dynamic interfaces that determine whether fatty acids are stored safely, mobilized for oxidation, processed into specialized lipid species or redirected toward lipotoxic intermediates. In this review, we synthesize evidence that ER-LD and LD-mitochondria contacts coordinate lipid storage and oxidative use, whereas peroxisome-centred contacts connect lipolysis, very-long-chain and branched-chain fatty acid processing, plasmalogen metabolism and mitochondrial remodelling. We further discuss how autophagy and lysosomal pathways maintain adipocyte quality control by regulating LD turnover, mitophagy and membrane renewal. Finally, we propose that obesity, insulin resistance, ectopic lipid deposition, lipodystrophy and adipose inflammation can be viewed as different manifestations of impaired spatial lipid routing. This framework does not replace classical metabolic models, but provides a mechanistic layer that may help identify contact-site-dependent vulnerabilities in metabolic disease.
    Keywords:  Adipose tissue; Lipid droplets; Lipophagy; Metabolic disease; Mitochondria; Organelle contact sites; Peroxisomes
    DOI:  https://doi.org/10.1016/j.lfs.2026.124624
  15. Exp Mol Med. 2026 Aug 05.
    Asymmetric distribution of mitochondrial Ca2+ regulators specifies compartment-specific mitochondrial function and neuronal development.
    Dong Cheol Jang, Su Yeon Kim, Won Seok Kim, In Young Choi, Eunsu Jang, Hyunsu Jung, Changuk Chung, Seokyoung Bang, Hong Nam Kim, Hae Woong Choi, Kihoon Han, Yongcheol Cho, Seok-Kyu Kwon.
      Neuronal polarization is essential for functional compartmentalization, enabling dendritic synaptic integration and axonal action potential generation. Although structural differences in mitochondria across compartments have been identified, their functional distinctions remain unclear. Here, we uncovered compartment-specific mitochondrial Ca2+ dynamics and their molecular determinants. In axonal mitochondria, Ca2+ uptake through mitochondrial Ca2+ uniporter occurs independently of ER-stored Ca2+ release, with faster matrix Ca2+ clearance than dendritic mitochondria, where Ca2+ uptake predominantly originates from ER Ca2+. The ER-independent mitochondrial Ca2+ uptake in axonal mitochondria is associated with enriched mitochondrial Ca2+ uniporter-regulating proteins, MICU1 and MICU2, whereas higher NCLX expression facilitates rapid Ca2+ clearance. Moreover, NCLX knockdown, which functionally mimics a mental retardation-associated mutation, caused more significant developmental defects of axons than dendrites in vivo, aligning with its enrichment in axons. These findings highlight fundamental Ca2+-modulating features and developmental importance of neuronal mitochondria in a compartment-specific manner and reveal the key underlying molecular determinants.
    DOI:  https://doi.org/10.1038/s12276-026-01803-2
  16. Neuron. 2026 Aug 06. pii: S0896-6273(26)00541-6. [Epub ahead of print]
    Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
    Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.
      Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience. Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Inhibition of RET ameliorates tau toxicity across species. RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.
    Keywords:  Alzheimer’s disease; NAD(+)/NADH ratio; NDUFS3; ROS; complex I; mitochondria; phosphorylation; reverse electron transport; tau; tauopathy
    DOI:  https://doi.org/10.1016/j.neuron.2026.07.012
  17. J Neuropathol Exp Neurol. 2026 Aug 06. pii: nlag058. [Epub ahead of print]
    Mitochondrial alterations in pellagra-associated central chromatolysis: Comparison with ballooned achromatic neurons of other etiologies.
    Araki Kimura, Ito Kawakami, Kenji Ikeda, Akito Nagakura, Kenichi Oshima, Tadafumi Kato, Masato Hasegawa.
      Neuronal central chromatolysis (CC) is the histopathological hallmark of pellagra encephalopathy, a neurological deficit resulting from vitamin deficiencies. Pellagrous CC neurons are morphologically similar to ballooned achromatic neurons in other conditions but the distinct pathomechanisms remain unclear. We performed a clinico-neuropathological analysis of 10 autopsy cases of pellagra encephalopathy. The pellagra encephalopathy cases were immunohistochemically compared with disease controls, including cases of axonal injury and neurodegenerative diseases. Electron microscopic evaluation and immunohistochemical examinations targeting mitochondrial fragmentation were performed for a representative case. Four of 10 pellagra encephalopathy patients exhibited prolonged impairment of consciousness distinguishable from alcohol withdrawal delirium. Pellagrous CC neurons were negative for cytoskeletal markers whereas ballooned achromatic neurons in the disease control cases were positive. Immunohistochemical analysis of mitochondrial markers revealed that CC neurons exhibited more intense immunoreactivity for COX-IV and mitochondrial fissure factor compared to the disease controls. Transmission electron microscopy of these CC neurons revealed a marked increase in the mitochondria with amorphous densities. These findings indicate that the pathomechanism of pellagrous CC is distinct from that of the ballooned achromatic neurons of other etiologies. Mitochondrial alterations in pellagrous CC neurons suggest that neuronal energy deficits resulting from nicotinamide adenine dinucleotide deficiency induce mitochondrial fragmentation.
    Keywords:  central chromatolysis; mitochondria; neuropathology; niacin; pellagra
    DOI:  https://doi.org/10.1093/jnen/nlag058
  18. Cell Calcium. 2026 Jul 24. pii: S0143-4160(26)00074-6. [Epub ahead of print]137 103181
    Piezo1-mitochondrial calcium coupling in mechanotransduction, mitochondrial stress, and cell fate.
    Peijie Shi, Xinyi Zhao, Miao Li, Xiangyang Wu, Yongnan Li, Qiming Zhao.
      Piezo1-derived Ca²⁺ signals provide a mechanosensitive route through which mechanical inputs are decoded by mitochondria. Piezo1 converts membrane tension, fluid shear stress, and matrix stiffening into ionic signals, but mitochondrial outcomes depend on how Ca²⁺ is spatially routed, buffered, and amplified. This review integrates plasma membrane-initiated entry, endoplasmic reticulum (ER)-mitochondria communication, voltage-dependent anion channel (VDAC)/mitochondrial calcium uniporter (MCU)-related transfer, cytoskeletal organization, and selected organelle-associated Piezo1 signals. We examine how mechanical dose, pathological microenvironments, and cell state shift mitochondrial decoding from adaptive bioenergetic, redox, and quality-control responses toward Ca²⁺ overload and organelle failure. A shared mitochondrial stress state can then bias apoptosis, ferroptosis, inflammatory death, or senescence, producing tissue-specific outcomes and therapeutic opportunities. The translational goal is not indiscriminate Piezo1 blockade, but restoration of a safe coupling range between Piezo1-derived Ca²⁺ entry and mitochondrial buffering, repair, and fate stability.
    Keywords:  Calcium signaling; Cell fate; Ferroptosis; Mechanotransduction; Mitochondria; Mitochondrial stress; Piezo1
    DOI:  https://doi.org/10.1016/j.ceca.2026.103181
  19. Mitochondrion. 2026 Aug 04. pii: S1567-7249(26)00089-9. [Epub ahead of print]91 102199
    Organ-specific mitochondrial heterogeneity: An under-recognized variable in preclinical drug toxicity screening.
    Nirupama Lal.
      Mitochondria exhibit substantial organ-specific heterogeneity arising from the distinct physiological, metabolic, and functional demands of individual organs. Differences in bioenergetics, oxidative stress handling, calcium homeostasis, and metabolic adaptability may influence mitochondrial responses to pharmacological agents and contribute to organ-selective drug toxicity. However, contemporary preclinical drug toxicity screening continues to rely predominantly on generalized experimental systems that may incompletely capture these organ-specific mitochondrial vulnerabilities. This Perspective proposes integrating organ-adapted mitochondrial physiology into preclinical drug safety evaluation through tissue-relevant cellular models, functional mitochondrial assays, and emerging microphysiological platforms to improve predictive toxicology and strengthen translational relevance.
    Keywords:  Drug safety screening; Mitochondrial heterogeneity; Mitochondrial toxicity; Organ-specific mitochondria; Predictive toxicology; Translational pharmacology
    DOI:  https://doi.org/10.1016/j.mito.2026.102199
  20. Nat Commun. 2026 Aug 07. pii: 8011. [Epub ahead of print]17(1):
    Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
    Jonathan Kölschbach, Hormos S Dafsari, Emily Baum, Anna Löhrke, Chun Kew, Ivan Dikic, Wenming Huang, Adam Antebi.
      mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.
    DOI:  https://doi.org/10.1038/s41467-026-76295-9
  21. Mov Disord. 2026 Aug 04.
    Complementary Mitochondrial and α-Synuclein Signatures Refine Biological Stratification of Parkinson's Disease.
    Julia C Fitzgerald, Patrick May, Anne Grünewald.
      
    DOI:  https://doi.org/10.1002/mds.70437
  22. Nature. 2026 Aug 05.
    An ancient mitochondrial program tunes translation to haem availability.
    Xiang Zhang, Max-Hinderk Schuler, Gonca Çetin, Eva-Maria Eckl, Lara Rheinemann, Julia Mergner, Barbara Steigenberger, Andreas Pichlmair, Lucas T Jae.
      Anaemia is a major global health burden that affects one-quarter of the human population and annually accounts for over 50 million years of healthy life lost1. It arises from nutritional iron deficiency, hereditary disorders (including thalassaemia and sickle cell disease) and malaria, and is characterized by haemoglobin imbalances2. Haem-the active component of haemoglobin-is both essential and potentially toxic, which necessitates tight control of levels. However, the molecular circuitry that monitors haem levels remains obscure. The cytosolic eIF2α kinase HRI counteracts anaemia amid iron deficiency or thalassaemia3,4 by acting as a gatekeeper of translation during erythroid differentiation, which has been attributed to its haem-binding ability5. Here we uncover that haem scarcity is sensed inside mitochondria through an OMA1-DELE1 axis. Mechanistically, haem deficiency triggers OMA1-dependent mitochondrial release of DELE1. In the cytosol, DELE1 releases inhibitory haem from HRI, which enables modifications in a crucial disordered segment of the kinase. We demonstrate that this sensor-actuator operates across human tissues, including erythroid progenitors, and is evolutionarily conserved down to bloodless invertebrates, thus predating the emergence of haemoglobin-based oxygen transport. Notably, pharmacological manipulation of this system enhances fetal globin expression-a central therapeutic objective in haemoglobinopathies. Together, these results reveal a primordial sentinel system that safeguards against haem-related toxicity from the single-cell to the organismic scale.
    DOI:  https://doi.org/10.1038/s41586-026-10885-x
  23. Cell Signal. 2026 Aug 02. pii: S0898-6568(26)00436-5. [Epub ahead of print]148 112778
    Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
    Wei Guan, Wenxu Li, Zijun Li, Lu Peng, Shidan Shao, Juanjuan Zhang.
      Leber's hereditary optic neuropathy (LHON) is a genetically inherited disease of the eye triggered by mtDNA mutations, leading to degeneration of RGCs. We previously reported that the mitochondrial tRNAThr (MT-TT) 15927G > A homoplasmic mutation disrupted the base pairing (28C-42G) conserved in the anticodon stem of tRNAThr, impairing t6A modification, aminoacylation, and steady-state tRNAThr levels, ultimately resulting in mitochondrial dysfunction. However, the absence of suitable animal and cell models for LHON has delayed efforts to elucidate disease pathophysiology, particularly tissue-specific effects. In this study, RGC-like cells were generated from iPSCs derived from a Chinese family member carrying the m.15927G > A mutation and from a control subject without this mutation. Mitochondrial dysfunction and autophagy/mitophagy defects were investigated at three differentiation stages: iPSCs, NPCs, and RGC-like cells. Both iPSCs and NPCs harboring this mutation exhibited abnormal mitochondrial dynamics, mitochondrial dysfunction, and defects in autophagy and mitophagy. RGC-like cells carrying the mutation showed significant abnormalities, including shorter neurites, imbalanced mitochondrial dynamics, elevated ROS production, reduced mitochondrial membrane potential, and impaired autophagy and mitophagy. These results indicate that the m.15927G > A mutation induces progressive mitochondrial dysfunction and developmental defects in RGCs, providing new insights into LHON pathogenesis and establishing a valuable model for future therapeutic development.
    Keywords:  Autophagy; Induced pluripotent stem cells (iPSCs); Leber's hereditary optic neuropathy (LHON); Neural progenitor cells (NPCs); Retinal ganglion cells (RGCs)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112778
  24. Dev Growth Differ. 2026 Aug;68(6): e70065
    Quantitative In Vivo Imaging of ATP Dynamics in Drosophila Using the Ratiometric Biosensor QUEEN.
    Yuhan Luo, Sayaka Sekine, Naoto Kasahara, Hiroyuki Uechi, Takafumi Toyohara, Takaaki Abe, Erina Kuranaga.
      Genetically encoded ATP biosensors enable monitoring of cellular energy status, but their application in multicellular organisms remains limited. QUEEN is a ratiometric ATP biosensor consisting of a bacterial ATP-binding protein fused to a circularly permuted fluorescent protein and has been primarily validated in cultured cells. Here, we generated transgenic Drosophila melanogaster lines expressing QUEEN-7μ, enabling tissue-specific expression through the GAL4/UAS system. We characterized its performance in motor neurons and muscles. QUEEN-7μ responses were validated using pharmacological and genetic perturbations of mitochondrial function. Mitochondrial inhibition decreased the QUEEN-7μ ratio, consistent with reduced ATP levels, whereas acute treatment with mitochonic acid-5 (MA-5), a small molecule that enhances mitochondrial ATP synthesis, increased the QUEEN-7μ ratio, with a larger effect at higher concentration. Consistently, genetic manipulations, including the mitochondrial Complex I knockdown and Mitofilin/MIC60 overexpression, produced corresponding decreases and increases in the QUEEN-7μ ratio. These results establish QUEEN-7μ as a reliable ratiometric ATP reporter for quantitative in vivo analysis in Drosophila. This system provides a versatile platform for investigating energy metabolism and mitochondrial function in Drosophila.
    Keywords:   Drosophila melanogaster ; ATP biosensor; QUEEN; energy metabolism; in vivo imaging; mitochondrial function; ratiometric sensor
    DOI:  https://doi.org/10.1111/dgd.70065
  25. Cell Metab. 2026 Aug 05. pii: S1550-4131(26)00324-4. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.026
  26. Mol Neurobiol. 2026 Aug 01. pii: 800. [Epub ahead of print]63(1):
    Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
    Mengqi Chu, Miaomiao Tan, Xulin Gan, Shumao Cui, Liyun Shi.
      Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.
    Keywords:  Microglia; Mitochondria; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-026-06091-5
  27. Dis Model Mech. 2026 Aug 03. pii: dmm.052921. [Epub ahead of print]
    Cardiac MRI reveals myocardial fibrosis and systolic dysfunction in mitochondrial trifunctional protein-deficient mice.
    Eduardo Vieira Neto, Shakuntala Basu, Thomas J Becker-Szurszewski, Sean Hartwick, Kristina E Schwab, Yijen Wu, Jerry Vockley.
      Cardiomyopathy is an important manifestation in patients with fatty acid oxidation disorders and represents a major cause of morbidity and early mortality in mitochondrial trifunctional protein (TFP) deficiency. Although a mouse model carrying the TFP β-subunit p.Met404Lys mutation (βTFP-deficient) has been described, cardiac involvement in this model has not been systematically characterized. Here, we combined cardiac histology and multiparametric cardiac MRI (CMR) to define myocardial structure, function, and tissue characteristics in this mouse model. Histological analysis with automated whole-slide collagen quantification revealed myocardial fibrosis with collagen deposition in mutant hearts, and CMR demonstrated increased myocardial extracellular volume in both male and female homozygous mutants. Homozygous males showed reduced ejection fraction, impaired systolic strain, and increased left ventricular end-systolic volume, indicating systolic dysfunction. Male mice were more severely affected than females and exhibited reduced survival. Together, these findings demonstrate that βTFP-deficient mice develop fibrotic cardiomyopathy with systolic dysfunction, reproducing important cardiac features observed in human TFP deficiency. This work establishes the model as a relevant platform for investigating disease mechanisms and therapeutic strategies for cardiomyopathy in TFP deficiency.
    Keywords:  Cardiac magnetic resonance imaging; Cardiomyopathy in mouse models; Fatty acid oxidation disorders; Mitochondrial trifunctional protein deficiency; Myocardial fibrosis
    DOI:  https://doi.org/10.1242/dmm.052921
  28. Case Rep Crit Care. 2026 ;2026 2778022
    Timely Diagnosis of Cobalamin C Disease via Rapid Genome Sequencing in a Neonate With Severe Prenatally Detected Biventricular Dysfunction.
    Yutaka Furuta, Samantha N Walkin, Scott K Ward, Rory J Tinker, Rizwan Hamid, John A Phillips, Rachel E Harris, Thomas A Cassini.
      Cobalamin C (Cbl-C) disease, the most common inborn error of cobalamin metabolism caused by biallelic pathogenic MMACHC variants, leads to multisystem involvement from methylmalonic acid and homocysteine accumulation. When diagnosed early, it is treatable. Rapid genome sequencing (GS) is becoming increasingly accessible and enables timely diagnosis and prompt treatment. We report a neonate who had severely decreased prenatal and postnatal biventricular function requiring inotropic support. Given the critically ill condition and unclear etiology, rapid GS was obtained and revealed homozygous pathogenic MMACHC variants, confirming a diagnosis of Cbl-C disease. This prompted the early initiation of treatment with high-dose hydroxocobalamin, betaine, levocarnitine, and folic acid. His cardiac function gradually improved, and he was discharged at 28 days of life. Critical care providers should suspect treatable inherited metabolic disorders in patients with unexplained presentations and recognize rapid GS as a powerful tool for early identification and treatment in critically ill patients.
    Keywords:  biventricular dysfunction; cardiomyopathy; cobalamin C disease; intensive care; rapid genome sequencing
    DOI:  https://doi.org/10.1155/crcc/2778022
  29. Cell Rep. 2026 Aug 03. pii: S2211-1247(26)00828-4. [Epub ahead of print]45(8): 117750
    Mechanistic basis for calmodulin‑dependent allosteric activation of the neuropathy-associated formin INF2.
    Bohan Zhang, Meng Zhang, Ke Liu, Chenhui Zhao, Jianwen Zhang, Zhijun Liu, Ying Fan, Ruo-Xu Gu, Lin Lin, Chuanhai Fu, Jinwei Zhu.
      Calcium signaling regulates the atypical formin INF2 to drive actin assembly in diverse cellular processes, yet the underlying molecular mechanism remains elusive. Here, we uncover a direct, nanomolar-affinity interaction between calcium-bound calmodulin (Ca2+-CaM) and the diaphanous inhibitory domain (DID) of INF2. The high-resolution crystal structure of the Ca2+-CaM-INF2 DID complex reveals a unique allosteric activation mechanism distinct from canonical Rho GTPase-mediated formin regulation. Ca2+-CaM binding induces conformational changes that disrupt the autoinhibitory DID-DAD interaction, triggering its actin assembly activity. We show that Ca2+-CaM activates ER-bound INF2, thereby promoting mitochondrial fission. We further demonstrate that a Charcot-Marie-Tooth neuropathy-associated INF2 mutation enhances Ca2+-CaM binding through optimized interfacial dynamics, revealing a gain-of-function disease mechanism. Our findings provide a mechanistic framework for Ca2+-CaM-dependent activation of INF2, establishing the CaM-INF2 axis as a direct activator of actin-dependent organelle dynamics, with implications for INF2-linked pathologies.
    Keywords:  CP: molecular biology; INF2; actin filament; allosteric regulation; autoinhibition; calcium signaling; calmodulin; formin; mitochondrial fission; neuroscience
    DOI:  https://doi.org/10.1016/j.celrep.2026.117750
  30. Elife. 2026 Aug 06. pii: RP95987. [Epub ahead of print]13
    LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics.
    Giulia Tombesi, Shiva Kompella, Giulia Favetta, Chuyu Chen, Marta Ornaghi, Yibo Zhao, Ester Morosin, Martina Sevegnani, Adriano Lama, Antonella Marte, Ilaria Battisti, Lucia Iannotta, Nicoletta Plotegher, Laura Civiero, Franco Onofri, Britta J Eickholt, Giovanni Piccoli, Giorgio Arrigoni, Dayne Beccano-Kelly, Claudia Manzoni, Loukia Parisiadou, Elisa Greggio.
      Parkinson's disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction results from the degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Increasing evidence suggests that synapse dysfunction precedes neuronal loss by years. Still, early synaptic alterations in PD remain poorly understood. Here, we integrate literature meta-analysis and multi-omics with biochemical, imaging, and electrophysiological measurements in Lrrk2 mouse models and human iPSC-derived neurons lacking LRRK2. We demonstrate that brain-derived neurotrophic factor (BDNF) activates LRRK2 in differentiated SH-SY5Y cells and primary mouse neurons, reshaping the LRRK2 interactome toward a network of actin cytoskeleton-related proteins. Gene-ontology analyses of both literature-curated LRRK2 interactors and phospho-proteome from striatal tissues with elevated LRRK2 activity highlight synapse-actin remodeling as major affected pathways. We further observed that loss of LRRK2 impairs BDNF signaling and alters postsynaptic density architecture. Young Lrrk2 knockout mice display structural alterations in dendritic protrusions, a phenotype that normalizes with age. In human iPSC-derived neurons, LRRK2 knockout affects maturation and BDNF-dependent regulation of spontaneous synaptic activity. Taken together, our study discloses a critical role of LRRK2 in BDNF-dependent synaptic modulation and identifies the synaptic actin cytoskeleton as a convergent site of LRRK2-associated pathophysiological processes in PD.
    Keywords:  BDNF; LRRK2; Parkinson's disease; actin cytoskeleton; drebrin; human; mouse; neuroscience; synapse
    DOI:  https://doi.org/10.7554/eLife.95987
  31. Brain Res. 2026 Aug 05. pii: S0006-8993(26)00349-5. [Epub ahead of print] 150487
    Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
    Shanshan Shi, Ruyue Liu, Chang Liu, Yuyao Chen, Yujun Pan, Chunyan Wang.
       BACKGROUND: Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD). While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is limited. We engineered mitochondrial-enriched sEVs (Exo-Mito) to evaluate their effects on microglia-neuron interactions in a PD-relevant model.
    METHODS: BMSC-Exo-Mito were characterized via TEM, NTA, and immunoblotting. Their therapeutic efficacy was assessed using an MPP + -induced BV2/SH-SY5Y transwell co-culture model. Assessments included ROS levels, mitochondrial membrane potential, ATP quantification, mitophagy flux, and signaling pathway analysis.
    RESULTS: Exo-Mito significantly restored mitochondrial homeostasis by reducing ROS, preserving membrane potential, and increasing ATP production. Mechanistically, Exo-Mito enhanced PINK1/Parkin-dependent mitophagy and PGC-1alpha/TFAM-mediated biogenesis. In BV2 microglia, Exo-Mito suppressed the NF-kappaB/NLRP3 axis, reduced proinflammatory cytokines, and promoted M2 polarization. In SH-SY5Y cells with dopaminergic phenotype, Exo-Mito was associated with reactivated PI3K/Akt/mTOR signaling, preserved tyrosine hydroxylase expression, and inhibited apoptosis. Functionally, Exo-Mito improved SH-SY5Y cell and restored microglial migratory capacity, showing superior efficacy to unmodified BMSC-Exo.
    CONCLUSION: Mitochondria-enriched BMSC sEVs protect SH-SY5Y cells by coordinating mitochondrial quality control and modulating neuroinflammation. These findings support Exo-Mito as a promising cell-free therapeutic strategy for Parkinson's disease.
    Keywords:  Mesenchymal stem cells; Mitochondria; Mitophagy; Neuroinflammation; PI3K/Akt/mTOR; Parkinson’s disease; Small extracellular vesicles
    DOI:  https://doi.org/10.1016/j.brainres.2026.150487
  32. Brain. 2026 Aug 02. pii: awag269. [Epub ahead of print]
    Multilevel impairment of mitochondrial respiration in inclusion body myositis.
    Ibrahim Shammas, Hazem Iaali, Jens O Watzlawik, Noemi Vidal Folch, Surendra Dasari, Graeme Preston, Thi Kim Oanh Nguyen, Wolfdieter Springer, Tamas Kozicz, Linda Hasadsri, Eugenia Trushina, Ian R Lanza, Elie Naddaf.
      Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.
    Keywords:  aging; mitochondrial DNA abnormalities; mitophagy; myopathy; oxidative phosphorylation; oxidative stress
    DOI:  https://doi.org/10.1093/brain/awag269
  33. Redox Biol. 2026 Aug 04. pii: S2213-2317(26)00337-X. [Epub ahead of print]96 104338
    Mitochondria as programmable redox rheostats: Advancing from transplantation to bioengineered organelle therapeutics.
    Vikky Awasthi, Eric Lalu, Fatma Saaoud, Aasthika Das, Pawan Sharma, Ellyes Adnane, Glenn Gerhard, Suyog Mokashi, Hong Wang, Rihab Bouchareb.
      Mitochondria are the primary arbiters of cellular redox homeostasis, bioenergetic flux, and programmed cell death. Their dysfunction, characterized by excessive reactive oxygen species (ROS) production, impaired oxidative phosphorylation (OXPHOS), and collapsed membrane potential, is a hallmark of diverse pathologies, including ischemia-reperfusion injury, neurodegeneration, and metabolic syndrome. Over the last decade, mitochondrial transplantation has emerged as a radical therapeutic paradigm for restoring metabolic competence via the exogenous delivery of intact organelles. While early evidence confirms that internalized mitochondria can rescue bioenergetic deficits and suppress apoptotic signaling, the transition to clinical practice is hindered by poor targeting specificity, low delivery kinetics, and post-isolation functional decay. This review highlights a pivotal shift toward mitochondrial engineering, where the organelle is no longer viewed as a static payload but as a programmable therapeutic unit. By integrating principles from synthetic biology, nanomedicine, and biomaterials, researchers are now modifying mitochondria to enhance their ROS-scavenging capacity, stability in the extracellular milieu, and cell-specific uptake. We critically evaluate emerging strategies for organelle modification, including surface functionalization, genetic modulation, and advanced delivery platforms like fusogenic capsules and photothermal nanoblades. Finally, we discuss the redox-dependent mechanisms underlying therapeutic efficacy and the translational hurdles essential for evolving mitochondrial engineering into a precise, scalable clinical reality.
    DOI:  https://doi.org/10.1016/j.redox.2026.104338
  34. FEBS J. 2026 Aug 03.
    A single-nucleus chromatin accessibility atlas reveals epigenetic dynamics in aging mouse skeletal muscle.
    Juan An, Guangyao Lai, Jing Zuo, Jianwen Yuan, Lixin Fu, Bo Zhang, Xiao Zhang, Yuan Lv, Pengcheng Guo, Dajiang Qin, Miguel A Esteban, Yancheng Song, Yiwei Lai.
      Skeletal muscle undergoes a progressive decline in mass and function with aging, a condition that in its extreme form is known as sarcopenia. This is driven by complex cellular and molecular alterations, such as shifts in myonucleus composition, increased fibrosis, and fat or immune cell infiltration. Despite extensive research, effective therapeutic interventions for sarcopenia remain limited. Recent advances in single-cell omics technologies have begun to unravel the cellular and molecular heterogeneity of mouse and human skeletal muscle across the lifespan, identifying age-enriched cell states and dynamic transcriptional changes. However, epigenetic regulation during skeletal muscle aging is less well characterized. To help address this gap, we performed single-nucleus Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) on skeletal muscle from young adult and aged male mice, generating chromatin accessibility profiles from over 43,000 nuclei. Among other findings, our analyses reveal an age-enriched pro-atrophy subpopulation of type IIb myonuclei marked by increased chromatin accessibility at the Ampd3 locus. Furthermore, we delineate the epigenetic mechanisms underlying the transition of healthy type IIb myonuclei into Ampd3+ myonuclei, revealing key chromatin remodeling events that drive this phenotypic shift. Moreover, by integrating with an existing single-nucleus RNA sequencing dataset of the same anatomical origin, we identified thousands of cell-type-specific cis-regulatory elements related to aging programs. Within these elements, we observed a broad depletion of binding motifs for transcription factors with roles in cellular identity and muscle regeneration, concomitant with the gain of stress-responsive transcription factors. Our work helps understand the epigenetic events underlying mammalian skeletal muscle aging.
    Keywords:  aging; chromatin accessibility; mouse skeletal muscle; snATAC‐seq
    DOI:  https://doi.org/10.1111/febs.70659
  35. Genome Res. 2026 Aug 03. pii: gr.281488.125. [Epub ahead of print]
    Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling.
    Diana Zagirova, Anna Kononkova, Kirill Morozov, Maria Molodova, Nikita Vaulin, Anastasiia Dudkovskaia, Polina Dozorova, Olga Efimova, Anna Tvorogova, Kirill Ulianov, Philipp Khaitovich, Sergey Razin, Maria Lagarkova, Sergey Ulianov, Ekaterina Khrameeva.
      Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly process datasets for 228 human and 89 mouse Hi-C and Snm3C-seq samples of different cell subtypes merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and post-mortem neuronal datasets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.
    DOI:  https://doi.org/10.1101/gr.281488.125
  36. Mitochondrion. 2026 Aug 06. pii: S1567-7249(26)00090-5. [Epub ahead of print] 102200
    Mas receptor activation promotes mitophagy and preserves neuronal function after traumatic brain injury.
    Ruili Dang, Lei Wang, Changshui Wang, Jinxiu Guo, Pei Jiang.
      Traumatic brain injury (TBI) is a leading global cause of death and long-term disability, primarily due to secondary injury mechanisms such as mitochondrial dysfunction and impaired mitophagy，the selective degradation of damaged mitochondria. While the ACE2/Angiotensin-(1-7)/Mas receptor (MasR) axis is recognized for its neuroprotective effects in various neurological disorders, its role in regulating mitochondrial quality control after TBI remains unclear. In this study, we investigated the regulatory function of MasR in post-traumatic mitophagy using controlled cortical impact (CCI) mice and scratch-injured neuronal cultures. We employed MasR knockdown (MasR-KD) and pharmacological activation with the selective MasR agonist AVE0991 to assess neurobehavioral outcomes, neuronal survival, and mitophagy flux. Activation of MasR significantly improved motor coordination, cognitive performance, and reduced anxiety-like behaviors following TBI, whereas MasR deficiency exacerbated neurological deficits. Histologically, MasR-KD mice exhibited increased neuronal loss, dendritic degeneration, and oxidative stress. In contrast, AVE0991 treatment preserved neuronal integrity and mitochondrial ultrastructure, effects that were abolished in MasR-KD animals. Mechanistically, MasR activation promoted PINK1/Parkin-mediated mitophagy, enhanced TOMM20-LC3 colocalization, stabilized mitochondrial membrane potential, reduced mitochondrial ROS production, and improved respiratory capacity. In vitro, Ang-(1-7) restored mitophagy flux through MasR-dependent clearance of damaged mitochondria, as confirmed by mt-Keima assays. Collectively, these findings identify MasR as an endogenous regulator of PINK1/Parkin-mediated mitophagy and mitochondrial homeostasis following TBI and demonstrate that MasR signaling is required for preserving mitochondrial function and neurological outcomes after injury.
    Keywords:  Mas receptor; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.mito.2026.102200
  37. Brief Bioinform. 2026 Jul 03. pii: bbag426. [Epub ahead of print]27(4):
    Exploring cell-type associations of rare disease phenotypes using non-diseased cell atlases.
    Jorge Novoa, Florencio Pazos, Monica Chagoyen.
      Rare diseases individually affect few patients but collectively impose a substantial global health burden. Many have a genetic origin, yet the cellular contexts in which disease genes exert their effects often remain unclear. Direct molecular investigation of disease-relevant tissues is often infeasible owing to small patient populations and frequent congenital or pediatric onset, limiting access to patient-derived samples. Here we investigate whether existing healthy human single-cell atlases can help identify candidate cellular contexts associated with rare disease phenotypes. Specifically, we test the hypothesis that cells expressing more genes linked to a phenotype than expected from their overall transcriptional activity may represent contexts particularly susceptible to disruption. Applied to more than 1300 phenotypes across multiple tissues, the analysis shows partial concordance with literature-derived phenotype-cell type relationships, with predictive performance reaching AUC ≈ 0.71 depending on the dataset. These findings suggest that transcriptional patterns captured in healthy single-cell atlases may contain informative signals about disease-relevant cellular contexts when the relevant cell populations are represented. At the same time, the results highlight the limitations of current reference resources and the need for continued efforts to improve single-cell atlases, phenotype-tissue mappings, and benchmarking datasets linking rare disease phenotypes to cellular contexts.
    Keywords:  human cell atlases; rare diseases; scRNA-seq
    DOI:  https://doi.org/10.1093/bib/bbag426
  38. Nat Genet. 2026 Aug;58(8): 1941-1952
    Mapping enhancer-gene regulatory interactions from single-cell data.
    Maya U Sheth, Wei-Lin Qiu, X Rosa Ma, Andreas R Gschwind, Evelyn Jagoda, Anthony S Tan, James Galante, Judhajeet Ray, Dulguun Amgalan, Hjörleifur Einarsson, Bram L Gorissen, Danilo Dubocanin, Christopher S McGinnis, Jacob Huang, Glen Munson, Kayla Brand, Ansuman T Satpathy, Thouis R Jones, Lars M Steinmetz, Anshul Kundaje, Berk Ustun, Jesse M Engreitz, Robin Andersson.
      Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation and human disease genetics. However, accurately predicting enhancer-gene regulatory interactions from single-cell datasets has been challenging. Here we introduce a family of classification models, scE2G, to predict enhancer-gene regulation. These models use features from single-cell assay for transposase-accessible chromatin with sequencing (ATAC-seq) or multiomic RNA and ATAC-seq data, and are trained on a CRISPR perturbation dataset including >10,000 evaluated element-gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped expression quantitative trait loci and genome-wide association study variant-gene associations and demonstrate state-of-the-art performance at prediction tasks across several cell types and categories of perturbations. We apply scE2G to build maps of enhancer-gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking INPP4B and IL15 to lymphocyte count. The scE2G models will enable accurate mapping of enhancer-gene regulatory interactions across thousands of human cell types.
    DOI:  https://doi.org/10.1038/s41588-026-02695-8
  39. J Endocrinol. 2026 Aug 03. pii: JOE-26-0176. [Epub ahead of print]
    Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner.
    Wafa B'chir, Catherine R Dufour, Sylvia Andrzejewski, Julie St-Pierre, Charlotte Scholtes, Vincent Giguère.
      Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERRα. In this study, we show that combining antimalaria drug chloroquine with rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERRα among top candidates. Using a mouse model with genetic ERRα ablation, we demonstrate a crucial dependency on ERRα activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERRα-null liver, chloroquine failed to reverse, and in some instances aggravated the upregulation of lipid metabolism genes by rapamycin, with evidence linking the impaired management of hepatic lipid overload to underling mitochondrial dysfunction. Together, these findings underscore a critical role of ERRα in reversing MASLD.
    Keywords:  RNA-seq; chloroquine; fibrosis; hepatic steatosis; lipid metabolism; mitochondria; nuclear receptor; transcription
    DOI:  https://doi.org/10.1530/JOE-26-0176
  40. Nature. 2026 Aug 05.
    Switching off the FNIP1 gene protects against metabolic disease.
      
    Keywords:  Diseases; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-02391-x
  41. Front Immunol. 2026 ;17 1876576
    Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis-generating candidate for nephrolithiasis.
    Yanting Wu, Shikai Ye, Ping Li, Zichi Wu, Zhiyuan Guo, Jun Bian, Ming Sheng, Dehui Lai.
       Background: Mitochondrial dysfunction is linked to urolithiasis, but causal genetic drivers remain unclear. We integrated multi-omics data using Mendelian randomization to identify mitochondrial-related genes causally associated with urolithiasis.
    Methods: We obtained mitochondrial methylation (mQTL), gene expression (eQTL), and protein abundance (pQTL) from respective quantitative trait locus (QTL) studies along with GWAS summary data for nephrolithiasis, ureterolithiasis and bladder calculus from the Million Veteran Program (discovery), with replication in FinnGen and UK Biobank. Summary-data-based Mendelian randomization (SMR) and colocalization were applied to infer causality.
    Results: Integrated analysis identified FXN as the leading candidate for nephrolithiasis. Genetically elevated circulating FXN protein was inversely associated with nephrolithiasis risk (OR 0.69, 95% CI 0.56-0.84). This protective effect was supported at the epigenetic level: FXN methylation at cg14656297 and cg13974534 correlated with lower nephrolithiasis risk. For ureterolithiasis, higher GRHPR protein levels were protective (OR 0.81, 95% CI 0.71-0.91). In a mouse kidney stone model, Fxn expression and frataxin protein levels were decreased, providing correlative in vivo support consistent with human genetic findings.
    Conclusion: This multi-omics MR study links mitochondrial genes, particularly FXN, to urolithiasis risk. Although colocalization evidence was weak (PP.H4 = 0.0239) and replication in independent cohorts was not statistically significant, the multi-omics consistency across methylation, expression, and protein levels prioritizes FXN as a hypothesis-generating candidate for further investigation. Because all QTL data are blood- or plasma-derived, this study provides blood/plasma QTL-based genetic prioritization rather than kidney-specific causal inference.
    Keywords:  FXN; Mendelian randomization; mitochondrial dysfunction; multi-omics; nephrolithiasis; urolithiasis
    DOI:  https://doi.org/10.3389/fimmu.2026.1876576
  42. Mol Biol Cell. 2026 Aug 05. mbcE25010022
    The identification of drp1 patient mutations that limit interactions with mff.
    Yuli Buckley, Anelise N Hutson, Brianna L Bauer, Isaiah M Waiters, Jasmine C Liu, Dayanlee De León Cordero, Maria S K Stoll, Jason A Mears.
      Patient mutations within Drp1, the master regulator of mitochondrial fission, lead to severe neurological defects and poor patient outcomes. Many of these mutations have been characterized as causing functional or assembly defects in Drp1, but our study highlights three mutations (G362S, E379K, E410K) that do not have an apparent defect in core Drp1 functions. We investigated the possibility that these mutations impact interactions with Mff, a pro-fission partner protein of Drp1. Negative stain electron microscopy and mass photometry were used to visualize and quantify assembly properties, while GTPase assays assessed the enzymatic activities of distinct proteins and protein complexes. In parallel, confocal microscopy highlighted the effects of overexpressing each mutation on mitochondrial morphology in cells. We discovered that G362S and E410K Drp1 mutations limit interactions with Mff, as co-assembly into larger filaments and the associated stimulation of GTPase activity was inhibited. Conversely, the E379K mutation is able to form functional complexes with Mff, and no apparent defect was observed, warranting additional studies focused on unique mitochondrial fission attributes. Overall, our data highlight the complex nature of disease-associated mutations in Drp1 and emphasize the importance of Drp1-Mff interactions in sustaining mitochondrial and cellular health.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0022
  43. J Pediatr Endocrinol Metab. 2026 Aug 10.
    Asparagine synthetase deficiency: clinical features and experience with asparagine supplementation.
    Tarık Yıldırım, Arzu Selamioğlu, Meryem Hilal Altaş, Abdulrahman Özel, Fatih Mete.
       OBJECTIVES: Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder characterized by congenital and progressive microcephaly, severe developmental delay, epilepsy, and progressive cerebral atrophy. Therapeutic experience with L-asparagine supplementation remains limited and heterogeneous.
    CASE PRESENTATION: We report a preterm female infant born to consanguineous parents who presented with congenital microcephaly and early-onset myoclonic epilepsy. During follow-up, diaphragmatic eventration was identified and contributed to recurrent episodes of respiratory failure. Metabolic screening studies were unremarkable; however, cerebrospinal fluid asparagine concentration was markedly reduced (4.42 μmol/L; reference range 8-34 μmol/L). Brain magnetic resonance imaging demonstrated cerebral atrophy with white matter involvement. Whole-exome sequencing identified a homozygous splice-site variant in the ASNS gene. Oral L-asparagine supplementation was initiated at 5 months of age (50 mg/kg/day and increased to 100 mg/kg/day after one week). A reduction in seizure frequency was observed following treatment initiation; however, this finding should be interpreted cautiously because it coincided with changes in antiepileptic therapy. No meaningful neurodevelopmental progress was observed during follow-up.
    CONCLUSIONS: ASNSD should be suspected in patients with progressive microcephaly and early-onset epilepsy despite normal metabolic screening, and CSF amino acid analysis is valuable for diagnosis. Although a reduction in seizure frequency was observed following L-asparagine supplementation in our patient, this finding should be interpreted cautiously because phenobarbital was discontinued and topiramate therapy was initiated during the same period. Therefore, the therapeutic efficacy of L-asparagine supplementation remains uncertain, and its impact on neurodevelopment appears limited.
    Keywords:  asparagine synthetase (ASNS); asparagine synthetase deficiency; diaphragmatic eventration; epilepsy; microcephaly
    DOI:  https://doi.org/10.1515/jpem-2026-0234
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