bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–07–19
58 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial transplantation and neuromuscular recovery after skeletal muscle injury.
  2. Exogenous Mitochondrial Transfer in Differentiating Brown Adipocytes and AGPAT2-Deficient Preadipocytes.
  3. The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
  4. Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.
  5. Karnofsky performance scale and modified Rankin scale as indicators of functional capacity in patients with mitochondrial disease.
  6. ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.
  7. Modification and aminoacylation of human mitochondrial tRNAs.
  8. More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
  9. Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.
  10. ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
  11. PISD acts as a switch between lipophagy and fatty acid transfer to mitochondria.
  12. Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.
  13. Pathogenic DRP1 variants reveal a role for biomolecular condensation in mitochondrial fission.
  14. Why do astronauts' bodies waste away? Space-station study points to mitochondria.
  15. NAXD Deficiency: Heterogeneous Phenotypes and Positive Response to Niacin Treatment.
  16. Mitochondrial transfer and mesenchymal stem cells in ophthalmology: current evidence and therapeutic implications.
  17. Mitochondrial Voltage-Dependent Anion Channel: From a Passive Pore to a Cellular Hub Through Protein Complexation.
  18. An encyclopedia of human enhancer-gene regulatory interactions.
  19. Dopaminergic neurons preferentially accumulate mtDNA rearrangements.
  20. Novel Homozygous Mitochondrial Calcium Uptake Protein 1 Variant (c.38T>C, p.Leu13Pro) in a 7-year-old Girl with Congenital Ptosis and Proximal Myopathy: Expanding the Phenotypic Spectrum.
  21. Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.
  22. Reduced LANCL1-AS1 in old human skeletal muscle diminishes mitochondrial activity, shortens mt-mRNA poly(A) tails, and suppresses myogenesis.
  23. Biallelic TXNIP deficiency is associated with a multisystemic metabolic disease.
  24. Impaired mitochondrial flexibility hinders fat pad remodeling in obese mice after 24 h of fasting.
  25. When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants.
  26. Epigenetic editing makes its mark.
  27. HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A.
  28. GPR180 deficiency impairs mitochondrial function and insulin secretion in pancreatic β-cells.
  29. Molecular and energetic basis of histidine switch dynamics in respiratory complex I.
  30. Beyond Bioenergetics: Moonlighting Functions of F1FO-ATPase From ATP Synthesis to an ATP-Wasting Death Switch.
  31. SAMM50 rs3761472 causes mitochondrial dysfunction and progression of metabolic dysfunction-associated steatotic liver disease.
  32. Brain mitochondria as key drivers of cognition and behaviour.
  33. Biallelic hexose-6-phosphate dehydrogenase variants cause mitochondrial dysfunction underlying Parkinson's disease.
  34. The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.
  35. Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
  36. Kidney outcomes of coenzyme Q10 supplementation in patients with genetically confirmed CoQ10 nephropathy in Japan.
  37. Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2).
  38. Protein engineering: Status report.
  39. MHRA's radical rare disease proposal.
  40. Combining modeling approaches for rapid preclinical evaluation of retinal gene therapy.
  41. Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.
  42. Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers.
  43. Caspase-3 cleaves CYLD to restrict interferon signaling during mitochondrial apoptosis.
  44. RNA molecules with different destinies are processed through overlapping pathways.
  45. A quantum interface with mitochondrial bioenergetics.
  46. Single-cell analysis of sterol-induced Ca2＋ signaling in human astrocytes by dynamic mode decomposition.
  47. Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity.
  48. Utilizing FLAMBE to study the structure-function relationship and regulation of monomeric BAX activation in solution.
  49. TRIM72 alleviates skeletal muscle atrophy by modulating mt-dsRNA/RIG-I signaling.
  50. Mitochondrial ncRNAs: From Pathological Regulation to Targeted Therapy in Cardiovascular Diseases.
  51. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
  52. Label-free segmentation of mitochondria for simultaneous morphological and metabolic studies.
  53. Context-Dependent Functional Outcomes of Mitochondrial Transfer: A Donor-Recipient Perspective.
  54. Liver-Targeted Triple-Modal Molecular Probe for Visualization of Aging Marginal Donor Livers.
  55. Dichloroacetate improves animal survival, growth, neuromuscular activity, mitochondrial stress and physiology, and elevated lactate in C. elegans pdha-1 and dld-1 RNAi models of pyruvate dehydrogenase complex deficiency (PDCD).
  56. A turning point for gene editing in severe blood disorders.
  57. Biallelic mutations in SUPV3L1 cause a variable leukodystrophy due to impaired mitochondrial degradosome function.
  58. Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
  1. J Physiol. 2026 Jul 15.
    Mitochondrial transplantation and neuromuscular recovery after skeletal muscle injury.
    Sina Hadipour-Lakmehsari, Sara Al Mouaswas.
      
    Keywords:  injury; mitochondria; mitochondrial transplantation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP291869
  2. J Vis Exp. 2026 Jun 26.
    Exogenous Mitochondrial Transfer in Differentiating Brown Adipocytes and AGPAT2-Deficient Preadipocytes.
    Antonio Moreno, Claudia Parra-Ruiz, Francisca Stolzenbach, Víctor Cortés.
      Mitochondria are key signaling hubs; however, whether mitochondrial mass expansion is mechanistically required for differentiation remains an open question. AGPAT2 catalyzes the conversion of lysophosphatidic acid into phosphatidic acid, and its deficiency leads to adipose tissue deficiency and impaired adipogenesis associated with reduced mitochondrial mass. The impact of mitochondrial mass expansion on adipogenesis was assessed by transferring exogenous mitochondria into differentiating brown adipocytes. Whether mitochondrial transfer could rescue the impaired adipogenesis of AGPAT2-deficient cells was also investigated. Human and murine mitochondria were successfully transferred and incorporated into the endogenous mitochondrial network of differentiating mouse preadipocytes and persisted throughout brown adipogenesis. Adipogenic differentiation was required for the retention of transferred mitochondria. Mitochondrial transfer did not modify the expression of molecular markers of mature brown adipocytes or lipid droplet content, although it affected the relative distribution of lipid droplet size in a species-dependent manner. In Agpat2-/- preadipocytes, mitochondrial transfer failed to rescue adipogenesis, indicating that mitochondrial mass expansion alone is insufficient to reverse the mechanisms leading to lipodystrophy in this model. These results indicate that, although exogenous human and murine mitochondria can be incorporated into the mitochondrial network of differentiating adipocytes, they do not directly influence the adipogenic program.
    DOI:  https://doi.org/10.3791/71223
  3. Int J Mol Sci. 2026 Jul 01. pii: 5931. [Epub ahead of print]27(13):
    The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
    Anastasia Kolotova, Alexandr Shestopalov, Sergey Kutsev.
      Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.
    Keywords:  apoptosis; ferroptosis; iron metabolism; lipid peroxidation; mitochondria; mitochondrial diseases; molecular crosstalk; oxidative stress; regulated cell death; tissue specificity
    DOI:  https://doi.org/10.3390/ijms27135931
  4. Res Sq. 2026 Jul 06. pii: rs.3.rs-10105855. [Epub ahead of print]
    Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.
    Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.
      Mitochondria are dynamic organelles essential for neuronal survival and synaptic function, and their dysfunction is a key consequence of excitotoxicity following traumatic brain injury (TBI). While intercellular mitochondrial transfer and exogenous mitochondrial transplantation have emerged as mechanisms to restore cellular bioenergetics, its in vivo relevance in the central nervous system remains incompletely understood. Here, we used astrocyte and neuron-specific mitochondrial reporters (GFP or Dendra2) in mice to assess cell-type-specific mitochondrial morphology, bioenergetics, and transfer 24hrs after TBI. Neurons exhibited marked mitochondrial dysfunction, including altered morphology and reduced bioenergetic capacity across somatic, synaptic, and non-neuronal fractions. In contrast, astrocytic mitochondria showed morphological changes but preserved bioenergetic function. Concomitantly, astrocyte-to-neuron mitochondrial transfer was significantly increased following injury, although transfer to synapses remained limited. Single-cell RNA sequencing of astrocytes revealed upregulation of genes involved in extracellular vesicle (EV) biogenesis and mitochondrial translation following injury compared to controls. In vitro co-culture studies confirmed that astrocytes transfer mitochondria to neurons via EVs containing mitochondria (EV-mito). Isolated EV-mito from astrocyte-conditioned media improves neuronal mitochondrial function under NMDA (N-methyl-D-aspartate) induced excitotoxic conditions. Together, these findings demonstrate that neuronal mitochondrial dysfunction drives astrocyte-mediated mitochondrial transfer as an adaptive neuroprotective response after TBI. This process preserves neuronal bioenergetics in the soma and neurites but not at synapses, highlighting both its therapeutic potential and spatial limitations.
    DOI:  https://doi.org/10.21203/rs.3.rs-10105855/v1
  5. Neurol Sci. 2026 Jul 15. pii: 629. [Epub ahead of print]47(8):
    Karnofsky performance scale and modified Rankin scale as indicators of functional capacity in patients with mitochondrial disease.
    Jasmin A Koskiniatis, Mika H Martikainen.
       BACKGROUND: Mitochondrial diseases are genetic multisystem disorders. Only symptomatic treatment is available, and clinical progression is common. We investigated whether two commonly used quantitative measures of functional capacity, modified Rankin scale (mRS) and Karnofsky Performance scale (KPS) scores, could be determined retrospectively based on electronic patient records (EPRs) and whether they provided insights into disability and disease progression.
    METHODS: Previously identified 52 patients (28 women) with clinically and genetically confirmed mitochondrial disease at Turku University Hospital (TUH, Turku, Finland) were investigated. Genetic diagnoses were the m.3243 A > G mitochondrial DNA (mtDNA) variant (N = 21), other pathogenic mtDNA variants (N = 22), and nuclear gene variants causing mitochondrial disease (N = 9). Mean age was 50 years (range 10-85 years); average follow-up was nine years. Available neurology and emergency medicine EPRs were reviewed, and mRS and KPS scores determined.
    RESULTS: Patients harbouring the m.3243 A > G, other mtDNA variants, or nuclear gene variants were compared. In all groups, functional capacity declined over time. Those with m.3243 A > G had lower first and latest KPS and mRS values than those with nuclear gene variants (p < 0.004 for all). Differences between the m.3243 A > G and other pathogenic mtDNA variants were not significant.
    CONCLUSION: Functional decline seems a common feature in mitochondrial disease. The KPS and mRS scales may offer a simple tool for long-term evaluation of the functional capacity of patients with mitochondrial disease, especially in non-specialist and primary healthcare. Further studies are needed to confirm whether patients with nuclear gene defects are at particular risk of progression.
    Keywords:  Functional capacity; Genetics; Mitochondrial disease; Performance scales
    DOI:  https://doi.org/10.1007/s10072-026-09212-z
  6. Sci Adv. 2026 Jul 17. 12(29): eaed2430
    ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.
    Julia Racho, Dylan Stobbe, Jan Jirschitzka, Marijana Croon, Carmelina Petrungaro, Muna Ali, Dario Wernet, Markus Habich, Nele Sophie Gawellek, Julian Strippel, Finn Dicke, Jörn Dengjel, Stephanie Kath-Schorr, Bent Brachvogel, Thomas Langer, Aleksandra Trifunovic, Ines Neundorf, Jan Riemer.
      Proteins in the mitochondrial intermembrane space (IMS) play essential roles in respiratory chain assembly, metabolism, signaling, and organelle dynamics. Their stability and functionality often depend on structural disulfide bonds introduced by the mitochondrial disulfide relay, mediated by MIA40 and ALR. In this system, the sulfhydryl oxidase ALR reoxidizes MIA40, which in turn oxidizes incoming substrate proteins. Although evidence has suggested that ALR can also act independently of MIA40, its endogenous substrates have remained unknown. In this study, we captured proteins directly oxidized by ALR. Among these, we found coproporphyrinogen III oxidase (CPOX), a key enzyme in heme biosynthesis. We show that ALR-mediated disulfide bond formation is crucial for maintaining CPOX stability in the IMS, thereby ensuring effective heme biosynthesis and mitochondrial functionality. Notably, while disulfide-deficient CPOX failed to rescue CPOX loss when localized to the IMS, it retained functionality when redirected to the cytosol. However, this bypass compromised pathway efficiency, leading to the accumulation of protoporphyrinogen IX, a highly hydrophobic and redox-active intermediate that sensitized cells to cell death. Together, our findings reveal that ALR has functions beyond the MIA pathway and highlight that oxidative protein folding in the IMS relies not only on a relay mechanism but also on a broader disulfide-introducing network of enzymes.
    DOI:  https://doi.org/10.1126/sciadv.aed2430
  7. Trends Biochem Sci. 2026 Jul 15. pii: S0968-0004(26)00204-5. [Epub ahead of print]
    Modification and aminoacylation of human mitochondrial tRNAs.
    Shi-Ying Yao, Meng Wang, Fan-Yan Wei, Xiao-Long Zhou.
      Mitochondrial tRNAs (mt-tRNAs) are central to energy production by translating essential oxidative phosphorylation subunits. Following transcription, mt-tRNAs undergo diverse processing steps, post-transcriptional modifications, and aminoacylation, which are critical for their functions. In this article, we review how human mt-tRNA-modifying enzymes deposit various post-transcriptional modifications onto mt-tRNAs, encompassing both well-characterized and less-understood marks. We also summarize the principles, peculiarities, and critical roles of mt-tRNA charging and proofreading, and highlight recently uncovered noncanonical functions of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Collectively, these recent findings demonstrate the dynamic regulatory mechanisms of mt-tRNA modification and aminoacylation, the extensive involvement of mt-aaRSs in cellular metabolic pathways, and the promising potential of targeting these enzymes in therapeutics.
    Keywords:  editing; mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs); mitochondrial diseases; mitochondrial translation; noncanonical functions; post-transcriptional modification
    DOI:  https://doi.org/10.1016/j.tibs.2026.06.009
  8. J Cell Biol. 2026 Aug 03. pii: e202606160. [Epub ahead of print]225(8):
    More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
    Mami Sato, Florencio Porto Freitas, José Pedro Friedmann Angeli.
      Coenzyme Q (CoQ or ubiquinone) is an essential cofactor for mitochondrial energy production and a vital radical-trapping antioxidant that maintains membrane integrity. Additionally, CoQ shares an early biosynthetic pathway with cholesterol biosynthesis. In this issue, Ndoci et al. (https://doi.org/10.1083/jcb.202507174) reveal a regulatory system that preserves mitochondrial CoQ levels when the mevalonate pathway is impaired, though this prioritization leaves cells vulnerable to oxidative stress.
    DOI:  https://doi.org/10.1083/jcb.202606160
  9. Drug Resist Updat. 2026 Jul 08. pii: S1368-7646(26)00094-4. [Epub ahead of print]88 101443
    Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.
    Gautam Sethi, Ilnaz Rahimmanesh, Akbar Davoodi, Yujiao Chen, Franklin R Tay, Chandra Sekhar Bhol, Pooyan Makvandi, Yi Xu.
      Therapeutic resistance is a major barrier to durable cancer control in contemporary oncology practice. Despite extensive studies on individual cell death pathways and mitochondrial stress responses, a comprehensive framework describing how mitochondrial organization contributes to the coordination of multiple regulated cell death programs and therapeutic resistance remains insufficiently defined. This review examines resistance as malignant cells evade regulated cell death and adapt to mitochondrial stress. Mitochondria are framed as integrative hubs that link bioenergetics, redox regulation, metabolic flexibility, and stress signaling to apoptotic competence. It also describes how apoptosis connects with other death programs through mitochondrial compartmentalization. Signals from the matrix, inner membrane, and cristae, intermembrane space, and outer membrane influence ferroptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and immunogenic cell death. Stress-response pathways are highlighted as interfaces between mitochondrial dysfunction and fate decisions, including the OMA1-DELE1-heme-regulated inhibitor kinase axis that activates the integrated stress response and ATF4-dependent transcription. Translationally, the review proposes a co-targeting framework that pairs apoptosis-directed therapies, especially BH3 mimetics, with interventions that destabilize mitochondrial homeostasis or tune stress signaling. Examples include electron transport chain inhibitors, integrated stress response modulators, and compartment-targeted strategies that alter cristae remodeling, calcium flux, or cardiolipin oxidation.
    Keywords:  BCL-2 family regulation; BH3 mimetics; Integrated stress response (ISR); Mitochondrial stress signaling; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.drup.2026.101443
  10. J Mol Endocrinol. 2026 Jul 15. pii: JME-25-0203. [Epub ahead of print]
    ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
    Dandan Chen, Yuxin Jia, Xiaohong Duan, Jianhua Huang, Xiaohong Deng.
      Mitochondrial dysfunction driven by chronic hyperglycemia is a hallmark of diabetes, yet how this metabolic stress communicates pathological signals beyond individual cells remains poorly understood. In this study, we identified a novel mechanism linking chronic hyperglycemia to systemic metabolic impairment through ROS-mediated extracellular release of structurally intact mitochondria and mitochondrial DNA (mtDNA). In HepG2 cells exposed to high glucose (HG), extracellular release of structurally intact mitochondria was visualized by co-staining of mitochondria and the plasma membrane, together with electron microscopy. Mitochondria-enriched fractions isolated from culture supernatants were further quantified using flow cytometry and qPCR. Cell-free mtDNA (cf-mtDNA) was visualized with co-staining of mitochondria and double- stranded DNA, isolated through differential centrifugation and ultrafiltration, and quantified by qPCR. We demonstrate that HG stimulates the release of exosome-enclosed mtDNA as well as fragmented cf-mtDNA. Concurrently, HG induces mitochondrial dysfunction and markedly increases mitochondrial ROS (mtROS). Treatment with MitoTEMPO, a mitochondria-targeted ROS scavenger, significantly reduced HG-induced extracellular release of mitochondria and mtDNA, supporting the ROS dependence of this process. In diabetic mice, we detected elevated circulating mtDNA copy number and pronounced mitochondrial dysfunction in liver and muscle, including reduced ATP production, mitochondrial swelling, cristae disruption, and elevated MDA levels. Resting metabolic rate was markedly decreased, indicating impaired systemic respiratory metabolism. Serum analyses revealed increased 8-OHdG, pyruvic acid, GDF-15, and FGF-21, along with reduced FT3, reflecting severe oxidative stress and mtDNA damage. These findings uncover a novel mechanism in which hyperglycemia-induced ROS drive mitochondrial extrusion, potentially linking metabolic stress to systemic metabolic deterioration.
    Keywords:  Diabetes mellitus; ROS; mitochondrial release; resting metabolic rate
    DOI:  https://doi.org/10.1530/JME-25-0203
  11. J Cell Biol. 2026 Sep 07. pii: e202605090. [Epub ahead of print]225(9):
    PISD acts as a switch between lipophagy and fatty acid transfer to mitochondria.
    Hanbing Xue, Xingwen Hu, Zhenni Yang, Yiqing Cao, Qi Zhu, Hongyu Zhao, Xiaoli Ma, Tianxin Lei, Dian Zhuang, Jing Zheng, Siqi Guo, Xiaochuan Fu, Ka Kit Chung, Pingsheng Liu, Xiaohong Zhuang, Zhengyu Liang, Sicong He, Hui Jiang, Yan G Zhao.
      Fatty acids (FAs) are transported from lipid droplets (LDs) to mitochondria for β-oxidation during cell starvation. Starvation also triggers engulfment of LDs by autophagosomes and their subsequent degradation by lysosomes (lipophagy). The mechanisms coordinating these pathways remain unclear. Here, we demonstrate that PISD-LD, an LD-localized isoform of phosphatidylserine decarboxylase, facilitates FA transfer while inhibiting lipophagy. PISD-LD mediates LD-mitochondrion (LD-mito) contacts via interaction with mitochondrial PISD. In PISD-LD KD cells, LDs are larger, and FA trafficking and mitochondrial FA β-oxidation are suppressed. The lipid transfer proteins ATG2A/B are recruited by PISDs to mediate FA transfer from LDs to mitochondria. Disruption of PISD-LD-mediated LD-mito contacts activates lipophagy, aiding LD degradation. PISD-LD binds the lipophagy receptor Spartin and inhibits lipophagy by impeding Spartin-LC3 interaction. PISD-LD also regulates LD-mito contacts and lipid metabolism in mouse liver. Thus, PISD-LD serves as a switch between LD-to-mitochondrion FA transfer and lipophagy, ensuring efficient energy production.
    DOI:  https://doi.org/10.1083/jcb.202605090
  12. Mol Ther Adv. 2026 Sep 10. 34(3): 201781
    Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.
    Anna Keegan, Özge Çetin, Ellie M Chilcott, Juan Antinao Diaz, Simon Eaton, Simon N Waddington, John R Counsell, Shamima Rahman, Rajvinder Karda.
      Pyruvate dehydrogenase complex deficiency (PDHD) is a severe mitochondrial disorder most frequently caused by pathogenic variants in PDHA1, leading to neurodevelopmental delay and early mortality, thus necessitating brain-targeted interventions. Using a brain-specific Pdha1 knockout mouse model, we compared intracerebroventricular delivery of AAV9 capsid and a recently described synthetic neurotropic AAV-F capsid, both expressing human PDHA1 coding sequence driven by a constitutive CAG promoter. Newborn mice received titer-matched AAV9, AAV-F, or AAV9 at 10-fold higher dose. Low-dose AAV-F and high-dose AAV9 significantly improved survival and restored PDH enzyme activity, metabolite profiles, and brain histopathology to near wild-type levels. However, mice treated by postnatal day 100 (P100) showed impaired motor function. Importantly, AAV-F achieved broad CNS transduction with minimal liver expression, thus outperforming low-dose AAV9. These results support the therapeutic potential of AAV-based gene therapy for PDHD and highlight AAV-F as a promising capsid for efficient, CNS-specific delivery.
    Keywords:  AAV-F; adeno-associated virus; clincal translation and pyruvate dehydrogenase deficiency; gene supplementation; neonatal gene therapy; preclinical
    DOI:  https://doi.org/10.1016/j.omta.2026.201781
  13. bioRxiv. 2026 Jul 08. pii: 2026.07.06.735726. [Epub ahead of print]
    Pathogenic DRP1 variants reveal a role for biomolecular condensation in mitochondrial fission.
    Kyle A Ross, Amanda M Travis, Megan C Harwig, Micaela S Young, Erica H Rodas Montejo, Michael J Donohue, Robert W Taylor, Monika Oláhová, R Blake Hill.
      Fission is essential for proper mitochondrial function and for cellular homeostasis. Dysfunction in mitochondrial fission is associated with several neurological disorders, including the rare and lethal encephalopathy EMPF1, which is caused by de novo heterozygous DNM1L variants. DNM1L encodes the mitochondrial fission mechanoenzyme DRP1, which can intrinsically self-assemble and induce membrane scission. Wild-type DRP1 puncta that appear throughout the cytoplasm are thought to be pre-scission complexes of well-ordered oligomeric assemblies. Immunofluorescence imaging of patient-derived EMPF1 fibroblasts carrying assembly-deficient DNM1L variants reveals elongated mitochondrial networks consistent with impaired fission. Despite this loss-of-function phenotype, these cells retain essentially wild-type numbers of DRP1 puncta. We confirmed the previously reported inability of purified pathogenic DRP1 variants p.Gly363Asp and p.Gly401Ser to assemble under conditions in which WT DRP1 forms helical polymers. Under macromolecular crowding conditions, however, both wild-type and mutant DRP1 access condensed states whose formation depends on protein concentration and solution conditions. Acute treatment of EMPF1 fibroblasts with 1,6-hexanediol preferentially alters DRP1 puncta fluorescence intensity and distribution in mutant cells relative to wild type, indicating genotype-dependent differences in puncta material properties. Together, these findings support a model in which DRP1 puncta occupy a continuum of condensed states, only a subset of which mature into fission-competent assemblies, revealing biomolecular condensation as a previously unrecognized layer of DRP1 regulation. Biasing DRP1 along this continuum may provide a mechanistic basis for impaired fission in EMPF1 and suggest opportunities to restore productive assembly in select pathogenic contexts.
    Significance Statement: DRP1 puncta associated with mitochondrial fission are thought to be well-ordered oligomeric assemblies that precede membrane scission. Yet their dynamic behavior within cells has remained difficult to reconcile as well-ordered assembly. Under prevailing models, cells bearing pathogenic DNM1L variants impaired in assembly would be expected to lack puncta, but we show these cells retain wild-type puncta levels. We demonstrate that both wild-type and pathogenic mutant DRP1 populate multiple condensed states in vitro , and that disease variants are biased toward more fluid, chemically sensitive assemblies. These findings identify biomolecular condensation as a regulatory layer of DRP1 organization and suggest that shifting DRP1 along this assembly continuum may restore productive fission in select pathogenic contexts.
    DOI:  https://doi.org/10.64898/2026.07.06.735726
  14. Nature. 2026 Jul 16.
    Why do astronauts' bodies waste away? Space-station study points to mitochondria.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-02089-0
  15. J Inherit Metab Dis. 2026 Jul;49(4): e70217
    NAXD Deficiency: Heterogeneous Phenotypes and Positive Response to Niacin Treatment.
    MitoMDT Diagnostic Network for Genomics and Omics
      Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in NAXD, in which febrile illness or infection triggers rapid clinical deterioration. We describe nine new cases that expand the clinical and molecular spectrum. Four children showed the typical presentation of severe neurological decline following fever or illness and carried variants affecting the enzyme domain. Four cases presented with illness-triggered cardiac dysfunction associated with variants in the mitochondrial targeting sequence. One case showed severe prenatal neurodegeneration resulting in stillbirth. In two patients, disease onset followed COVID-19 infection. Functional analysis of five missense variants demonstrated impaired NAXD protein solubility, reduced NADHX dehydratase activity and/or decreased thermostability. Patient fibroblasts confirmed accumulation of damaged cofactors (S-, R- and cyclic NADHX) and reduced NAXD protein levels. Comparative proteomic analysis revealed distinct molecular profiles in atypical cardiac and prenatal cases compared with typical neurological presentations. Four patients received high-dose niacin (vitamin B3) and survived repeated febrile episodes. These findings support early recognition and suggest that niacin therapy may improve outcomes across the clinical spectrum of PEBEL2.
    Keywords:  NAXD; PEBEL2; mitochondria; neurodegeneration; niacin; paediatric
    DOI:  https://doi.org/10.1002/jimd.70217
  16. Exp Biol Med (Maywood). 2026 ;251 11128
    Mitochondrial transfer and mesenchymal stem cells in ophthalmology: current evidence and therapeutic implications.
    Xiaoli Liu, Mingqi Zhang, Zhuoshi Wang.
      Mitochondrial dysfunction, driven by genetic mutations or oxidative stress, is a central contributor to the onset and progression of ophthalmic diseases. In recent years, intercellular mitochondrial transfer (MT) has emerged as a novel mechanism of cellular communication and repair in ocular tissues. MT occurs through tunneling nanotubes, extracellular vesicles (EVs), cell fusion, or transmitophagy, and has been shown to support photoreceptor survival, maintain retinal homeostasis, and protect against oxidative injury. Mesenchymal stem cells (MSCs), owing to their remarkable reparative and immunomodulatory properties, have attracted particular attention as efficient mitochondrial donors. Evidence from experimental models demonstrates that MSC-mediated MT can restore bioenergetics, mitigate oxidative stress, and rescue cellular function in inherited optic neuropathies, corneal injuries, retinal degenerative diseases, and ischemic retinopathies. This review summarizes current evidence of MT in ophthalmology, highlights the therapeutic contributions of MSCs, discusses the molecular and microenvironmental factors regulating MT efficiency, and outlines unresolved challenges. We further provide perspectives on how mitochondrial transfer may be translated into innovative therapies for ocular disorders.
    Keywords:  clinical translation; mesenchymal stem cells; mitochondrial transfer; ophthalmic diseases; retinal degeneration
    DOI:  https://doi.org/10.3389/ebm.2026.11128
  17. Int J Mol Sci. 2026 Jun 26. pii: 5804. [Epub ahead of print]27(13):
    Mitochondrial Voltage-Dependent Anion Channel: From a Passive Pore to a Cellular Hub Through Protein Complexation.
    Megha Rajendran, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The voltage-dependent anion channel (VDAC) is the primary conduit for ion and metabolite transport across the mitochondrial outer membrane. Positioned at the interface between the cytosol and the mitochondrial compartment, VDAC is uniquely accessible to proteins on both sides of the membrane, making it an interaction hub whose biophysical properties and signaling functions are shaped by protein complexation in addition to its intrinsic pore specialization. Mammals express three isoforms-VDAC1, VDAC2, and VDAC3-sharing a conserved β-barrel scaffold with about 70% identity. However, minor differences in the sequence lead to drastic changes in VDAC isoform affinity with other proteins. Here, we review the molecular mechanisms and physiological consequences of VDAC complexation with a set of well-characterized partners: hexokinase, dimeric tubulin, α-synuclein, mitochondria-associated membrane proteins, B-cell lymphoma 2 (BCL-2) family proteins, and the translocase of the outer membrane (TOM) protein import complex. For each complex, we evaluate the available structural, biophysical, and genetic evidence for isoform specificity, highlight where mechanistic understanding is most advanced, and identify open questions. A consistent principle emerges across all complexes: functionally nonredundant isoform contributions are primarily governed by differential partner affinity and complexation, rather than by differences in pore architecture alone. This framework has direct implications for mitochondria-associated pathologies, including cancer, cardiovascular disease, and neurodegeneration, as well as for the rational design of VDAC-targeting therapeutics.
    Keywords:  BCL-2 family proteins; TOM complex; VDAC; hexokinase; mitochondrial-associated membrane (MAM); tubulin; α-synuclein
    DOI:  https://doi.org/10.3390/ijms27135804
  18. Nature. 2026 Jul 15.
    An encyclopedia of human enhancer-gene regulatory interactions.
    Andreas R Gschwind, Kristy S Mualim, Alireza Karbalayghareh, Maya U Sheth, Kushal K Dey, Evelyn Jagoda, Ramil N Nurtdinov, Wang Xi, Anthony S Tan, James Galante, Hank Jones, X Rosa Ma, David Yao, Dulguun Amgalan, Judhajeet Ray, Chad J Munger, Joseph Nasser, Žiga Avsec, Benjamin T James, Muhammad S Shamim, Neva C Durand, Suhas S P Rao, Ragini Mahajan, Benjamin R Doughty, Kalina Andreeva, Jacob C Ulirsch, Kaili Fan, Elizabeth M Perez, Tri C Nguyen, David R Kelley, Hilary K Finucane, Jill E Moore, Zhiping Weng, Manolis Kellis, Michael C Bassik, Berk Ustun, Alkes L Price, Michael A Beer, Roderic Guigó, John A Stamatoyannopoulos, Erez Lieberman Aiden, William J Greenleaf, Christina S Leslie, Lars M Steinmetz, Anshul Kundaje, Jesse M Engreitz.
      Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
    DOI:  https://doi.org/10.1038/s41586-026-10781-4
  19. Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2601897123
    Dopaminergic neurons preferentially accumulate mtDNA rearrangements.
    Tania Arguello, Christian D Alcalde Pretel, Nadee Nissanka, Derek Van Booven, Milena Pinto, Monica Rodriguez-Silva, Lise-Michelle Theard, Anthony J Griswold, Carlos T Moraes.
      High levels of mitochondrial DNA (mtDNA) deletions have been described in the substantia nigra. However, the mechanisms involved are poorly understood. We found that transient expression of a mitochondrial targeted restriction endonuclease (mitoPstI) in mice leads to an accumulation of mtDNA rearrangements that involve both the PstI cleavage sites and unrelated specific regions of the mtDNA, including the MTERF1 binding site and the edge of the D-loop. This pattern of rearrangements after double-strand breaks supports the presence of recombination hotspots in the mtDNA. Transient expression of mitoPstI in dopaminergic neurons led to further accumulation of mtDNA rearrangements in dopaminergic neurons after expression was suppressed, a pattern that was not observed in glutamatergic neurons. This accumulation was also blunted when a mtDNA replisome factor was absent, suggesting that robust mtDNA replication is required for the accumulation of preexisting mtDNA rearrangements in dopaminergic neurons over time.
    Keywords:  Parkinson’s disease; deletions; dopaminergic; double strand break; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2601897123
  20. Ann Afr Med. 2026 Jul 15.
    Novel Homozygous Mitochondrial Calcium Uptake Protein 1 Variant (c.38T>C, p.Leu13Pro) in a 7-year-old Girl with Congenital Ptosis and Proximal Myopathy: Expanding the Phenotypic Spectrum.
    Poornima Lakshmi, Shiji Chalipat, Manasseh Kunchepu, Shailaja Mane.
       ABSTRACT: Myopathy with extrapyramidal signs (OMIM #615673) is a rare autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in Mitochondrial calcium uptake protein 1 (MICU1), which encodes the gatekeeper of the mitochondrial calcium uniporter complex. We report a 7-year-old Indian girl with global developmental delay, congenital nonfatiguable right ptosis, proximal-predominant myopathy without calf hypertrophy, multi-system dysmorphism (elongated facies, baggy cheeks, large prominent ears, partial webbed neck, bilateral clinodactyly, fetal finger pads, pes planus, and sandal gap), and thickened corpus callosum on magnetic resonance imaging. Creatine kinase ranged between 4068 and 4732 U/L; electromyography demonstrated a myogenic pattern with normal nerve conduction and nondecremental repetitive nerve stimulation. Whole-exome sequencing identified a novel homozygous missense variant, c.38T>C (p.Leu13Pro), in exon 1 of MICU1, classified as a variant of uncertain significance. To our knowledge, this is the first reported pediatric MICU1 case with congenital ptosis, absence of calf hypertrophy, and a structural corpus callosum abnormality, substantially broadening the phenotypic spectrum of MICU1-related myopathy.
    Keywords:  Case report; Rapport de cas; congenital ptosis; mitochondrial calcium uniporter; mitochondrial calcium uptake protein 1; myopathie avec signes extrapyramidaux; myopathy with extrapyramidal signs; phenotypic spectrum; protéine 1 d’absorption mitochondriale du calcium; ptosis congénital; spectre phénotypique; uniporteur mitochondrial du calcium
    DOI:  https://doi.org/10.4103/aam.aam_493_26
  21. Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2537017123
    Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.
    Kristof Torkenczy, Lucas C Reineke, Sean W Dooling, Benjamin W Henderson, Benjamin Yang, Dongze He, Richard M Myers, Peter Walter, Stefka Tyanova, Mauro Costa-Mattioli.
      Persistent activation of the integrated stress response (ISR) is a central driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. However, the cell type-specific mechanisms underlying these deficits remain poorly understood. By integrating single-cell RNA-seq and single-cell assay for transposase-accessible chromatin sequencing, we generated a brain ISR atlas using Ppp1r15bR658C mice, a clinically relevant model of intellectual disability characterized by selective and persistent ISR activation. We find that distinct brain cell types differentially engage transcriptional and chromatin remodeling programs. Notably, selective deletion of the major ISR downstream effector ATF4 in GABAergic neurons, but not in glutamatergic neurons, exacerbates ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes rely on distinct ISR effectors. We define a molecular single-cell signature of persistent ISR activation that serves as a metric of ISR-mediated cellular vulnerability and as a biomarker for cognitive dysfunction across human cognitive disorders. These findings demonstrate that cell type-specific responses drive cognitive dysfunction during persistent ISR activation.
    Keywords:  cellular homoeostasis; cognitive decline; single-cell ATAC-sequencing; single-cell RNA-sequencing
    DOI:  https://doi.org/10.1073/pnas.2537017123
  22. bioRxiv. 2026 Jul 06. pii: 2026.07.05.736613. [Epub ahead of print]
    Reduced LANCL1-AS1 in old human skeletal muscle diminishes mitochondrial activity, shortens mt-mRNA poly(A) tails, and suppresses myogenesis.
    Jen-Hao Yang, Elizabeth K Izydore, Krystyna Mazan-Mamczarz, Dimitrios Tsitsipatis, Julie A Mattison, Brigette Romero, Changyou Shi, Xiaoling Yang, Rachel Munk, Jennifer L Martindale, Carlos Anerillas, Martin Salamini-Montemurri, Martina Rossi, Yulan Piao, Jinshui Fan, Ya-Chen Chen, Bernardo Abel Cedeno-Veloz, Roberto Ferrero, Marta Montes, Nicolás Martínez-Velilla, Tian-Huei Chu, Kotb Abdelmohsen, Chang-Yi Cui, Mona Batish, Supriyo De, Payel Sen, Luigi Ferrucci, Rafael de Cabo, Myriam Gorospe.
      Regeneration of skeletal muscle preserves muscle mass and function, which decline with age. Here, we sought to identify long noncoding (lnc)RNAs involved in skeletal muscle myogenesis and potentially relevant to muscle aging. Cross-sectional analysis of skeletal muscle transcriptomes from healthy 22-through 89-year-old individuals revealed lncRNA LANCL1-AS1 among the top declining transcripts. Conversely, LANCL1-AS1 increased robustly during skeletal myogenesis and promoted myogenic differentiation in culture. Affinity pulldown by ChIRP followed by mass spectrometry revealed that LANCL1-AS1 associated with the mitochondrial protein LRPPRC, enhancing the formation of the chaperone complex LRPPRC-SLIRP, which maintains longer poly(A) tails of mitochondrial (mt-)mRNAs and stabilizes mt-mRNAs. Importantly, while myoblasts from old rhesus monkey muscle expressed lower levels of LANCL1-AS1 and mt-mRNAs, and displayed lower mitochondrial activity than young monkey myoblasts, overexpressing LANCL1-AS1 in old myoblasts restored mitochondrial activity and myogenesis. We propose that the age-associated reduction in LANCL1-AS1 contributes to impaired mitochondrial function and reduced myogenic capacity in aging skeletal muscle.
    DOI:  https://doi.org/10.64898/2026.07.05.736613
  23. Mol Metab. 2026 Jul 14. pii: S2212-8778(26)00098-0. [Epub ahead of print] 102414
    Biallelic TXNIP deficiency is associated with a multisystemic metabolic disease.
    Julia-Josefine Scholz, Sharlaine Y L Piel, Ioannis Evangelakos, Christian Müller, Daniela Karall, Birgit Reinhart-Steininger, Katja Steinbrücker, Thomas Stulnig, Julia Rohde, Johannes Mayr, Matias Wagner, Ali Biabani, Thomas Mair, Kilian Müller, Hartmut Schlüter, Sören Weidemann, Viktoria Chirico, Christina Weiler-Normann, Christian Hagel, A S Knisely, Joerg Heeren, Benedikt Schoser, Christian Kubisch, Maja Hempel, Holger Prokisch, Saskia B Wortmann, Anna Worthmann, Christian Schlein.
      Thioredoxin-interacting protein (TXNIP) is a protein involved in redox metabolism, but also a key regulator of glucose and lipid metabolism in preclinical models. To date, four patients with biallelic loss-of-function variants in TXNIP have been described, presenting with lactic acidosis and variable hypoglycemia, hepatomegaly, developmental delay and seizures. However, the role of TXNIP in human metabolism and its mechanistic effects across different organs are not fully understood. Here, we characterize a cohort of six additional individuals with biallelic pathogenic variants in TXNIP, confirming lactic acidosis as the main clinical sign and adding adult-onset cardiomyopathy, skeletal muscle weakness, and dyslipidemia to the extended disease spectrum. Heart, liver and muscle patient specimens showed pathological lipid accumulation, and mechanistic studies uncovered increased fatty acid synthesis markers and complex rearrangements of the lipidome and proteome. In a preclinical model of TXNIP deficiency, restricting dietary carbohydrates partially rescued fatty acid synthesis markers and lipid storage in the heart but led to dyslipidemia. Our studies show that TXNIP is an important metabolic modifier in cardiac and skeletal muscle as well as in lipoprotein metabolism and that biallelic pathogenic variants in TXNIP lead to a pleiotropic disease affecting cellular lipid metabolism in multiple organ systems, with potentially fatal adult-onset cardiomyopathy.
    Keywords:  Cardiomyopathy; Hypertriglyceridemia; Inborn errors of metabolism; Mitochondria; TXNIP
    DOI:  https://doi.org/10.1016/j.molmet.2026.102414
  24. Life Sci. 2026 Jul 13. pii: S0024-3205(26)00403-0. [Epub ahead of print]402 124594
    Impaired mitochondrial flexibility hinders fat pad remodeling in obese mice after 24 h of fasting.
    Mariele Lino Silva, Laura Dos Santos Fernandes, Joyce Elisa Heredia, Amanda Carla Clemente de Oliveira, Adma Maciel Babetto, Gustavo de Oliveira Zanetti, Dawit Albieiro Pinheiro Gonçalves, Mauro Martins Teixeira, Geneviève Marcelin, Marina Chaves de Oliveira, Adaliene Versiani Matos Ferreira.
      Obesity involves positive energy balance and mitochondrial dysfunction. Mitochondria play a vital role in reshaping tissues by oxidizing substrates; however, tissue-specific organellar plasticity during energy deprivation remains poorly characterized in obesity. We investigated the effects of 24-h fasting on mitochondrial dynamics in adipose tissue, liver, and muscle of lean and diet-induced obese (DIO) male C57BL/6 mice. Fasting reduced body weight by 13% and subcutaneous adipose tissue (SAT) by 40% in lean mice, but only 6.4% in DIO mice, which maintained SAT mass. Indirect calorimetry revealed an attenuated reduction in the respiratory exchange ratio (RER) in DIO mice during the fed-to-fasting transition. In lean mice, fasting triggered tissue-specific mitochondrial morphological adaptations, characterized by increased mitochondrial size in the SAT, liver, and muscle, alongside higher mitochondrial density in the liver. In contrast, DIO mice displayed blunted mitochondrial morphological plasticity. Interestingly, fasting increased endoplasmic reticulum (ER)-mitochondria proximity (MAMs) and modulated mitochondrial chaperone and protease expression in specific tissues of DIO mice. Furthermore, fasted DIO mice showed a downregulation of mtDNA-encoded genes and selected mitochondrial unfolded protein response (UPRmt) markers. In brown adipose tissue (BAT), mitochondrial architecture remained largely unaltered after fasting in both groups. These findings demonstrate that obesity impairs tissue-specific mitochondrial structural adaptations and blunts systemic metabolic flexibility during fasting. Conversely, acute fasting partially promotes ER-mitochondria ultrastructural proximity in obese mice in a tissue-specific manner, establishing a baseline for future functional interventions.
    Keywords:  Fasting; Mitochondria; Mitochondria-ER interactions; Obesity; Transmission electron microscopy
    DOI:  https://doi.org/10.1016/j.lfs.2026.124594
  25. J Clin Med. 2026 Jul 07. pii: 5289. [Epub ahead of print]15(13):
    When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants.
    Kamil Dzwilewski, Magdalena Krygier, Jakub Szymarek, Marta Zawadzka, Urszula Stodolska-Koberda, Maria Mazurkiewicz-Bełdzińska.
      Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
    Keywords:  DNAJC30; LHONAR1; NMOSD; area postrema syndrome
    DOI:  https://doi.org/10.3390/jcm15135289
  26. Nature. 2026 Jul;655(8123): 812-814
    Epigenetic editing makes its mark.
    Amber Dance.
      
    Keywords:  CRISPR-Cas9 genome editing; Epigenetics; Gene therapy; Technology
    DOI:  https://doi.org/10.1038/d41586-026-02151-x
  27. JCI Insight. 2026 Jul 14. pii: e200106. [Epub ahead of print]
    HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A.
    Lydia H Jestice, Larissa Butler, Rebecca A Lea, Kathryn I Adamson, Jonas Van Lent, Stuart L Johnson, Hollie Weedon, Eldriena D'Silva, Gabriele Gelezauskaite, Bob Asselbergh, Eloise Brown, Owen Laing, Christopher J Price, Dylan Stavish, Anestis Tsakiridis, Mark O Collins, Vincent Timmerman, Kurt J De Vos, Alison E Twelvetrees, Andrew J Grierson, Ivana Barbaric.
      Charcot-Marie-Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.
    Keywords:  Cell biology; Neuromuscular disease; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.200106
  28. Mol Metab. 2026 Jul 15. pii: S2212-8778(26)00104-3. [Epub ahead of print] 102420
    GPR180 deficiency impairs mitochondrial function and insulin secretion in pancreatic β-cells.
    Matus Antal, Tina Dahlby, Peter Makovicky, Anastasiia Novak, Carla Horvath, Daniela Stanikova, Simona Gazova, Radana Brumarova, Eliska Ivanovova, Martina Horejsova, David Friedecky, Olga Krizanova, Marta Novotova, Daniela Gasperikova, Miroslav Balaz, Lucia Balazova.
       OBJECTIVE: G protein-coupled receptor 180 (GPR180) has been implicated in systemic energy metabolism, primarily in adipose tissue and the liver. Given impaired whole-body glucose tolerance following GPR180 dysfunction, we aimed to determine whether GPR180 regulates pancreatic β-cell function. We investigated whether GPR180 contributes to β-cell insulin secretion by modulating metabolic processes that couple glucose sensing to mitochondrial energy production.
    METHODS: Phenotyping of whole-body (Gpr180-/-) and β cell-specific Gpr180 (bGpr180-KO) knockout mice was combined with gain- and loss-of-function studies in MIN6 cells. Glucose-stimulated insulin secretion, pancreatic endocrine architecture and identity, transcriptomic and metabolic profiles, as well as mitochondrial function were assessed using in vivo and in vitro approaches, including metabolic challenge tests, histology, RNA sequencing, targeted metabolomics, respirometry, and transmission electron microscopy.
    RESULTS: Loss of GPR180 impaired first-phase insulin secretion and glucose tolerance without affecting insulin sensitivity. These defects were β-cell-autonomous, as confirmed in the bGpr180-KO mice and in MIN6 cells. Functional studies revealed that GPR180 regulates mitochondrial substrate utilization, anaplerotic support of the TCA cycle, and ATP generation without affecting glucose uptake or mitochondrial biogenesis. In particular, Gpr180-deficient β cells showed mitochondrial membrane depolarization, reduced oxygen consumption, and endoplasmic reticulum remodeling, altering the local mitochondrial microenvironment. In vivo, Gpr180 deletion in β cells led to downregulation of mitochondrial gene programs in islets, along with altered endocrine cell identity.
    CONCLUSIONS: GPR180 is a previously unrecognized regulator of pancreatic β-cell metabolic competence and identity, linking defects in insulin secretion with alterations in mitochondrial function and endocrine cell identity.
    Keywords:  GPR180; insulin secretion; mitochondrial metabolism; pancreatic β-cells; β-cell identity
    DOI:  https://doi.org/10.1016/j.molmet.2026.102420
  29. Protein Sci. 2026 Aug;35(8): e70720
    Molecular and energetic basis of histidine switch dynamics in respiratory complex I.
    Erik Endres, Mahdi Torabi, Mai Jousmäki, Kim Vy Huynh, Cristina Pecorilla, Oleksii Zdorevskyi, Volker Zickermann, Vivek Sharma.
      The respiratory complex I in mitochondria and bacteria drives the two-electron reduction of quinone to pump protons across the membrane. The molecular basis of this catalytic reaction remains enigmatic despite significant progress in structural characterization of the complex. A highly conserved histidine residue in the distal antiporter-like subunit of its membrane domain has been shown to undergo conformational changes in molecular simulations and cryo-EM structures. However, the function of histidine switch dynamics and the energetics of its conformational transitions remain unclear. Here, by applying enhanced sampling classical molecular dynamics simulations, we evaluate the energetics of the histidine switch dynamics and demonstrate that it is coupled to the tautomeric state of histidine and to the charge state of lysine residues ca. 10 Å apart, which cause hydrogen bond restructuring and stabilize the histidine residue in specific conformations. Hybrid QM/MM metadynamics-based free energy simulations show that the histidine switch participates in gated proton transfer and may function as a proton confurcation device in complex I and related proteins.
    Keywords:  bioenergetics; enhanced sampling simulations; hybrid QM/MM; mitochondrial respiration; proton pumping
    DOI:  https://doi.org/10.1002/pro.70720
  30. Med Res Rev. 2026 Jul 13.
    Beyond Bioenergetics: Moonlighting Functions of F1FO-ATPase From ATP Synthesis to an ATP-Wasting Death Switch.
    Salvatore Nesci.
      Mitochondrial F1FO-ATPase is classically viewed as the "splendid" rotary nanomachine that sustains life by converting the proton-motive force (pmf) into ATP. Yet this same complex can adopt a second, context-dependent function that links bioenergetics to cell fate. When oxygen becomes limiting during ischemia, stroke, hypoxia, or anoxia, respiratory chain activity declines, pmf collapses, and the enzyme reverses direction: ATP hydrolysis drives rotor turnover and pumps H+ across the inner mitochondrial membrane to partially restore pmf. This reverse mode can be protective by preserving membrane potential and basic mitochondrial homeostasis, but it also imposes a severe energetic burden on the cell. A key determinant of whether F1FO-ATPase acts as an energy-conserving or energy-dissipating machine is the identity of the catalytic divalent cation. Under physiological conditions, Mg2+ supports efficient, reversible ATP synthesis/hydrolysis. In pathology, mitochondrial Ca2+ overload may replace Mg2+ at catalytic sites, shifting catalysis toward ATP hydrolysis and promoting an ATP-wasting state that triggers mitochondrial permeability transition pore (mPTP) formation and regulated cell death. Thus, ATP hydrolysis by F1FO-ATPase beyond regulation by pmf and inhibitory proteins such as IF1, cation cofactor selection emerges as a decisive switch that repurposes the enzyme from "enzyme of life" to "enzyme of death." Here, this cofactor-dependent reversibility is framed as a moonlighting role of F1FO-ATPase, integrating energy conversion with death signaling. Conceptual questions are outlined to resolve current debate and to exploit this switch for therapeutic insight.
    Keywords:  F1FO‐ATPase; cation cofactor switching; mitochondrial permeability transition pore; regulated cell death
    DOI:  https://doi.org/10.1002/med.70088
  31. Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00107-9. [Epub ahead of print] 102423
    SAMM50 rs3761472 causes mitochondrial dysfunction and progression of metabolic dysfunction-associated steatotic liver disease.
    Suyeon Kim, Young Jin Kim, Nahyun Kim, Uijin Kim, Yi Seul Park, Jun Ho Yun, Jiwon Heo, Hyunwoo Lee, Jiwon Choi, Sinwoo Park, Inhae Jeong, Bong-Jo Kim, Ha Youn Shin.
      Mitochondria play a key role in metabolic liver disease, yet how inherited genetic variation perturbs mitochondrial integrity in vivo remains poorly understood. Here, we demonstrate that SAMM50 rs3761472, a population-enriched single-nucleotide polymorphism (SNP) previously associated with metabolic dysfunction-associated steatotic liver disease (MASLD), exerts a direct functional impact on mitochondrial function. We performed genome-wide and phenome-wide analyses across large Biobank cohorts and identified a significant association between rs3761472 and MASLD. To define its underlying mechanism, we generated Samm50 knock-in (KI) mice carrying the rs3761472 corresponding D110G substitution using CRISPR/Cas9 genome editing. KI mice exhibited impaired mitophagy, reduced ATP production, elevated oxidative stress, and inflammatory activation in the liver, accompanied by disrupted mitochondrial organization. Under high-fat diet conditions, the variant drove hepatic steatosis, liver injury, insulin resistance, and glucose intolerance, recapitulating key features of MASLD. Together, our findings establish rs3761472 as a functional genetic variant linking mitochondrial architecture to metabolic liver disease pathogenesis, with potential relevance as a genetic biomarker for MASLD susceptibility.
    Keywords:  CRISPR/Cas9; Genetic biomarker; Metabolic dysfunction-associated steatotic liver disease; Mitochondria; SAMM50; Single nucleotide polymorphism
    DOI:  https://doi.org/10.1016/j.molmet.2026.102423
  32. Nat Rev Neurosci. 2026 Jul 13.
    Brain mitochondria as key drivers of cognition and behaviour.
    Carmen Sandi, Mary Kay Lobo, Fiona Hollis, Yusuke Hirabayashi, Jaime de Juan-Sanz, Juan P Bolaños.
      Cognition and behaviour arise from computations in neural circuits, which can differ in their readiness for recruitment or in the computations and behavioural outputs that they generate. Mitochondria contribute to both circuit properties and their variability by shaping the cellular processes on which circuit function depends. Across neurons and glia, mitochondria provide bioenergetic support, regulate Ca2+ dynamics and reactive oxygen species levels, influence neurotransmitter synthesis and turnover, and sustain quality control programmes that preserve cellular integrity. The capacity of mitochondria to provide this support and their plasticity have been linked to circuit architecture, engagement and adaptation, with implications for learning and memory, reward and reinforcement, state-trait anxiety and motivation. Here we describe two complementary modes of mitochondrial support: a baseline mode, in which mitochondria sustain circuit architecture and physiological properties over long timescales, and an activity-evoked mode, in which local mitochondrial outputs support synaptic transmission and plasticity. Distinguishing these two modes helps to explain how behavioural modulators, including stress hormones, immune activity and metabolic signals, can shape behaviour by altering either baseline mitochondrial control of circuit readiness or activity-evoked mitochondrial support during circuit engagement.
    DOI:  https://doi.org/10.1038/s41583-026-01061-1
  33. Sci Bull (Beijing). 2026 Jul 13. pii: S2095-9273(26)00791-7. [Epub ahead of print]
    Biallelic hexose-6-phosphate dehydrogenase variants cause mitochondrial dysfunction underlying Parkinson's disease.
    Miao Zhao, Yuwen Zhao, Juan Huang, Yu Guo, Wenjun Yu, Haiyan Hou, Yilin Huang, Xinying Du, Yu Zhang, Mujun Xie, Zuowen Ren, Haoyu Guan, Hongxu Pan, Wenwen Xu, Qiying Sun, Qian Xu, Lingling Lv, Chunyu Wang, Lifang Lei, Heng Wu, Lu Shen, Hong Jiang, Xinxiang Yan, Jinchen Li, Pengli Zheng, Jifeng Guo, Beisha Tang, Jieqiong Tan, Zhenhua Liu.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder influenced by complex genetic and environmental factors. We report that biallelic variants in hexose-6-phosphate dehydrogenase (H6PD), which encodes a key enzyme in the endoplasmic reticulum (ER) pentose phosphate pathway, contribute to PD and investigate its role in maintaining mitochondrial homeostasis. Through whole-exome sequencing of 2223 patients with PD and 1229 controls, together with whole-genome sequencing of 4010 patients and 6072 controls, we found 13 biallelic H6PD variants in eight probands, including two homozygous and six compound heterozygous cases (six early-onset PD, two late-onset PD). Functional studies were conducted using cultured cells, Drosophila, and AAV-shRNA-mediated H6PD knockdown mice. Mitochondrial function and redox status were assessed using confocal imaging, flow cytometry, and Seahorse metabolic flux analysis. ER-mitochondria contacts, Ca2⁺ dynamics, and mitophagy were evaluated using SPLICS sensors, calcium imaging, and PINK1-Parkin pathway assays. Our study revealed that H6PD depletion impaired NADPH generation, disrupted ER-mitochondria coupling, caused abnormal Ca2+ release, mitochondrial fragmentation, reduced respiratory capacity, and suppressed PINK1-Parkin-dependent mitophagy. PD-related H6PD variants lost the ability to maintain NADPH/redox balance and mitochondrial protective function. In Drosophila, H6PD loss induced dopaminergic neurodegeneration, locomotor deficits, and shortened lifespan, all partially rescued by human H6PD. Similarly, H6PD knockdown in mice aggravated MPTP-induced neuronal loss and mitochondrial abnormalities. In conclusion, our study identifies biallelic variants in H6PD as a novel cause of PD. H6PD maintains ER NADPH/redox homeostasis, stabilizes ER-mitochondria communication, and preserves mitochondrial function and mitophagy, thereby supporting dopaminergic neuron survival.
    Keywords:  Biallelic variants; Endoplasmic reticulum-mitochondria coupling; H6PD; Mitochondrial dysfunction; Mitophagy; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.scib.2026.07.038
  34. Front Immunol. 2026 ;17 1881243
    The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.
    Yu Huan, Qiqi Wang, Rongkaixuan Fang, Yue Sun, Meiya Suo, Chenghong Cao, Shuya Zhang, Lan A, Wenzhou Xu.
      The conversion of metabolic disequilibrium into chronic inflammatory signaling represents a central and actively investigated question in ageing biology. Among stromal cells, fibroblasts are key effectors of tissue remodeling and inflammation, acquiring a senescence-associated secretory phenotype (SASP) that sustains age-related pathology. Here, we delineate a mechanistic framework in which disruption of energy homeostasis drives mitochondrial dysfunction, innate immune activation, and SASP secretion. Mitochondria act as metabolic sentinels that sense energetic stress through altered AMP/ATP and NAD+/NADH ratios, leading to the generation of mitochondrial danger signals-reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). These signals converge on canonical immune pathways, including the cGAS-STING axis, NLRP3 inflammasome, and NF-κB signaling, thereby converting metabolic distress into persistent pro-inflammatory output. Using periodontal ligament fibroblasts as a disease-relevant model, we highlight how microbial biofilm exposure induces mitochondrial metabolic reprogramming that amplifies fibroblast SASP, promotes osteoclastogenesis, extracellular-matrix degradation, and alveolar bone resorption. At the transcriptional level, regulatory networks involving NF-κB, C/EBPβ, STATs, and the mTOR-AMPK hub integrate mitochondrial signals to sustain inflammatory senescence. We propose that restoring mitochondrial metabolic homeostasis serves as a highly promising strategy to break the self-perpetuating cycle in which energy imbalance triggers SASP activation, which in turn contributes to chronic inflammation. Researchers must first characterize the tissue-specific mitochondrial signatures of SASP. Subsequently, developing precise, lesion-targeted metabolic interventions will open new avenues for mitigating inflammaging and rejuvenating stromal function across ageing tissues.
    Keywords:  cellular senescence; fibroblasts; inflammaging; innate immune signaling; metabolic reprogramming; mitochondrial dysfunction; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3389/fimmu.2026.1881243
  35. Cell Metab. 2026 Jul 14. pii: S1550-4131(26)00246-9. [Epub ahead of print]
    Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
    Dandan Wang, Mark Li, Tian Lu, Mami Matsushita, Juro Sakai, Masayuki Saito, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less explored. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a critical role for BAT in the clearance of circulating branched-chain amino acids and triglycerides. We also identified a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced primarily by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.
    Keywords:  bioenergetics; brown adipose tissue; inter-organ communication; metabolic health; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.020
  36. Clin Exp Nephrol. 2026 Jul 11.
    Kidney outcomes of coenzyme Q10 supplementation in patients with genetically confirmed CoQ10 nephropathy in Japan.
    China Nagano, Katsumi Ushijima, Yuko Tezuka, Takayuki Okamoto, Yasuhiro Inaba, Akinori Miyazono, Naoko Takeda, Taro Aoki, Akira Mizutani, Hiroki Miyano, Masaki Yamamoto, Mariko Imai, Takehiko Kawaguchi, Toshiyuki Komiya, Masayuki Ishihara, Yoshiki Nagao, Naoaki Mikami, Yuta Inoki, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Kandai Nozu.
       BACKGROUND: Coenzyme Q10 (CoQ10) nephropathy is a rare mitochondrial kidney disease caused by defects in CoQ10 biosynthesis and represents a unique form of steroid-resistant nephrotic syndrome with a disease-specific therapy. However, data on treatment outcomes of this disease in Japanese patients remain limited.
    METHODS: We conducted a retrospective observational study of Japanese patients. Patients with a genetically confirmed diagnosis of CoQ10 nephropathy who received CoQ10 supplementation and had available longitudinal clinical data were included. Changes in the urinary protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate before and after treatment were evaluated, and adverse events were assessed.
    RESULTS: Twelve patients were included in the analysis. The median age at treatment initiation was 9.0 years, and COQ8B was the predominant causative gene (n = 11). One patient harbored a COQ6 variant. CoQ10 supplementation was initiated at a median dose of 10.0 mg/kg/day. The median UPCR decreased from 1.66 g/gCr at baseline to 0.19 g/gCr at 12 months, and 6/7 (86%) patients with available 12-month data achieved a ≥ 50% reduction in proteinuria. Kidney function remained stable, and no patients progressed to end-stage kidney disease during a median follow-up of 28.8 months. Adverse events were mild and did not lead to treatment discontinuation.
    CONCLUSIONS: In Japanese patients with CoQ10 nephropathy, CoQ10 supplementation was associated with a substantial reduction in proteinuria and stabilization of kidney function. These findings indicate the importance of early genetic diagnosis and prompt initiation of targeted therapy for this treatable hereditary kidney disease.
    Keywords:  COQ6; COQ8B; CoQ10 nephropathy; CoQ10 supplementation
    DOI:  https://doi.org/10.1007/s10157-026-02917-7
  37. J Exp Med. 2026 Aug 03. pii: e20251331. [Epub ahead of print]223(8):
    Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2).
    Conor Gruber, Meredith Ramba, Bineeta Debnath, Lorenzo Cuollo, Anna-Lena Neehus, Angelica Lee, Sofija Buta, Marta Martin-Fernandez, Jérémie Rosain, Laureline Berteloot, Philippe Drabent, Tom Le Voyer, Camille Soudée, Jessica Peel, Yoann Seeleuthner, Anne Puel, Shen-Ying Zhang, Michael J Ciancanelli, Carlos A Arango-Franco, Mélanie Migaud, Marie-Louise Frémond, Florence Renaldo, Odile Boespflug-Tanguy, Imen Dorboz, Beatrice Dubern, Tristan Fonteneau, Nima Parvaneh, Rasol Molatefi, Mohammad Shahrooei, Darragh Duffy, Vincent Bondet, Gillian I Rice, Yanick J Crow, Thierry Jo Molina, Nathalie Boddaert, Jean-Laurent Casanova, Veronique Houdouin, Isabelle Melki, Alice Hadchouel, Jacinta Bustamante, Dusan Bogunovic.
      Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.
    DOI:  https://doi.org/10.1084/jem.20251331
  38. Protein Eng Des Sel. 2026 Jul 17. pii: gzag020. [Epub ahead of print]
    Protein engineering: Status report.
    Hui-Wang Ai, Frances H Arnold, Doug Barrick, Hagan Bayley, Alfie-Louise R Brownless, Robert E Campbell, Roger Castells-Graells, Pimchai Chaiyen, Roberto A Chica, Lauren O Chisholm, Daniel Christ, Guo-Chao Chu, Michael Chungyoun, Vincent G H Eijsink, Michael B Elowitz, Douglas J Fansher, Rudi Fasan, Gabriel Foley, Michelle S Frei, Andreas Gagsteiger, Ruiyan Gao, Elizabeth M J Gillam, Jeffrey J Gray, Luis F Guerra, Birte Höcker, Zhiyang Jin, Shina Caroline Lynn Kamerlin, Nobuyasu Koga, Roland E Kontermann, Brian Kuhlman, Olivia A Langlois, Dongyang Li, Roberto D Lins, Chang C Liu, Lei Liu, Diego López Barreiro, Peilong Lu, Sohum Mehta, Ikumi Miyazaki, Manuel M Müller, Serge Muyldermans, Naoto Nemoto, Jeff Nivala, James K Nuñez, Izaiah J Ornelas, Joelle N Pelletier, Andreas Plückthun, Owen T Porth, Kridsadakorn Prakinee, Yujia Qing, Julia C Reisenbauer, Sandy Schmidt, Oliver Seifert, Mikhail G Shapiro, Rachna Sharma, Nilmani Singh, Benjamin J Smith, Jamie B Spangler, Rie Tatsumi-Koga, Takuya Terai, Henrik Terholsen, Mattias Tolhurst, Katherine W Tripp, Vanessa Tanja Trossmann, Chandra L Tucker, Onur Turak, James A Van Deventer, Anikó Várnai, Isabelle F T Viana, Amy M Weeks, K Dane Wittrup, Kingsley L-J Wong, Chenggang Xi, Todd O Yeates, Andy Hsien-Wei Yeh, Jin Zhang, Tiger S Zhang, Huimin Zhao, Fang Zheng, Jingyi Zhu, Sacha Zinn.
      With this status report, we aim to provide a timely snapshot of the protein engineering field as a broad and rapidly advancing discipline that integrates computational, molecular biology, structure-guided, evolutionary, and synthetic approaches to create new and improved proteins with tailored structures and useful functions. The report is organized into eight thematic areas spanning core methodologies and major application domains, including enzymes, therapeutics, detection, synthetic biology, and materials. Contributions from experts across these areas highlight both the historical foundations and recent advances in their respective fields, with particular emphasis on the growing influence of machine learning and artificial intelligence-based methods. Emerging from this broad overview is a central message: protein engineering appears to be entering a golden age, defined by a rapidly accelerating pace of progress, even as significant challenges in design, screening, and real-world application remain. Looking ahead, the continued integration of computational and experimental strategies is poised to further accelerate the impact of protein engineering across an expanding range of economically and societally important sectors, from therapeutics and molecular imaging to diagnostics, plastic recycling, and industrial chemistry.
    Keywords:  application areas; computational methods; experimental techniques
    DOI:  https://doi.org/10.1093/protein/gzag020
  39. Nat Biotechnol. 2026 Jul;44(7): 1070
    MHRA's radical rare disease proposal.
      
    DOI:  https://doi.org/10.1038/s41587-026-03244-8
  40. Mol Ther Adv. 2026 Sep 10. 34(3): 201785
    Combining modeling approaches for rapid preclinical evaluation of retinal gene therapy.
    Krishanu Saha.
      
    DOI:  https://doi.org/10.1016/j.omta.2026.201785
  41. Drug Discov Today. 2026 Jul 17. pii: S1359-6446(26)00147-9. [Epub ahead of print] 104742
    Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.
    Alise Zagare, Javier Jarazo, Jens Schwamborn.
      Parkinson's disease (PD) poses a major unmet therapeutic challenge, with most drug candidates failing in clinical translation despite promising animal model data. Human induced pluripotent stem cell-derived midbrain organoids recapitulate key PD pathological hallmarks - including dopaminergic neuron loss, α-synuclein aggregation, and neuroinflammation - in a genetically defined, human-specific context. This review summarizes drug screening studies in midbrain organoids across genetic, toxin-based, and α-synuclein preformed fibril models. We highlight therapeutic interventions that rescue PD phenotypes, compare organoid and animal model systems, and discuss the personalized medicine potential of patient-derived organoids. We also critically assess current limitations and outline how artificial intelligence integration and assembloid platforms are advancing organoid-based drug discovery towards regulatory acceptance.
    Keywords:  Parkinson’s disease; drug development; organoids; translational models
    DOI:  https://doi.org/10.1016/j.drudis.2026.104742
  42. Molecules. 2026 Jul 01. pii: 2317. [Epub ahead of print]31(13):
    Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers.
    Wojciech Rzeski.
      Aging is the dominant risk factor for most chronic diseases, yet the mechanisms driving this relationship remain poorly integrated across biological scales. Existing frameworks have catalogued key hallmarks of aging but do not explain how these processes converge to produce organism-level decline and multimorbidity. A systems-level framework is introduced in which aging is conceptualized as progressive destabilization of interacting regulatory networks. Mitochondrial quality control, nutrient-sensing pathways, and chronic inflammatory signaling form a putative high-centrality network core: mitochondria coordinate redox balance, bioenergetics, and transcriptional adaptation, while NAD+-dependent signaling and NLRP3 inflammasome activation propagate perturbations across regulatory layers. This architecture provides a mechanistic basis for the convergence of neurodegenerative, cardiovascular, metabolic, and oncological phenotypes as emergent consequences of shared network instability. Reframing the hallmarks as coupled network nodes shifts the explanatory focus from isolated mechanisms to system-level resilience and non-linear dynamics. This narrative and conceptual review integrates evidence across mitochondrial biology, metabolic signaling, and inflammatory pathways to develop these arguments, with explicit acknowledgment that the proposed framework is hypothesis-generating rather than formally validated. Interventions targeting high-centrality nodes, including mTOR modulation, NAD+ restoration, mitophagy activation, and anti-inflammatory strategies, may exert system-wide effects by reconfiguring network dynamics rather than correcting individual pathways. This perspective suggests that biomarker-stratified, network-calibrated interventions may offer a broader systems-level therapeutic rationale than single-pathway approaches.
    Keywords:  NAD+ metabolism; aging; chronic inflammation; integrative biology; mitochondria; mitophagy; multimorbidity; network medicine
    DOI:  https://doi.org/10.3390/molecules31132317
  43. EMBO Rep. 2026 Jul 15.
    Caspase-3 cleaves CYLD to restrict interferon signaling during mitochondrial apoptosis.
    Yanis M Macé, Tiphaine Douanne, Jane Jardine, Kilian Trillet, Rosalie Moreau, Joanna Re, Cara J Ellison, Nadine Laguette, Paul R Elliott, Julie Gavard, Nicolas Bidère.
      Mitochondrial outer membrane permeabilization is a pivotal event in programmed cell death by apoptosis, leading to the activation of the cysteine protease caspase-3 (CASP3) and the release of mitochondrial nucleic acids. This release triggers the activation of the Interferon Regulatory Factor 3 (IRF3) transcription factor and the subsequent IRF3-mediated type I interferon production and cell death. CASP3 ensures apoptosis remains immunologically silent, though the mechanisms are unclear. We report that CASP3 cleaves CYLD, a deubiquitinating enzyme crucial for cell fate and inflammatory signaling. This proteolysis occurs at a site distinct from the previously reported CASP8 site, which is involved in limiting cell lysis and inflammation during extrinsic apoptosis. Although cleaved CYLD retains its enzymatic activity in vitro, knocked-in cells expressing CASP3-resistant CYLD show increased interferon signaling and enhanced cell death. Thus, a proteolytic code regulates CYLD to balance inflammation during programmed cell death.
    DOI:  https://doi.org/10.1038/s44319-026-00876-4
  44. Nature. 2026 Jul 14.
    RNA molecules with different destinies are processed through overlapping pathways.
    Rosemary Kiernan.
      
    Keywords:  Cell biology; Molecular biology; Non-coding RNAs
    DOI:  https://doi.org/10.1038/d41586-026-02041-2
  45. bioRxiv. 2026 Jul 09. pii: 2026.07.03.736226. [Epub ahead of print]
    A quantum interface with mitochondrial bioenergetics.
    Parisa Aghaei, Sangjun Noh, Javier Noé Ramos-Silva, Minghao Jiang, Phang-Lang Chen, Yumay Chen, Fatemeh Goodarzinia, Robert Usselman, Philip Hemmer, Douglas C Wallace, Peter J Burke.
      Recent work has shown that genetically engineered proteins can serve as quantum bits in living systems. These quantum bits arise from the photochemistry of protein-bound flavins: blue-light excitation drives electron transfer to form a spin-correlated radical pair whose coherent singlet-triplet interconversion makes the protein's fluorescence sensitive to weak magnetic fields. Because this radical-pair reaction depends on the redox state of the flavin-itself a central electron carrier in cellular metabolism-the magneto-fluorescence of a biological qubit is intrinsically coupled to the biochemistry around it. This suggests a powerful application of fundamental significance in biology, until now an unsolved problem in the field of quantum sensing. Here we show a new class of quantum sensor, mtMagLOV2, that interfaces directly to a defining feature of life itself: the bioenergetic state of the cell. We genetically engineer flavin mononucleotide (FMN)-containing, magnetic-field-sensitive fluorescent proteins ("biological qubits") to be expressed and translocated into the key bioenergetic machinery of the cell: the mitochondrial matrix. Using confocal and super-resolution microscopy, mtMagLOV2 localizes to the mitochondrial cristae, home of the electron transport chain complexes I-V and ATP synthase-the site of oxidative phosphorylation (OXPHOS). By pharmacological manipulation of OXPHOS, we show that the sensor's magneto-fluorescence tracks the redox (oxidation-reduction) state of the mitochondrial flavins, providing a quantum readout of redox status. The response differs between cancer cells (which rely heavily on glycolysis) and cardiomyocytes (which rely predominantly on OXPHOS), demonstrating "quantum bioenergetic profiling". Together, these results establish biological qubits as quantum sensors capable of probing mitochondrial bioenergetics, opening a quantum window into the energetic machinery of living cells. More broadly, we anticipate that coupling quantum redox sensitivity to specific biochemical targets will extend the reach of quantum technologies across the life sciences.
    DOI:  https://doi.org/10.64898/2026.07.03.736226
  46. Cell Calcium. 2026 Jul 09. pii: S0143-4160(26)00060-6. [Epub ahead of print]136 103167
    Single-cell analysis of sterol-induced Ca2＋ signaling in human astrocytes by dynamic mode decomposition.
    Miklas P W Larsen, Line Lauritsen, Amanda T Pauli, Rasmus Jensen, Ralf Zimmermann, Max Lehmann, Pablo Wessig, Daniel Wüstner.
      Ca2＋ signaling in astrocytes is a central mechanism of intercellular communication in the brain and plays a key role in regulating neuronal excitability, synaptic plasticity, and energy metabolism. Disruption of astrocytic Ca2＋ dynamics is a characteristic of neurodegenerative diseases, as are deviations in cholesterol trafficking and metabolism, which are essential for maintaining membrane structure and function. Although recent studies have begun to explore links between Ca2＋ signaling and sterol homeostasis in astrocytes, unbiased analytical workflows and mechanistic insight into how cholesterol and related sterols regulate astrocytic Ca2＋ dynamics remain limited. Here, we apply dynamic mode decomposition to dissect and classify Ca2＋ signals obtained from time-lapse imaging of human astrocytes. Using both synthetic and experimental datasets, we show that delay-embedded dynamic mode decomposition combined with clustering separates heterogeneous Ca2＋ activity into distinct dynamical states. This analysis reveals that increasing cholesterol levels shift astrocytes toward more active oscillatory states, whereas acute cholesterol depletion suppresses Ca2＋ activity. In addition, pretreatment with the oxysterols 24-, 25-, and 27-hydroxycholesterol impaired cholesterol-induced Ca2＋ oscillations. Together, this work presents a general computational framework for decomposing and analyzing complex spatiotemporal Ca2＋ signals, with broad applicability to quantitative imaging in cell biology.
    Keywords:  Astrocytes; Calcium imaging; Clustering; Dynamic mode decomposition; Fluorescence; Microscopy; Signaling
    DOI:  https://doi.org/10.1016/j.ceca.2026.103167
  47. bioRxiv. 2026 Jul 10. pii: 2026.07.09.737340. [Epub ahead of print]
    Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity.
    Kiyoshi Uemasu, Kazuya Tanimura, Atsushi Miyamoto, Koichi Hasegawa, Zachary Lane, Reika Nyunoya, Haruka Uemasu, Brett A Kaufman, Corrine R Kliment, Divay Chandra, Frank Sciurba, Charles Dela Cruz, Prithu Sundd, Jonathan K Alder, Jian Hu, Toru Nyunoya.
      Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear. We show that QKI expression is reduced in human COPD lungs and that alveolar type 2 epithelial (AT2) cell QKI protein levels correlate strongly with spirometric indices and diffusing capacity (DL CO ). Lung epithelium-specific QKI knockout mice (QKI Δ/Δ ) developed spontaneous airspace enlargement with emphysema-like mechanics, and QKI-deficient AT2 cells showed impaired spheroid colony formation and increased apoptosis. Integrated transcriptomic and proteomic analyses of primary AT2 cells revealed a selective reduction in functional mitochondrial (respiratory-chain and metabolic) protein abundance despite relatively preserved transcript levels, consistent with mitochondrial transcriptome-proteome discordance. QKI loss increased mtDNA abundance and TOMM20 staining but decreased ATP5A, indicating accumulation of structurally increased but functionally dysfunctional mitochondria. In human epithelial cells, CRISPR-mediated QKI deficiency reduced oxidative respiration, increased glycolytic reliance, elevated mitochondrial ROS and membrane potential, and increased apoptosis; these phenotypes were partially rescued by QKI re-expression. These findings identify epithelial QKI as a regulator of mitochondrial integrity and stress tolerance in COPD.
    DOI:  https://doi.org/10.64898/2026.07.09.737340
  48. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00128-7. [Epub ahead of print]209 1-26
    Utilizing FLAMBE to study the structure-function relationship and regulation of monomeric BAX activation in solution.
    Jesse D Gelles, Md Abdullah Al Noman, Jarvier N Mohammed, Jerry Edward Chipuk.
      The BCL‑2 family member BAX is responsible for inducing mitochondrial outer membrane permeabilization (MOMP) and committing a cell to apoptosis. Specifically, native BAX is an inactive cytosolic monomer, which, upon activation by direct activator BCL‑2 family proteins, undergoes intramolecular rearrangements and structural changes, resulting in BAX translocation to the mitochondrial outer membrane, oligomerization, and MOMP - collectively, we refer to this progression of structural conformers as the BAX activation continuum. In vitro BAX activation studies are invaluable tools for investigating BAX structure-function biology and studying cellular and pharmacological modulators of apoptosis; however, such methodologies are commonly limited to endpoint functional phenotypes (e.g., membrane permeabilization) and thus overlook molecular regulation of soluble monomeric BAX. To address this methodological gap, we developed FLAMBE (a fluorescence polarization ligand assay for monitoring BAX early-activation), a solution-based kinetic assay that infers BAX activation via the concomitant dissociation of a labeled BH3 peptide. FLAMBE maintains the benefits of rapid kinetic data generation in an economical microplate format using commercially available reagents without requiring specialized equipment or large quantities of protein. Herein, this protocol describes how to perform FLAMBE assays, the recommended optimization workflow, and a dual-metric parameterization strategy to distill kinetic data for comparative analyses.
    Keywords:  Apoptosis; BAX; BCL-2 family; Fluorescence polarization; Regulated cell death
    DOI:  https://doi.org/10.1016/bs.mcb.2026.04.007
  49. Metabolism. 2026 Jul 17. pii: S0026-0495(26)00209-X. [Epub ahead of print]183 156696
    TRIM72 alleviates skeletal muscle atrophy by modulating mt-dsRNA/RIG-I signaling.
    Liwei Liao, Ziwen Zheng, Weidong Xu, Junwei Guo, Simin Yao, Xinyue Huang, Zilin Wang, Chang Li, Jiaye Li, Qin Zhang, Yiding Bian, Kai Wang, Jinrui Miao, Ruixia Li, Han Wang, Xiaoming Zhou, Mingming Deng, Gang Hou.
      Skeletal muscle atrophy is characterized by diminished muscle mass and function, which can arise from aging, nerve damage, and disease-related secondary atrophy. A central unresolved question is how these diverse stressors trigger common downstream mechanisms to cause sustained muscle deterioration. Here, we confirmed the role of cytosolic double-stranded RNA (dsRNA) in muscle atrophy across multiple murine models (aging, denervation and dexamethasone). Accumulated dsRNA released from damaged mitochondria aberrantly activated the innate immune sensor RIG-I signaling, triggering inflammation and muscle wasting. Moreover, adoptive transfer of mitochondrial dsRNA (mt-dsRNA) into healthy myotubes was sufficient to recapitulate the atrophic phenotype and activate RIG-I signaling. Furthermore, E3 ligase TRIM72 was identified as muscle-specific regulator of RIG-I signaling. TRIM72 attenuates the mt-dsRNA/RIG-I axis through two mechanisms. One is ubiquitinating RIG-I via interaction with its CARD domain to trigger degradation, the other is preserving mitochondria to prevent dsRNA leakage. Consequently, TRIM72 deficiency exacerbated atrophy while supplementation with recombinant TRIM72 (rhT72) improved muscle conditions and suppressed RIG-I signaling in vivo. In a clinic cohort, plasma TRIM72 level declined with muscle atrophy across multiple pathologies and rose with muscle recovery. Overall, our findings revealed mt-dsRNA/RIG-I axis as a key pathogenic pathway in muscle atrophy and identified TRIM72 as a key regulator and potential therapeutic agent.
    Keywords:  Mitochondrial double-stranded RNA (mt-dsRNA); RIG-I; Skeletal muscle atrophy; Tripartite motif containing 72 (TRIM72)
    DOI:  https://doi.org/10.1016/j.metabol.2026.156696
  50. J Cardiovasc Transl Res. 2026 Jul 13. pii: 90. [Epub ahead of print]19(1):
    Mitochondrial ncRNAs: From Pathological Regulation to Targeted Therapy in Cardiovascular Diseases.
    Cheng Li, Qiong Yuan.
      Heart failure (HF) is closely linked to mitochondrial dysfunction, featured by abnormal energy metabolism, excessive reactive oxygen species (ROS), and imbalanced mitochondrial dynamics. Clinically, effective targeted therapies for mitochondrial dysfunction are still lacking, which aggravates HF and multi-organ injury. Mitochondrial non-coding RNAs (mt-ncRNAs) form a regulatory network critical for mitochondrial function. Among them, mitochondrial-encoded circular RNAs (mecciRNAs) and mitochondrial double-stranded RNAs (mt-dsRNAs) are research hotspots. mecciRNAs protect the heart by assisting protein import and regulating mitochondrial pores and ROS; their degradation worsens HF, while exogenous supplementation alleviates injury. mt-dsRNAs arise from aberrant mitochondrial transcription and contribute to myocardial injury and remodeling via MAVS, cGAS-STING, and PNPT1 pathways. Gene therapy targeting mecciRNAs and mt-dsRNAs combined with mitochondrial delivery represents a promising strategy for HF treatment.
    Keywords:  Heart failure; Mitochondrial genome; Mitochondrial-penetrating peptides; Mt-dsRNA; Mt-mitochondrial-encoded circular RNAs
    DOI:  https://doi.org/10.1007/s12265-026-10809-0
  51. Science. 2026 Jul 16. 393(6808): eadx8675
    A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
    Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.
      The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
    DOI:  https://doi.org/10.1126/science.adx8675
  52. Commun Biol. 2026 Jul 15.
    Label-free segmentation of mitochondria for simultaneous morphological and metabolic studies.
    Kideog Bae, Muzaffer Özbey, Alexander Ho, Edita Aksamitiene, Kevin K D Tan, Janet E Sorrells, Rishyashring R Iyer, Mark A Anastasio, Stephen A Boppart.
      The dynamics in the mitochondrial structure and function are closely related to cellular health. Traditional fluorescence imaging techniques for observing mitochondria are limited by phototoxicity, photobleaching and staining artifacts. In this study, we propose RedoxSegNet, an AI-enhanced imaging platform that enables label-free segmentation of mitochondria for concurrent morphological and functional analysis without the aid of labeling dyes. Our approach uses high-resolution two-photon excitation fluorescence microscopy, in conjunction with a custom-built conditional diffusion model, to reconstruct mitochondrial features from NAD(P)H autofluorescence images. Subsequent segmentation through post-processing algorithms demonstrates a task-specific performance error of less than 6% on average compared to the mitochondria-stained images. Our trained model effectively extracts mitochondrial features from label-free images, thereby facilitating mapping of mitochondria-specific optical redox ratios. We find that our analysis elucidates metabolic heterogeneity both within and between the organelles. Further validation under mitochondrial stress conditions induced by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) confirms that RedoxSegNet can capture dynamic mitochondrial fragmentation and heterogeneous metabolic response. Overall, these findings establish our technique as a non-invasive, reliable tool for investigating mitochondrial morpho-functional dynamics in native cellular environments.
    DOI:  https://doi.org/10.1038/s42003-026-10687-x
  53. Adv Biol (Weinh). 2026 Jul;10(7): e70137
    Context-Dependent Functional Outcomes of Mitochondrial Transfer: A Donor-Recipient Perspective.
    Bin Wang, Tian Lin, Xinying Mo, Benson Peter Mugaka, Guangjie Tai, Ming Xu.
      Intercellular mitochondrial transfer has emerged as a fundamental mechanism regulating tissue homeostasis and disease progression, yet its complex regulatory network remains incompletely understood. This review synthesizes the principal transfer mechanisms, focusing on tunneling nanotube (TNT)-mediated direct contact and extracellular vesicle (EV)-mediated indirect transport. Based on the functional disparity between donor and recipient cells, we categorize four prototypical pairing modes and delineate the functional diversity of mitochondrial transfer in metabolic support, tissue repair, and stress responses. Building on this framework, we propose five key determinants as the core dimensions for understanding transfer efficiency and functional outcomes across various contexts: donor mitochondrial quality, donor transfer capacity, recipient metabolic demand, recipient integration capacity, and donor-recipient compatibility. Integrating these factors provides a conceptual basis for explaining the dual effects of mitochondrial transfer-supporting tissue regeneration and functional recovery while, in certain microenvironments, driving pathological reprogramming. This review offers a comprehensive framework for mechanistic studies and clinical translation of mitochondrial transfer and highlights its therapeutic potential in regenerative medicine, aging intervention, and cancer therapy.
    Keywords:  cell communication; extracellular vesicles; metabolic reprogramming; mitochondria; tumor microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.1002/adbi.70137
  54. Anal Chem. 2026 Jul 11.
    Liver-Targeted Triple-Modal Molecular Probe for Visualization of Aging Marginal Donor Livers.
    Min Zhao, Yongcheng Dai, Gang Xu, Leyi Wang, Xi Xu, Jiayin Yang, Zhenyu Duan, Zixuan Zhan, Kui Luo.
      Rapid and accurate assessment of senescence in aging marginal donor livers is critically important for liver transplantation, yet remains analytically challenging in clinical practice. Herein, we report CyC, a liver-targeted triple-modal molecular probe that integrates naked-eye colorimetric sensing with near-infrared fluorescence/photoacoustic (NIRF/PA) imaging for rapid evaluation of hepatic senescence. Upon activation by senescence-associated β-galactosidase (β-Gal), CyC produces a turn-on NIRF/PA response accompanied by a distinct blue-to-green color change visible to the naked eye. The probe exhibits high sensitivity and specificity for β-Gal, efficient liver enrichment, and strong signal contrast in senescent cells and aged mouse liver tissues. When applied to small fragments of clinical human liver samples via simple ex vivo immersion, CyC readily detects β-Gal activity. This platform integrates molecular imaging with visual sensing, offering a practical tool for rapid senescence assessment in aging marginal donor liver evaluation. By enabling immediate, instrument-free visual feedback alongside quantitative imaging, CyC has the potential to streamline intraoperative decision-making, reduce unnecessary graft discard, and ultimately expand the safe use of marginal donor livers in transplantation.
    DOI:  https://doi.org/10.1021/acs.analchem.6c03607
  55. bioRxiv. 2026 Jul 10. pii: 2026.07.08.737008. [Epub ahead of print]
    Dichloroacetate improves animal survival, growth, neuromuscular activity, mitochondrial stress and physiology, and elevated lactate in C. elegans pdha-1 and dld-1 RNAi models of pyruvate dehydrogenase complex deficiency (PDCD).
    Cristina Remes, Neal D Mathew, Victoria Miranda, Suraiya Haroon, Tyler O'Hara, Vernon E Anderson, Manuela Lavorato, Kelsey Keith, Rui Xiao, Eiko Nakamaru-Ogiso, Marni J Falk.
      Pyruvate dehydrogenase complex (PDHc) deficiency (PDCD) is a primary mitochondrial disorder characterized by neurodevelopmental disability, altered intermediary metabolism and early mortality. Dichloroacetate (DCA), a pyruvate analogue, is a well-described PDHc activator that remains under clinical investigation for treatment of PDCD. Here, we studied the in vivo efficacy of a 5-point log concentration range of DCA on animal health and metabolism in C. elegans with feeding RNA interference (RNAi) expression knockdown of either PDHA-1 or DLD-1 homologues at graded degrees to model variable disease severity. These worm models recapitulate phenotypic features of PDCD observed in human patients, including reduced survival, delayed growth, locomotor impairment, and elevated lactate and/or pyruvate tissue levels. DCA treatment appeared well-tolerated, with no gross morphologic toxicity seen at doses up to 25 mM. Significantly improved health, survival, tissue lactate levels, and mitochondrial physiology were observed at 25 mM in pdha-1(RNAi) knockdown animals. DCA treatment in dld-1(RNAi) C. elegans models (undiluted, 1:20 dilution, and 1:100 dilution) showed significant therapeutic benefits on survival, neuromuscular function and metabolic phenotypes primarily in the moderate (1:20) and/or mild (1:100) dld-1(RNAi) deficiency strains, but not in full-dose dld-1(RNAi) . Importantly, linear growth, neuromuscular activity, and mitochondrial physiology were significantly improved with DCA treatment even in the most severe dld-1(RNAi) undiluted model. Overall, preclinical modeling provides objective evidence of DCA therapeutic efficacy in C. elegans expression knockdown strains for two well-conserved homologues of PDHA1 and DLD that represent distinct genetic etiologies of PDHc deficiency, with demonstrated beneficial effects on survival, healthspan, tissue lactate, and mitochondrial physiology. These data further confirm that DCA's therapeutic effect correlates with PDHc disease phenotype severity in dld-1(RNAi) animals. SYNOPSIS: Dichloroacetate (DCA) treatment demonstrated significant preclinical beneficial effect on survival, neuromuscular function, linear growth, tissue lactate, and mitochondrial metabolism in two C. elegans models with variable degrees of pyruvate dehydrogenase complex (PDHc) deficiency (PDCD), providing confirmatory evidence to support its therapeutic potential in human PDCD patients.
    DOI:  https://doi.org/10.64898/2026.07.08.737008
  56. Nat Med. 2026 Jul 15.
    A turning point for gene editing in severe blood disorders.
    Carrie Arnold.
      
    DOI:  https://doi.org/10.1038/d41591-026-00035-1
  57. Res Sq. 2026 Jul 08. pii: rs.3.rs-4356120. [Epub ahead of print]
    Biallelic mutations in SUPV3L1 cause a variable leukodystrophy due to impaired mitochondrial degradosome function.
    Lydia Green, Noémie Hamilton, Marilena Elpidorou, Reza Maroofian, Maha S Zaki, Andrew G L Douglas, Katrin Õunap, Ailsa M S Rose, Erica L Harris, Diogo Candeias, Stone Elworthy, Stephen A Renshaw, Elizabeth C Low, David H Dockrell, Kristian Tveten, Geoffrey Wells, Sarah A Harris, Almundher Al-Maawali, Khalid Al-Thihli, Sana Al-Zuhaibi, Amna Al Futaisi, Daniel Calame, Ivan Chinn, Kristen S Fisher, Mario Sa, Daniel Warren, Mina Zamani, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Tahere Seifi, Erum Afzal, Mark A Tarnopolsky, Lauren Brady, Stephan L Zuchner, Niloofar Chamanrou, Annarita Scardamaglia, Emma Wakeling, Prab Prabhakar, Carla Roca-Bayerri, Gillian I Rice, Clément Prouteau, Céline Bris, Marine Tessarech, Inger Sandvig, Noureddine Hedjem, Aaisha AlBalushi, Dana Marafi, Henry Houlden, Eamonn G Sheridan, Colin A Johnson, John H Livingston, Yanick J Crow, James A Poulter.
      Purpose Sensing and degradation of double stranded RNA (dsRNA) in the cell is tightly regulated to avoid activation of type I interferon signalling. The mitochondrial dsRNA degradosome complex is formed by PNPT1 and SUPV3L1. While biallelic PNPT1 mutations are an established cause of early-onset encephalopathy, the clinical and radiological impact of SUPV3L1 dysfunction is yet to be fully defined. Methods Through an international collaboration, we identified 21 patients with biallelic SUPV3L1 mutations. Available clinical and radiological data were compared. A supv3l1 knock-out zebrafish was generated to investigate the impact of supv3l1 loss in vivo . Results Fifteen different biallelic loss-of-function SUPV3L1 variants were identified in twenty-one individuals presenting with a wide clinical spectrum including neonatal haematological disturbance, infant-onset motor disorder and acute encephalopathy. Most individuals demonstrated significant neurodevelopmental involvement, manifesting as moderate to severe motor delay with intellectual impairment. Other common clinical features include microcephaly and spasticity. Three out of four patients tested showed an increased interferon signature in peripheral blood. A supv3l1 knock-out zebrafish exhibited defective mitochondria morphology and microglial function, with a significant activation of type 1 interferon signalling. Conclusion We define the genetic, clinical and radiological spectrum of SUPV3L1 -asociated disease and suggest activation of the type 1 interferon innate immune pathway by dysplastic microglia as a possible underlying cause.
    DOI:  https://doi.org/10.21203/rs.3.rs-4356120/v2
  58. Nat Metab. 2026 Jul 14.
    Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
    Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.
      Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01572-2
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