bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–11–01
sixty-four papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome.
  2. Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
  3. A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA.
  4. Mitochondrial Dyes with Balanced Permeability-Fixability for Live, Fixed, and Expanded Multicellular Imaging.
  5. Mitochondrial amino acid export preserves mitochondrial volume at the egg-to-embryo transition.
  6. When do mitochondrial processes become instructive during pluripotent-state transitions.
  7. Structural and biochemical characterization of disease-associated mutations in the human mitochondrial processing peptidase α-subunit.
  8. Measurement of Oxygen Consumption Rate of Primary Mouse Skeletal Muscle Stem Cells and Their Progeny on the Seahorse Analyzer.
  9. Intercellular Mitochondria Transfer as a Bioenergetic Rescue Mechanism in CNS Injury: Mechanisms, Therapeutic Potential, and Translational Barriers.
  10. BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?
  11. Mitochondrial NAD+ import gates neuronal resilience to active SARM1.
  12. Random mtDNA mutagenesis maps genotype-phenotype associations across metabolic contexts and lineages.
  13. Mitochondrial acquisition after the Asgard revolution: Reconstructing eukaryogenesis with insights for mitochondrial transplantation.
  14. Dopamine turns mitochondrial stress into inflammation.
  15. Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies.
  16. Animal Model Selection and Deep Phenotyping in Mitochondrial Genetic Diseases: Connecting Human Variants, Multisystem Pathology, and Preclinical Evidence.
  17. Berberine as a Mitochondrial Metabolic Reprogrammer in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Adaptive Energetic Stress, Quality Control, and Translational Limitations.
  18. Hereditary Optic Neuropathy Associated with a Novel MT-RNR1 Mutation: A Case Report.
  19. A Pediatric Case of Homocystinuria Due to MTHFR Deficiency with Early Clinical Features Resembling Leigh Encephalopathy.
  20. Characterization of Large-Scale Mitochondrial DNA Rearrangements Using Complementary Short- and Long-Read Sequencing Approaches.
  21. Flow Cytometry Analysis of Mitochondrial Function in Muscle Stem Cells.
  22. Lactate takes a shortcut into mitochondria to power the heart.
  23. MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
  24. Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
  25. Citrin Deficiency: Biochemical Mechanisms Underlying a Complex Hepatic Metabolic Disorder.
  26. Taking the brakes off a stress response.
  27. Mitochondrial Dysfunction Across the Addiction Cycle: A Stage-Resolved Narrative Review.
  28. Mitochondrial Lactate Signaling and Protein Lactylation in Neurological Diseases.
  29. Mitochondria as the core regulator of cell death: from classical programmed cell death to the novel mitoxyperiosis pathway.
  30. Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons.
  31. Pseudodominant inheritance in paraplegin (SPG7)-associated CPEO-ataxia syndrome.
  32. Donor-Cell Senescence Redirects PINK1-Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3-Stabilized HSPA9.
  33. FaceKit: a Toolkit for Interpretable Facial Phenotyping, Synthetic Image Generation and Privacy Analysis in Rare Diseases.
  34. Mitochondrial Genomic Variation in Rare and Metabolic Diseases: From Heteroplasmy to Precision Medicine.
  35. Photosynthetic chimeric stem cells function as mitochondrial batteries.
  36. Mitochondrial Copper Homeostasis in Diabetic Kidney Disease: Emerging Links Between Metabolic Stress, Respiratory Chain Dysfunction, and Renal Injury.
  37. Biomaterials Targeting Mitochondrial NAD+ Metabolism for Tissue Regeneration.
  38. Visual acuity changes in idebenone treatment‑naïve patients with Leber hereditary optic neuropathy: insights from the CRS-2 study.
  39. Mitochondrial transplantation as a therapeutic strategy: From energy replacement to metabolic and immune reprogramming.
  40. Optimized Dissociation of Skeletal Muscle Tissue to Recover Muscle Stem Cells.
  41. Disrupted valine metabolism and SCPC-mediated neurological toxicity in ECHS1 deficiency.
  42. Snapshots of ATP-driven substrate translocation by the mitochondrial AAA+ protease AFG3L2.
  43. PINK1 and PARKIN Deficiency Increases Neuronal Vulnerability to Autoimmune Neuroinflammation Through Mitochondrial Fragmentation in Aged Mice.
  44. Mitochondrial Remodeling and Impaired Bioenergetics Define Neuronal Vulnerability in Fragile X-Related Disorders.
  45. Mitochondrial dysfunction in diabetic neuropathy: a core pathogenic hub and therapeutic implications.
  46. Beyond Mitochondrial Fission: Emerging Roles of Drp1 in Skeletal Muscle Physiology and Disease.
  47. Paraganglioma and childhood-onset optic atrophy in a SDHA compound heterozygous patient: an example of dual dominant and recessive inheritance.
  48. Exposure to airborne PM2.5 suppresses mitochondrial associated membranes and MAM-associated metabolic regulators in mouse liver.
  49. Mitochondria, Cell Death, and Neurodegeneration.
  50. Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis.
  51. Integrated map of somatic mosaicism across human tissues in 25 individuals.
  52. MitImpact 4: a genome-wide resource for the interpretation of coding and non-coding mitochondrial DNA variants.
  53. Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability.
  54. Stimulated protein degradation to promote mitochondrial function and neuronal survival.
  55. Recombinant human growth hormone exposure preceding multisystem manifestations in a patient with MT-TL1 m.3243 A > G-related mitochondrial disease: a ten-year case report.
  56. Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.
  57. Expanding the genetic spectrum of inherited peripheral neuropathies in complex neurogenetic disorders using whole-exome sequencing.
  58. Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.
  59. Encapsulated mitochondrial transplantation: Advancing organelle therapeutics.
  60. Mitochondrial remodeling with mitochondrial fusion promoter M1 for osteoarthritis therapy.
  61. Mitochondria-Targeted Polymer-Lipid Hybrid Nanoprobes for Imaging of K+ and O2 Dynamics in Living Cells.
  62. Suppressing the SREBP-mediated lipogenic pathway rescues pink1 deficiency in Drosophila and influences mitochondrial morphology.
  63. MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains.
  64. ADP-ribose induces neuronal ferroptosis through ENT2-mediated nucleotide rewiring.
  1. Nat Commun. 2026 09 24. pii: 11098. [Epub ahead of print]17(1):
    Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome.
    Mazen E Aljghami, Trevor M Morey, Mark F Mabanglo, Jonathan J Meyrick, Huw B Thomas, Jiacheng Yu, Arveen Tahmasebi, King Lam Lai, Benjamin Bernard Armando Raymond, Matthias Trost, Robert W Taylor, Raymond T O'Keefe, William G Newman, Uwe Richter, Walid A Houry.
      The ClpXP ATP-dependent unfoldase-protease complex plays important roles in maintaining protein homeostasis in the mitochondria. Pathogenic variants of CLPP have been identified in patients with Perrault syndrome type 3 (PRLTS3), a rare recessive mitochondrial disease characterized by sensorineural hearing loss, ovarian dysfunction, and neurological abnormalities. However, it remains unclear how these ClpP variants cause this disease. Here we identify three cellular substrates of ClpXP using proteomic analysis of PRLTS3 patient-derived fibroblasts, with follow up studies using induced pluripotent stem cells (iPSCs) and iPSC-derived neural progenitor cells, alongside in vitro biochemical assays. These substrates are: CHCHD2, a bi-organellar regulator of oxidative phosphorylation and mitochondrial stress responses; ALAS1, which catalyzes the rate-limiting step in heme biosynthesis; and TFAM, an essential mitochondrial transcription factor. Efficient degradation of these substrates by ClpXP requires the adaptor protein PDIP38. We propose that dysregulated cellular levels of these substrates might contribute to the etiology of PRLTS3.
    DOI:  https://doi.org/10.1038/s41467-026-77888-0
  2. Sci Adv. 2026 Oct 30. 12(44): eaeg5364
    Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
    John Soukar, Kayli Jones, Natalie M Garza, Valeria Duran Salas, Shounak Roy, Vishal M Gohil, Akhilesh K Gaharwar.
      Cells exhibit innate reparative communication, enabling the exchange of bioactive molecules and, in some cases, entire organelles. Harnessing this endogenous process of intercellular organelle transfer represents an emerging therapeutic paradigm for restoring cellular function in diseases driven by organelle dysfunction. Mitochondrial transfer has gained prominence for its ability to restore bioenergetic capacity, mitigate oxidative stress, and rescue metabolic function in cells with impaired mitochondrial activity. Given that genetic or acquired defects in mitochondrial function are associated with diverse pathologies, including neurodegeneration, cardiovascular diseases, metabolic disorders, skeletal muscle defects, immune dysregulation, and age-associated decline, mitochondrial transfer offers broad therapeutic potential. Mitochondrial transfer seeks to deliver functional mitochondria to injured cells to reestablish metabolic competence. However, insufficient organelle trafficking and limited control over transfer dynamics remain critical barriers to clinical translation. Recent biotechnological developments aimed at enhancing donor-recipient connectivity, increasing mitochondrial availability, and modulating transfer machinery have begun to address some of these key challenges. This review highlights recent advances in mitochondrial transfer bioengineering, emerging therapeutic applications, and key challenges that must be resolved to enable clinical deployment.
    DOI:  https://doi.org/10.1126/sciadv.aeg5364
  3. Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01073-9. [Epub ahead of print]45(11): 117995
    A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA.
    Diego Perez-Rodriguez, Ilaria Dalla Rosa, Anastasia Magoulopoulou, Sara Ricciardi, Samantha Davidson, Rebecca Lasalandra, Renata Kabiljo, Aine Moylett, Tamara Hill, Tengfei Wan, Aleck W E Jones, Chloe F Moss, Charlotte Zierz, Melissa L Salazar, Radha Desai, Shar-Yin N Huang, Yves Pommier, Monika Hofer, Robert D S Pitceathly, Martin A M Reijns, Joanna Poulton, Christos Proukakis, J Paul Simons, Mats Nilsson, Robert W Taylor, Ian J Holt, Antonella Spinazzola.
      Mitochondrial DNA (mtDNA) depletion and multiple deletions frequently coexist in mitochondrial disease, neurodegeneration, and aging, yet how the two relate and why deletions accumulate focally remain unresolved. Here, longitudinal bulk and in situ analyses of Mpv17-/- murine muscle reveal that a compensatory rise in mitochondrial transcripts per mtDNA initially offsets severe, uniform mtDNA depletion, preserving the respiratory chain. However, this response carries a delayed cost: by six months transcripts decline, mtDNA deletions emerge, and respiratory-deficient fibers appear. Paradoxically, fibers harboring deletions accumulate supra-physiological amounts of mtDNA, despite prior depletion. This expansion is invariably accompanied by elevated Hsp60, and the same holds in human mitochondrial myopathy. We propose that depletion reprograms mitochondrial DNA and RNA metabolism, inadvertently promoting deletion formation and creating an Hsp60-high fiber state permissive for clonal expansion. Therefore, depletion and multiple deletions can be sequential phases of a common degenerative process, relevant also to aging and neurodegeneration.
    Keywords:  CP: molecular biology; Hsp60; clonal expansion; mTORC1; mitochondrial DNA; mitochondrial DNA deletions; mitochondrial DNA depletion; mitochondrial myopathy; nanopore sequencing of mitochondrial DNA; single-fiber analysis; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117995
  4. J Am Chem Soc. 2026 Sep 23. 148(37): 40556-40567
    Mitochondrial Dyes with Balanced Permeability-Fixability for Live, Fixed, and Expanded Multicellular Imaging.
    Jingting Chen, Yue Ma, Peng Chen, Biaoyi Yu, Ying Yu, Zhenzhen Zhang, Xiaomin Zhang, Buqing Ye, Jianzhong Jeff Xi, Xiaohong Peng, Zhixing Chen.
      Mitochondrial inner-membrane ultrastructure plays a central role in cellular metabolism, aging, and cell death. However, super-resolution imaging of mitochondria after fixation remains challenging: commercially available fixable probes often lack sufficient reactivity for strong retention during fixation, whereas state-of-the-art probe PKMO FX, despite high fixation efficiency, suffers from low cellular permeability due to the introduction of highly hydrophilic groups. Here, we overcome this "permeability-fixability trade-off" by introducing a rational design strategy centered on amide-to-ester substitution. We report mitochondrial probes, PK Mito 590 FIX and PK Mito 647 FIX, which leverage optimized lipophilic ester linkages to achieve rapid mitochondrial labeling kinetics (labeling within 10 min) and superior aldehyde cross-linking efficiency (>90% signal retention). This molecular engineering enables a seamless transition from live-cell dynamics to post-fixation super-resolution microscopy with unprecedented signal-to-background ratios. Crucially, the enhanced permeability of these probes unlocks post-fixation imaging of multicellular samples, allowing the visualization of mitochondrial architectures within patient-derived cell clusters and isolated mouse islets. Furthermore, we demonstrate that these probes withstand the harsh polymerization conditions of expansion microscopy (ExM), democratizing mitochondrial ultrastructural imaging via standard confocal platforms. Collectively, this toolkit bridges the gap between physiological dynamics and structural definition, offering a versatile platform for multiscale interrogation of mitochondrial biology in both adherent cells and complex multicellular systems.
    DOI:  https://doi.org/10.1021/jacs.6c16881
  5. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757432. [Epub ahead of print]
    Mitochondrial amino acid export preserves mitochondrial volume at the egg-to-embryo transition.
    Melissa C Pamula, Lauren Clamon, Samuel Block, Suzanne Savage, Christoph Gaebelein, Ashid Amarsanaa, Margaret E Bisher, David Mankus, Abigail Kr Lytton-Jean, Nora Kory, Ruth Lehmann.
      In animals, the transition from egg to embryo marks a rapid shift in cellular physiology, yet how mitochondria adapt to support this conversion remains poorly understood. We performed a targeted RNAi screen of conserved, nuclear-encoded mitochondrial proteins in Drosophila melanogaster to identify maternal effects. We identified distinct phenotypic classes affecting mitochondrial distribution or morphology in early embryos. We focused on Sideroflexin-1/3 (Sfxn1-3), a conserved mitochondrial inner membrane transporter, because it uniquely affects embryonic mitochondrial morphology. Maternal loss of Sfxn1-3 causes striking mitochondrial enlargement in embryos but not in oocytes, placing the trigger at the egg-to-embryo transition. Combining mitochondrial immunopurification with LC/MS-based metabolomic profiling, we show that amino acids are markedly enriched in Sfxn1-3-deficient mitochondria in both oocytes and embryos. This accumulation developmentally uncouples the metabolic and morphological phenotypes. By selectively disrupting discrete steps of egg activation, including translational activation, cell cycle re-entry, and fertilization, we demonstrate that mitochondrial swelling is independent of each, prompted instead by egg hydration. Beyond its reported role in proliferating cells as a serine importer, our data support a role for germline Sfxn1-3 in regulating inner mitochondrial membrane permeability to osmotically active amino acids. This activity is crucial for preserving organelle volume during the osmotic challenge of oocyte hydration. When this export fails, amino acid accumulation amplifies osmotic stress and drives rapid mitochondrial swelling. Together, these findings identify mitochondrial inner membrane permeability to amino acids as a key regulatory step that couples pre-established metabolite compartmentalization to osmotic adaptation at egg activation, and reveal how mitochondrial metabolic integrity and volume control are coordinated at this critical developmental transition.
    DOI:  https://doi.org/10.64898/2026.10.08.757432
  6. Med Rev (2021). 2026 Oct;6(5): 444-448
    When do mitochondrial processes become instructive during pluripotent-state transitions.
    Miao He, Xiaoshuai Huang.
      Pluripotent-state transitions are accompanied by coordinated changes in mitochondrial architecture, signaling, metabolism, and turnover, yet whether these changes drive, follow, or reciprocally interact with cell-state transitions remains incompletely resolved. Here, we evaluate evidence across three mitochondrial routes: architecture and positioning, mitochondria-to-nucleus communication, and mitochondrial quality control. Direct perturbation and rescue studies show that selected mitochondrial processes can promote or restrain pluripotency acquisition and transitions between pluripotent states. However, their effects depend on transition identity and phase, perturbation timing, duration and magnitude, species, and culture context. We therefore propose that mitochondrial processes should be considered instructive only when they bias a defined pluripotent-state transition through a state-relevant mechanism rather than simply altering cellular fitness or state stability.
    Keywords:  epigenetic regulation; mitochondria; mitochondrial retrograde signaling; mitophagy; pluripotent-state transitions; somatic cell reprogramming
    DOI:  https://doi.org/10.1515/mr-2026-0047
  7. J Struct Biol. 2026 Oct 26. pii: S1047-8477(26)00100-0. [Epub ahead of print]218(4): 108384
    Structural and biochemical characterization of disease-associated mutations in the human mitochondrial processing peptidase α-subunit.
    Danielle M Simons, Sibei Qin, Kim Munro, Lindsay A Matthews, Christopher J Thibodeaux, Jean-François Trempe.
      The mitochondrial processing peptidase (MPP) is an essential heterodimeric protease responsible for cleavage of N-terminal mitochondrial targeting sequences (N-MTSs) from most nuclear-encoded mitochondrial proteins following import into the mitochondrial matrix. Pathogenic variants in the α-subunit of MPP (PMPCA) cause a spectrum of mitochondrial disorders, including spinocerebellar ataxia type 2 (SCAR2), encephalopathy, and severe neurodevelopmental disease; however, the molecular mechanisms underlying these phenotypes remain poorly understood. Here, we combined biochemical and structural approaches to characterize five disease-associated PMPCA variants (S96L, R185W, R268W, A377T, and G515R). Enzymatic analyses revealed variant-specific defects in substrate processing, with most mutations severely impairing cleavage of the rapidly processed substrate malate dehydrogenase 2. In contrast, several variants exhibited only modest impairment in the processing of the slowly cleaved substrate PINK1. Mass photometry demonstrated reduced heterodimerization of all variants, whereas circular dichroism identified varying degrees of structural destabilization, particularly for S96L and G515R. To define the structural basis of these defects, hydrogen-deuterium exchange mass spectrometry was performed on wild type MPP and selected variants. Pathogenic mutations altered substrate-induced conformational changes within previously characterized substrate-recognition elements, including the glycine-rich loop. Furthermore, we identified a previously unrecognized region, termed the INS loop, that exhibited substrate-dependent protection uniquely in the wild type enzyme but was consistently disrupted across pathogenic variants. Together, these findings demonstrate that PMPCA mutations impair MPP function through diverse mechanisms involving protein stability, dimerization, substrate selectivity, and allosteric conformational dynamics. Our work provides a mechanistic framework for understanding genotype-phenotype relationships in PMPCA-associated disease.
    Keywords:  Hydrogen‑deuterium exchange mass spectrometry; MPP; Mitochondria; PMPCA; Peptidase; SCAR2
    DOI:  https://doi.org/10.1016/j.jsb.2026.108384
  8. Methods Mol Biol. 2027 ;3093 185-194
    Measurement of Oxygen Consumption Rate of Primary Mouse Skeletal Muscle Stem Cells and Their Progeny on the Seahorse Analyzer.
    Audrey Saugues, Lucie Ancel, Ha My Ly, Lola E R Lessard, Rémi Mounier, Anita Kneppers.
      To establish mature myofibers with a complex mitochondrial network, skeletal muscle stem cells (MuSCs) need to undergo large metabolic alterations. This goes beyond an increase in mitochondrial abundance during myogenesis and includes mitochondrial morphological adaptations by fusion and fission. Recent insights into the epigenetic, transcriptomic, and cell signaling alterations supported by mitochondrially generated intermediates and end products demonstrate how mitochondrial metabolism dictates MuSC behavior. The measurement of mitochondrial oxidative phosphorylation (OXPHOS), as an indicator of mitochondrial function under stressed states, therefore gives crucial insight into metabolic alterations that drive MuSC function. In this chapter, we describe the measurement of the oxygen consumption rate of primary mouse skeletal muscle stem cells and their progeny on the Seahorse analyzer.
    Keywords:  Cellular respiration; Metabolism; Muscle stem cells; Myotubes; Oxygen consumption rate; Seahorse technology; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-5643-3_14
  9. Mol Neurobiol. 2026 Oct 30. pii: 1003. [Epub ahead of print]63(1):
    Intercellular Mitochondria Transfer as a Bioenergetic Rescue Mechanism in CNS Injury: Mechanisms, Therapeutic Potential, and Translational Barriers.
    Afra Wasama Islam, Swapna Bejoy, Prarthana Motdhare, Afrah Riyas, Chris Puthenpurayil Abraham, Mehadiya Afreen Hussain.
      Acute central nervous system (CNS) injuries, including ischemic stroke, traumatic brain injury, and spinal cord injury, are characterized by profound mitochondrial dysfunction that drives secondary neuronal damage through ATP depletion, oxidative stress, and calcium dysregulation. Neuronal survival is critically dependent on mitochondrial integrity, making bioenergetic failure a central determinant of injury progression. In this context, intercellular mitochondria transfer has emerged as a potential adaptive mechanism through which functional mitochondria are delivered from donor cells-primarily astrocytes, microglia, and mesenchymal stem cells-to metabolically compromised neurons. Mitochondria transfer occurs via both contact-dependent pathways, such as tunneling nanotubes, and contact-independent mechanisms, including extracellular vesicles and free mitochondrial release. These processes are regulated by signaling pathways such as CD38/cADPR-mediated calcium flux and MIRO1-dependent mitochondrial trafficking, facilitating organelle mobilization and uptake. Functionally, transferred mitochondria have been associated with improved oxidative phosphorylation, reduced reactive oxygen species accumulation, altered calcium homeostasis, and modulation of survival pathways including PI3K/Akt and MAPK/ERK signaling in selected experimental models; however, the extent to which these effects are directly dependent on mitochondria transfer remains incompletely established. Preclinical evidence across multiple CNS injury models demonstrates improved neuronal viability, enhanced synaptic function, and attenuation of neurodegenerative processes following mitochondria transfer. However, whether mitochondria transfer represents a primary driver of neurorepair or a secondary compensatory response remains unresolved. In addition, inconsistencies in mechanistic pathways, variability in transfer efficiency, and limited reproducibility across experimental systems hinder translational interpretation. Therapeutic approaches including exogenous mitochondria transplantation, stem cell-mediated delivery, and bioengineered mitochondrial systems show promise but face substantial barriers related to targeting specificity, mitochondrial viability, immunogenicity, and lack of standardized protocols. This review critically evaluates the molecular mechanisms, functional consequences, and therapeutic potential of intercellular mitochondria transfer in CNS injury. It further highlights key limitations and knowledge gaps that must be addressed to determine whether mitochondria transfer can be effectively harnessed as a clinically viable strategy for neuro-restoration.
    Keywords:  Central nervous system injury; Intercellular mitochondria transfer; Mitochondrial dysfunction; Neuronal bioenergetics; Neuroprotection
    DOI:  https://doi.org/10.1007/s12035-026-06303-y
  10. Cells. 2026 Oct 10. pii: 1839. [Epub ahead of print]15(20):
    BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?
    Naibo Zhang, Daniel D Freeman, Brian M Polster.
      Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.
    Keywords:  MDV; MLKL; NLRP3; STING; apoptosis; cGAS; inflammasome; mPTP; mitophagy; mtDNA
    DOI:  https://doi.org/10.3390/cells15201839
  11. bioRxiv. 2026 Oct 11. pii: 2026.10.05.756890. [Epub ahead of print]
    Mitochondrial NAD+ import gates neuronal resilience to active SARM1.
    Lilianne Barbar, Anushka Bhat, Si Jia Chen, Amy Strickland, Sarah V Schurr, Shea Sundali, Hayoung Kim, Yo Sasaki, A Joseph Bloom, Jeffrey Milbrandt, Aaron DiAntonio.
      SARM1 is an inducible NADase that executes pathological axon degeneration, but how NAD+ destruction causes neuronal failure remains unclear. Because SARM1 is predicted to act outside the mitochondrial matrix, cytosolic NAD+ loss has been viewed as the critical lethal lesion. We show that SARM1 activation rapidly depletes cytosolic and mitochondrial NAD+ and collapses ATP in both compartments, revealing early, coupled metabolic failure. Enhancing mitochondrial NAD+ import through SLC25A51, the mitochondrial NAD+ transporter, preserves mitochondrial NAD+, maintains mitochondrial function, and delays axon degeneration and neuronal death despite ongoing SARM1 activity. Unexpectedly, SLC25A51 restores cytosolic NAD+-dependent metabolism, reversing a glycolytic block and increasing NAD+ synthesis during stress. Glycolytic inhibition attenuates protection, identifying cytosolic metabolic recovery as an important component of neuronal resilience. AAV-SLC25A51 improves function in a chronic SARM1-dependent neuropathy model. Thus, mitochondrial NAD+ import gates SARM1-driven degeneration by limiting coupled mitochondrial-cytosolic metabolic failure, presenting a downstream intervention point for axon preservation.
    DOI:  https://doi.org/10.64898/2026.10.05.756890
  12. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757705. [Epub ahead of print]
    Random mtDNA mutagenesis maps genotype-phenotype associations across metabolic contexts and lineages.
    Amir Giladi, Ron Baik, Chih-Yao Chung, Minsoo Kim, Josephine Adams, Rahul Saha, Max Land, Ruobing Cui, Emily DeBitetto, Megan E Kelley, Craig B Thompson, Ed Reznik, Roshan Sharma, Ronan Challinge, R Stefan Isaac, Josi Peterson, Alexander van Oudenaarden, Agnel Sfeir.
      Mitochondrial DNA (mtDNA) mutations cause inherited disease, accumulate with age, and recur in tumors, yet their effects remain unresolved because existing models interrogate one engineered allele at a time. We developed mtDIVE, a random C→T mutagenesis platform for pooled mitochondrial forward genetics in human epithelial cells and zebrafish embryos. mtDIVE generates genotypes ranging from single substitutions to >100 mutations per molecule, impairs respiration, and causes lineage-specific developmental delay. Coupling single-cell transcriptomics with mtDNA genotyping revealed that selection on mutant genomes and their transcriptional consequences depend on metabolic state and developmental lineage. Obligate OXPHOS eliminates highly mutated cells by apoptosis, whereas glycolytic conditions promote their competitive displacement. Individual loci exert modest but non-redundant effects that predict cell state beyond aggregate mutation burden, and cancer-recurrent variants are enriched among mutations linked to reduced mitochondrial transcription. Thus, mtDIVE links mtDNA genotypes to cellular phenotypes, separating the consequences of mutation identity from mutational load.
    DOI:  https://doi.org/10.64898/2026.10.08.757705
  13. Exp Gerontol. 2026 Oct 29. pii: S0531-5565(26)00352-9. [Epub ahead of print] 113372
    Mitochondrial acquisition after the Asgard revolution: Reconstructing eukaryogenesis with insights for mitochondrial transplantation.
    Yuan-Yuan Li, Kevin B Frazier, Franklin R Tay.
      Mitochondria arose from an alphaproteobacterial endosymbiont that became integrated within an archaeal host during eukaryogenesis. The discovery of Asgard archaea has clarified host ancestry and supports reconstructions in which aspects of cytoskeletal and membrane complexity preceded mitochondrial acquisition. Organellogenesis involved genome reduction, gene transfer, protein import, metabolic coupling, and vertical inheritance. These evolutionary principles complement current mitochondrial transplantation recommendations by generating testable predictions about recipient dependence and the duration of rescue. Transplanted mitochondria are mature organelles introduced into cells already equipped to maintain mitochondria; the requirement for transient or durable function must nevertheless be tested for each indication. Aging can modify organelle delivery, recipient quality control, and tissue responses, with particular implications for the neurovascular unit and neuronal function. Extracellular vesicle delivery requires verification of mitochondrial cargo, potency, and compatibility. Measurable criteria distinguish delivery, uptake, cytosolic access, network interaction, persistence, and functional benefit, while separating evidence from aging, acute ischemia, and inherited disease models.
    Keywords:  Asgard archaea; Endosymbiosis; Eukaryogenesis; Horizontal mitochondrial transfer; Mitochondrial transplantation; Organellogenesis
    DOI:  https://doi.org/10.1016/j.exger.2026.113372
  14. Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01217-9. [Epub ahead of print]45(11): 118138
    Dopamine turns mitochondrial stress into inflammation.
    Rodrigo Pacheco.
      Daniali et al. show that dopamine drives mitochondrial stress, mtDNA release, and cGAS-STING-dependent IL-6 production in human macrophages. These findings suggest a mechanism linking dopaminergic signaling to mtDNA damage signatures increasingly detected in blood from patients with Parkinson's disease.
    DOI:  https://doi.org/10.1016/j.celrep.2026.118138
  15. Biochim Biophys Acta Mol Cell Res. 2026 Oct 24. pii: S0167-4889(26)00140-0. [Epub ahead of print] 120241
    Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies.
    Maria Falkenberg, Claes M Gustafsson.
      Replication of the mitochondrial genome is essential to sustain cellular energy conversion, and defects in this process cause severe, progressive mitochondrial diseases that have long lacked curative treatment. This is now beginning to change: mechanistic insight into the replication machinery has started to translate into therapy, with the first disease-modifying treatment recently approved and others entering clinical evaluation. Here we review the molecular mechanisms of mitochondrial DNA replication, with emphasis on replication initiation, deletion formation, and replication completion, and discuss how insights into these processes are opening new therapeutic possibilities for treating mitochondrial disease.
    Keywords:  DNA replication; Deletion formation; Mitochondrial disease; POLG; Treatment
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120241
  16. Genes (Basel). 2026 Sep 22. pii: 1165. [Epub ahead of print]17(10):
    Animal Model Selection and Deep Phenotyping in Mitochondrial Genetic Diseases: Connecting Human Variants, Multisystem Pathology, and Preclinical Evidence.
    Nobuya Sasaki, Masaki Watanabe.
      Mitochondrial genetic diseases arise from variants in mitochondrial DNA (mtDNA) or nuclear genes required for mitochondrial function. Although many involve several organs, the predominant clinical manifestations may be confined to particular organs. Experimental models are used to investigate variant pathogenicity, organ vulnerability, disease progression, therapeutic response, and safety. We discuss how to select animal models and other experimental systems for specific research questions. We focus on genetically engineered mice (constitutive knockout, knock-in/humanized, conditional/tissue-specific, inducible, and heteroplasmic mtDNA models) and consider when yeast, worms, flies, zebrafish, rats, large animals, companion animals, and human in vitro models can complement or replace particular animal experiments. We define deep phenotyping by five minimum characteristics: longitudinal assessment across defined disease stages; prespecified relationships among molecular, mitochondrial, organ, and whole-animal measurements; integration of repeated and terminal endpoints; alignment with patient-relevant disease stages; and separation of primary from exploratory outcomes. Model selection depends on the experimental objective and the evidence needed to address it. We also propose a multidomain framework that distinguishes target engagement, molecular correction, downstream pharmacodynamic responses, organ function, and whole-animal or patient-relevant benefit without assuming that effective treatments must improve every domain sequentially. We also discuss reporting practices, the 3Rs (Replacement, Reduction, and Refinement), and the implications of mtDNA editing, iPSC-derived systems, organoids, and automated phenotyping for study design.
    Keywords:  3Rs; animal model; deep phenotyping; heteroplasmy; mitochondrial disease; mouse model; mtDNA editing; preclinical research; reproducibility; translational research
    DOI:  https://doi.org/10.3390/genes17101165
  17. Nutrients. 2026 Oct 14. pii: 3366. [Epub ahead of print]18(20):
    Berberine as a Mitochondrial Metabolic Reprogrammer in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Adaptive Energetic Stress, Quality Control, and Translational Limitations.
    Hossein Rafiei, Kosar Omidian, Miguel Tolentino, Ali Jafari, Hossein Bahari, Mousa Khalafi.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to mitochondrial dysfunction, including altered oxidative phosphorylation, disrupted fatty-acid oxidation, redox imbalance, abnormal mitochondrial dynamics, and impaired quality control. Berberine (BBR), a plant-derived isoquinoline alkaloid used as a nutraceutical, has been described both as a partial inhibitor of respiratory-chain complex I and as an intervention that improves mitochondrial function. This narrative review critically synthesizes evidence from hepatoma cells, primary hepatocytes, animal models, and human studies to reconcile these divergent effects. The preclinical literature supports a proposed, context-dependent model in which BBR imposes an energetic constraint during nutrient overload while activating AMP-activated protein kinase- and sirtuin-linked pathways that remodel substrate handling, respiration, redox balance, mitochondrial architecture, and autophagy. The strongest mechanistic evidence supports complex I-associated respiratory remodeling, SIRT3-mediated deacetylation of long-chain acyl-CoA dehydrogenase, SIRT1-mediated stabilization of carnitine palmitoyltransferase 1A, and SIRT1-dependent autophagy. Evidence for consistent mitochondrial biogenesis, selective mitophagy, mitochondria-endoplasmic reticulum contact-site remodeling, mitochondrial DNA danger signaling, and ferroptosis regulation in MASLD remains limited. Human evidence is mixed: a recent placebo-controlled trial found no significant reduction in liver fat with pure BBR, and no included trial directly measured hepatic mitochondrial function or established a mitochondria-mediated clinical effect. Therefore, BBR is best viewed as a context-dependent modulator of hepatic mitochondrial metabolism rather than a uniform mitochondrial enhancer. Pure BBR should not be conflated with whole barberry fruit, uncharacterized botanical preparations, or berberine ursodeoxycholate (HTD1801). Translation requires characterized formulations, exposure-matched models, and direct mitochondria-focused endpoints.
    Keywords:  berberine; metabolic dysfunction-associated steatotic liver disease; mitochondrial function; mitochondrial quality control; nonalcoholic fatty liver disease; oxidative phosphorylation; oxidative stress; sirtuins
    DOI:  https://doi.org/10.3390/nu18203366
  18. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 1031-1037
    Hereditary Optic Neuropathy Associated with a Novel MT-RNR1 Mutation: A Case Report.
    Asma Bilgasem, Haoran Charles Li, Jonathan A Micieli.
       Introduction: Hereditary optic neuropathies are mitochondrial disorders characterized by retinal ganglion cell degeneration and optic nerve dysfunction. Variants in MT-RNR1, a gene classically associated with aminoglycoside-induced and nonsyndromic sensorineural hearing loss, are increasingly recognized in hereditary optic neuropathy. We report the first case of hereditary optic neuropathy associated with the novel MT-RNR1 m.960delC variant, expanding the known genetic spectrum of this emerging mitochondrial optic neuropathy phenotype.
    Case Presentation: A 61-year-old woman presented with bilateral optic neuropathy characterized by optic disc pallor out of proportion to cupping, diffuse retinal nerve fiber layer and ganglion cell layer thinning, and bilateral visual field abnormalities. Best-corrected visual acuity was 20/30 in the right eye and 20/20 in the left eye, with intraocular pressures within the normal range. Gonioscopy demonstrated open angles bilaterally. Visual field testing demonstrated nonglaucomatous defects, and laboratory investigations were unremarkable. MRI of the orbits and brain with gadolinium was normal. Mitochondrial genetic testing identified the novel MT-RNR1 m.960delC variant at 87.2% heteroplasmy. The overall phenotype was consistent with hereditary optic neuropathy associated with mitochondrial dysfunction.
    Conclusion: This case expands the spectrum of MT-RNR1-associated hereditary optic neuropathy through identification of the novel m.960delC variant. The proximity of m.960delC to the previously reported m.956delC variant raises the possibility of a functionally important region within MT-RNR1. These findings further support MT-RNR1 as an emerging candidate gene in hereditary optic neuropathy, with important implications for genetic testing and disease recognition.
    Keywords:  Case report; Hereditary optic neuropathy; MT-RNR1; m960delC
    DOI:  https://doi.org/10.1159/cop/acaag016
  19. Children (Basel). 2026 Sep 30. pii: 1332. [Epub ahead of print]13(10):
    A Pediatric Case of Homocystinuria Due to MTHFR Deficiency with Early Clinical Features Resembling Leigh Encephalopathy.
    Tatsunori Itabashi, Jiro Abe, Midori Nakajima, Yuki Ueda, Kiyoshi Egawa, Masayoshi Nagao, Atsuhito Takeda.
      Background: Leigh encephalopathy is one of the most common phenotypes of mitochondrial diseases. It is characterized by progressive psychomotor regression, accompanied by elevated lactate/pyruvate ratios in blood and cerebrospinal fluid (CSF) and lactate on MRS, and symmetric lesions in the bilateral basal ganglia on brain MRI. A clinical diagnosis is made based on these findings and is confirmed by demonstrating mitochondrial dysfunction through genetic or enzymatic testing. However, some patients who present with clinical features of Leigh encephalopathy actually develop secondary mitochondrial dysfunction due to inborn errors of metabolism, thereby exhibiting a Leigh syndrome phenotype. Case Presentation: The patient was born at term without perinatal complications. Poor feeding was noted from two months of age, and microcephaly and hypotonia were identified at the 4-month health checkup. At 5 months, the patient was admitted for further evaluation. CSF analysis revealed an elevated lactate-to-pyruvate ratio of 21. Brain MRI demonstrated symmetrical T2-weighted hyperintensities in the bilateral basal ganglia, and MR spectroscopy detected a lactate peak in the same region. Based on clinical findings, CSF results, and MRI features, Leigh encephalopathy was suspected. At 9 months, mitochondrial DNA sequencing of skeletal muscle showed no significant mutations, and skeletal muscle biopsy revealed no findings suggestive of neuromuscular disease. At 7 years of age, two weeks after contracting COVID-19, the patient was admitted to the hospital with acute metabolic decompensation characterized by acidosis and complicated by a small intraventricular hemorrhage. Tandem mass spectrometry performed during the episode suggested homocystinuria due to MTHFR deficiency. Subsequent trio-based genetic testing revealed compound heterozygous variants in MTHFR. Measurement of MTHFR enzyme activity revealed a profound reduction, confirming the diagnosis of homocystinuria due to MTHFR deficiency. After initiation of specific metabolic therapy, including betaine, both urinary and plasma homocysteine levels decreased, and clinical symptoms improved. Conclusions: Homocystinuria due to MTHFR deficiency may cause secondary mitochondrial dysfunction, leading to a Leigh syndrome phenotype. When Leigh encephalopathy is suspected, metabolic screening should be performed to avoid missing potentially treatable diseases.
    Keywords:  Leigh encephalopathy; Leigh syndrome spectrum; homocystinuria due to MTHFR deficiency; methylenetetrahydrofolate reductase (MTHFR)
    DOI:  https://doi.org/10.3390/children13101332
  20. Genes (Basel). 2026 Sep 22. pii: 1161. [Epub ahead of print]17(10):
    Characterization of Large-Scale Mitochondrial DNA Rearrangements Using Complementary Short- and Long-Read Sequencing Approaches.
    Jing Wang, Joe Chan, Mian Umair Ahsan, Amy Goldstein, Rebecca D Ganetzky, Sonal Sharma, James T Peterson, Douglas C Wallace, Tanaya Jadhav, Ramakrishnan Rajagopalan, Kai Wang.
       BACKGROUND: Large-scale mitochondrial DNA (mtDNA) rearrangement, including deletion or duplication, is one of the important causes of primary mitochondrial disease. In clinical practice, short-read sequencing (SRS)-based assays typically detect these rearrangements by identifying regional mtDNA copy-number changes but generally do not directly distinguish deletions from duplications. As a result, mtDNA duplications may be misclassified as deletions, potentially leading to inaccurate molecular diagnoses and genotype-phenotype correlations. This study aimed to evaluate the utility of long-read sequencing (LRS) for the definitive characterization of large-scale mtDNA rearrangements.
    METHODS: Two individuals who had been reported to possess single large-scale mtDNA deletions using SRS-based clinical tests were re-evaluated because their clinical presentations were not consistent with typical mtDNA deletion syndromes. Existing SRS data were reanalyzed, and the suspected rearrangements were independently characterized using both Pacific Biosciences (PacBio) and Oxford Nanopore Technologies long-read sequencing platforms.
    RESULTS: Reanalysis of SRS data suggested that the reported deletions were more consistent with mtDNA duplications. This finding was confirmed by both PacBio and Oxford Nanopore LRS in one case. Reclassifying the deletion to a duplication in this case substantially improved genotype-phenotype interpretation and better explained the atypical clinical features observed in this individual. However, LRS could not capture sufficient long reads that give direct evidence of duplication in the second case due to low heteroplasmy of the mtDNA structural variant. Therefore, this case remains inconclusive.
    CONCLUSIONS: SRS and LRS provide complementary information for the evaluation of large-scale mtDNA rearrangements. SRS can sensitively identify mtDNA large deletions, but it cannot distinguish mtDNA deletion from duplication. On the other hand, LRS can provide direct structural information and confirm duplication. However, LRS may have limited sensitivity for low-level heteroplasmic structural variants. An integrated approach incorporating both methods, together with clinical correlation and reanalysis of potentially discordant findings, may improve the characterization and interpretation of mtDNA rearrangements.
    Keywords:  Illumina short-read sequencing; Oxford Nanopore Technologies long-read sequencing; PacBio long-read sequencing; mitochondrial DNA (mtDNA); mtDNA deletions and duplications
    DOI:  https://doi.org/10.3390/genes17101161
  21. Methods Mol Biol. 2027 ;3093 167-184
    Flow Cytometry Analysis of Mitochondrial Function in Muscle Stem Cells.
    Lucia Acampora, Melania Murolo, Shahragim Tajbakhsh, Barbara Gayraud-Morel.
      Mitochondrial metabolism plays a central role in regulating muscle stem cell (MuSC) quiescence, activation, and differentiation, with dynamic metabolic transitions accompanying changes in cell fate and function. Flow cytometry-based analysis of mitochondrial function provides a rapid and accessible approach to characterize metabolic states at the single-cell level. Here, we present a detailed protocol to analyze mitochondrial activity, particularly by assessing mitochondrial membrane potential and mitochondrial mass in freshly isolated MuSCs and myoblasts using the fluorescent dyes TMRE and MitoTracker Deep Red in cytometry. This method is compatible with antibody-based identification of MuSCs and includes controls using mitochondrial uncouplers to validate ΔΨm-dependent staining. This protocol enables reliable discrimination between quiescent, activated, and differentiating muscle cells and can be applied to study physiological and pathological conditions in different contexts, including injury, aging, and diseases.
    Keywords:  Flow cytometry; Metabolism; MitoTracker; Mitochondria; Satellite cells; Skeletal muscle; Stem cells; TMRE
    DOI:  https://doi.org/10.1007/978-1-0716-5643-3_13
  22. Nature. 2026 Oct 28.
    Lactate takes a shortcut into mitochondria to power the heart.
    Trace Thome, Zolt Arany.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-03261-2
  23. Nature. 2026 Oct 28.
    MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
    Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, James Carrington, Luis Cedeño-Rosario, Giulia C Napoli, Ji Eon Kim, Thirupura S Shankar, Marisa J Brothwell, Rana Hamouche, Álvaro J Narbona-Pérez, Jing Ling, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, David R Eberhardt, Jing Li, Claire E Stanley, Queren A Alcantara, Tarun Yadav, Ryan L Maves, Wojciech I Swiatek, Nicholas A Offei, Bhavya Blaze, Sumangala P Shetty, Dipayan Chaudhuri, Tingting Hong, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Eleni Tseliou, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.
      The heart possesses a dynamic capacity to oxidize a variety of fuels, including glucose and lactate, to meet its energetic demands under diverse dietary, exertion and injury stressors1. Oxidation of carbohydrate substrates is thought to converge on the cytosolic generation of pyruvate, which is transported by the mitochondrial pyruvate carrier (MPC) for entry into the tricarboxylic acid cycle2. Here we find that glucose-derived carbon is oxidized in mouse myocardium even when the MPC is genetically ablated. Using genetic and pharmacological tools, we demonstrate that lactate monocarboxylate transporter 1 (MCT1, encoded by Slc16a1) is required for the oxidation of glucose carbon by MPC-deficient myocardium. We further observe that MCT1, traditionally localized to the plasma membrane, also resides in the inner mitochondrial membrane of mouse and human cardiomyocytes. Together with matrix-localized LDHB, MCT1 enables mitochondrial lactate conversion to pyruvate and NADH, directly fueling the electron transport chain. Loss of MCT1 impairs lactate oxidation, disrupts metabolic flexibility and accelerates the development of heart failure with increased mortality after hyperactivation of the neurohormonal axis or ischemia-reperfusion injury. Thus, the existence of a parallel lactate-based pathway for carbohydrate oxidation can sustain cardiac energetics and maintain myocardial structure and function under diverse stress conditions.
    DOI:  https://doi.org/10.1038/s41586-026-11182-3
  24. Nat Metab. 2026 Oct 27.
    Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) impair ETC activity and oxidative phosphorylation, but their phenotypic consequences vary with heteroplasmy levels. Whether increasing mtDNA heteroplasmy creates metabolic dependencies not present in respiratory-competent cells remains unknown. Here, we show that low pyruvate carboxylase (PC) expression creates an asparagine dependency in high-mtDNA-heteroplasmy, respiration-compromised cells. In isogenic cells carrying similar mtDNA deletions, respiration declines linearly with increasing heteroplasmy, whereas redox imbalance emerges only above 50% heteroplasmy. Above 70% heteroplasmy, integrated stress-response-associated translational defects emerge, which can be reversed by either exogenous asparagine or PC overexpression. Asparagine dependence inversely correlates with PC expression across respiration-deficient cells. Consistent with this pattern, patient-derived thyroid tumour cells harbouring a high-heteroplasmy complex I mutation and low PC levels exhibit asparagine auxotrophy and sensitivity to L-asparaginase. Together, these findings demonstrate a role for mitochondrial PC in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.1038/s42255-026-01651-4
  25. Biomolecules. 2026 Oct 07. pii: 1460. [Epub ahead of print]16(10):
    Citrin Deficiency: Biochemical Mechanisms Underlying a Complex Hepatic Metabolic Disorder.
    Ismael García-Lobo, Araceli Del Arco, Jorgina Satrústegui, Laura Contreras.
      Citrin Deficiency (CD), caused by pathogenic variants in SLC25A13, is a rare inherited metabolic disorder with age-dependent manifestations ranging from neonatal intrahepatic cholestasis to adult-onset citrullinemia. Although the genetic basis of CD is well established, the mechanisms linking loss of the mitochondrial aspartate/glutamate carrier (citrin) to the CD phenotype remain incompletely understood. This review examines current evidence from patients and available cellular and animal models supporting the biochemical mechanisms underlying CD. We discuss how disruption of the malate-aspartate shuttle alters cytosolic redox homeostasis and its consequences for interconnected pathways of carbohydrate, lipid, and nitrogen metabolism, including glycolysis, gluconeogenesis, galactose metabolism, fatty acid oxidation, lipogenesis, and ureagenesis. We also distinguish mechanisms supported by experimental evidence from those that remain hypothetical and highlight major unresolved questions regarding metabolic adaptation, disease progression, and the transition to the adult phenotype.
    Keywords:  Citrin Deficiency (CD); NADH/NAD+ ratio; aspartate/glutamate carrier (AGC); galactosemia; gluconeogenesis; hepatic metabolism; malate–aspartate shuttle (MAS); urea cycle
    DOI:  https://doi.org/10.3390/biom16101460
  26. Science. 2026 Oct 29. 394(6823): 488-489
    Taking the brakes off a stress response.
    Ramanujan S Hegde.
      A small molecule improves the fitness of cells containing diseased mitochondria.
    DOI:  https://doi.org/10.1126/science.aem1560
  27. Neuropsychiatr Dis Treat. 2026 ;22 640824
    Mitochondrial Dysfunction Across the Addiction Cycle: A Stage-Resolved Narrative Review.
    Zhaleh Jamali, Ahmad Salimi, Khatereh Isazadehfar.
      Addiction is a chronic, relapsing brain disorder defined by compulsive drug use, diminished self-control, and persistent vulnerability to relapse. Although addiction is conventionally framed in terms of synaptic and circuit-level adaptations within the mesolimbic dopamine system, prefrontal cortex, hippocampus, and amygdala, accumulating evidence indicates that these neuroadaptations are themselves substantially dependent on the bioenergetic integrity of the neurons that compose these circuits. Mitochondria, as the principal site of ATP synthesis, calcium buffering, and redox regulation, occupy a position from which their dysfunction can propagate outward to compromise synaptic transmission, plasticity, and ultimately behavior. This review synthesizes current evidence indicating that opioids, psychostimulants, alcohol, cannabinoids, and nicotine, despite engaging distinct primary pharmacological targets, converge on a common downstream phenotype of impaired oxidative phosphorylation, excessive reactive oxygen species production, disrupted mitochondrial fission-fusion dynamics, and defective mitophagy. Building on, and extending, existing cross-substance syntheses of drug-induced mitochondrial dysfunction, we integrate evidence on the signaling architecture, PGC-1α/NRF1/2, sirtuins, AMPK-mTOR, and BDNF-CREB, that couples mitochondrial quality control to synaptic plasticity, and we examine how oxidative, neuroinflammatory, and epigenetic mechanisms, including reciprocal signaling among neurons, astrocytes, and microglia, interact to convert transient drug-induced bioenergetic stress into durable, self-perpetuating dysfunction. Mapping these mechanisms onto the initiation, maintenance, and withdrawal/relapse phases of the addiction cycle reveals a dynamic trajectory in which mitochondria shift from an adaptively taxed to a chronically failing state, with direct implications for craving and relapse vulnerability. Finally, we critically evaluate mitochondria-targeted antioxidants, biogenesis modulators, exercise, metabolic interventions, and emerging biomarker-based strategies as candidate interventions, and we propose an integrated bioenergetic framework in which mitochondrial health functions both as a biological substrate and as a measurable target for understanding and treating substance use disorders. Because the underlying evidence base is drawn largely from preclinical and, in places, non-addiction models, we treat the relationship between mitochondrial dysfunction and addiction, whether causal, consequential, or self-perpetuating, as an open empirical question, and we present the resulting synthesis as a testable, stage-resolved theoretical framework rather than as an established mechanism.
    Keywords:  addiction; mitochondria; mitochondria-targeted therapeutics; mitochondrial dynamics; neuroinflammation; oxidative stress; relapse; reward circuitry
    DOI:  https://doi.org/10.2147/NDT.S640824
  28. Mol Neurobiol. 2026 Oct 28. pii: 997. [Epub ahead of print]63(1):
    Mitochondrial Lactate Signaling and Protein Lactylation in Neurological Diseases.
    Yu Gu, Potao Zhang, Chunyan Lei, Wenyan Xu, Yunyu Cui.
      The brain, as a highly metabolically active organ, depends on mitochondrial oxidative phosphorylation (OXPHOS) to sustain energy demands. When mitochondrial function is impaired, cells undergo metabolic reprogramming toward aerobic glycolysis, leading to lactate accumulation. Beyond its traditional role as a metabolic byproduct, lactate is now recognized as a signaling molecule that links metabolism to epigenetic regulation through protein lactylation, a post-translational modification identified by Zhang et al. in 2019. Research on lactylation has progressed through three stages: initial discovery in histone lactylation as an epigenetic mark, expansion to non-histone proteins revealing roles in metabolic and structural regulation, and recent identification of mitochondrial protein lactylation influencing OXPHOS, the tricarboxylic acid (TCA) cycle, and reactive oxygen species (ROS) production. This review summarizes the mitochondrial-lactate-lactylation axis in the nervous system, including brain lactate metabolism, the astrocyte-neuron lactate shuttle, and regulatory mechanisms of lactylation (writers, erasers, and readers). We further discuss its roles in histone and non-histone modification, its bidirectional relationship with mitochondrial dysfunction, and its involvement in neurodegenerative, cerebrovascular, and neuropsychiatric disorders. Finally, we highlight the therapeutic potential of targeting lactylation pathways. Collectively, mitochondrial lactate signaling and protein lactylation emerge as a central link between metabolic reprogramming and epigenetic dysregulation in neurological diseases, providing new avenues for therapeutic intervention.
    Keywords:  Epigenetics; Lactylation; Metabolic reprogramming; Mitochondria; Neurological disorders; Oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s12035-026-06291-z
  29. J Transl Med. 2026 Aug 13. pii: 1356. [Epub ahead of print]24(1):
    Mitochondria as the core regulator of cell death: from classical programmed cell death to the novel mitoxyperiosis pathway.
    Jianxiong Xiao, Shuaiyong Qi, Yuzhen Li, Yafen Li, Heng Tang.
      Mitochondria are recognized as pivotal regulators in cell fate determination, and their dysfunction is implicated in numerous major diseases. While mitochondria control classical programmed cell death pathways, including apoptosis, necroptosis, and pyroptosis, the recent identification of mitoxyperiosis, a BAX/BAK1/BID-dependent and spatially restricted mode of oxidative death, has added complexity to this regulatory framework. Nonetheless, a systematic understanding of how mitochondria coordinate these diverse pathways, particularly the mechanistic relationship between canonical death pathways and this newly identified mode, remains insufficiently explored. In this review, we address three fundamental questions: (1) Through which key molecular mechanisms, including mitochondrial outer membrane permeabilization, reactive oxygen species bursts, mitochondrial DNA release, and alterations in mitochondrial dynamics, do mitochondria regulate each major death pathway? (2) How does mitoxyperiosis diverge from and intersect with classical ferroptosis and other death modalities, and what unique features characterize its execution? (3) What therapeutic opportunities and challenges emerge from targeting mitochondrial death checkpoints to protect cells in pathological conditions and to treat cancer? By critically integrating current evidence, we propose a comprehensive framework that elucidates the regulatory logic of mitochondria-mediated cell death and underscores mitochondrial plasticity as a crucial determinant of cellular outcomes. This perspective not only clarifies the integrative role of mitochondria within the cell death network but also suggests new avenues for developing precision therapies for diseases associated with mitochondrial dysfunction.
    Keywords:  Apoptosis; Cell death; Mitochondria; Mitochondrial permeability transition pore; Mitoxyperiosis; Necroptosis; Pyroptosis; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s12967-026-08823-6
  30. Front Neurol. 2026 ;17 1915238
    Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons.
    Celina Böse, Adriana Rehm, Zhixiao Wu, Anna-Sophia Karl, Sanja Augustyniak, Pia Renk, Anke Salmen, Ralf Gold, Konstanze F Winklhofer, Barbara Gisevius, Verian Bader, Jeremias Motte.
       Background: Genetic factors are estimated to account for approximately 30-50% of the risk for developing Multiple sclerosis (MS). Distinct mitochondrial variants, impairments in the respiratory chain, and mitochondrial dysfunction have been reported in individuals affected by MS. Mitochondria and the endoplasmic reticulum (ER) form membrane contact sites (ERMCs) that control important biological functions. Dysregulated ERMCs have been associated with a number of severe consequences for homeostasis, including altered mitochondrial calcium levels, impaired ATP production and abnormal lipid transfer. All of these mechanisms are thought to play an important role in the pathogenesis and disease progression of MS. Here, we investigated the hypothesis that the mitochondrial predisposition plays a crucial role in contributing to MS development.
    Methods: Mitochondrial functionality was analyzed in a model of human induced primary neurons (iPNs), and neuronal precursor cells (NPCs), differentiated from induced pluripotent stem cells (iPSCs) from people with MS and healthy controls (HCs). Seahorse analysis was performed for investigation of the bioenergetic profile of the cells. ERMC and mitochondrial morphological analysis were carried out to investigate the potential impact of mitochondrial dysfunction in MS-derived neurons.
    Results: Seahorse analysis revealed significant differences in the respiratory complexes (spare capacity: p = 0.0002; non-mitochondrial oxygen consumption: p = 0.0207) and glycolysis (p = 0.0001; glycolytic reserve p = 0.0018) from MS-derived iPNs compared to HCs. We further investigated mitochondrial dysfunction in NPCs (maximal respiration p = 0.0491; non-mitochondrial oxygen consumption: p = 0.0226) and a significant difference in glycolytic reserve (p = 0.0359) from MS-derived NPC compared to HCs. Furthermore, we identified a significantly higher amount of ERMCs (p < 0.0001) and altered mitochondrial morphology in MS-derived iPNs compared to HC.
    Discussion: Our data are highlighting the importance of genetic mitochondrial contribution to MS pathology, by showing that MS-derived NPCs and iPNs exhibit altered mitochondrial behavior and morphology compared to healthy control (HC)-derived cells.
    Keywords:  endoplasmic reticulum; endoplasmic reticulum-mitochondria contacts; metabolism; mitochondria; multiple sclerosis
    DOI:  https://doi.org/10.3389/fneur.2026.1915238
  31. Neurogenetics. 2026 Oct 28. pii: 84. [Epub ahead of print]27(1):
    Pseudodominant inheritance in paraplegin (SPG7)-associated CPEO-ataxia syndrome.
    Weber Liu, Serge Geara, Simon Rowe, Carolyn Mary Sue.
      SPG7 encodes paraplegin, a mitochondrial AAA-metalloprotease critical for inner mitochondrial membrane protein quality control. Pathogenic variants most commonly cause autosomal recessive hereditary spastic paraplegia (HSP) but its phenotypic spectrum includes cerebellar ataxia, progressive external ophthalmoplegia, myopathy and parkinsonism.We report a 47 year old man presenting with a progressive external ophthalmoplegia, ptosis, progressive gait disturbance, and spasticity. Ten-year follow-up of this individual showed slowly progressive spastic ataxia with ocular motor involvement and neurogenic bladder. His mother and maternal aunt both had marked spasticity, ataxia, ptosis and external ophthalmoplegia. Genetic testing demonstrated compound heterozygous pathogenic variants in paraplegin in this individual. Genetic testing in his mother and aunt revealed homozygous canonical splice-site variants (c.2182-2 A > G). Cascade testing of his asymptomatic father showed a common pathogenic missense variant p.(Ala510Val) in the same gene.This family demonstrates a pseudodominant inheritance pattern, instead of the expected autosomal recessive trait that applies to paraplegin. We highlight diagnostic pitfalls in relying on family history and assumed inheritance traits. We emphasise the importance of segregation analysis and comprehensive genomic testing. Recognition of pseudodominance inheritance has important implications for genetic counselling, family planning and cascade testing.
    Keywords:   SPG7 ; Cascade testing; Mitochondrial disease; Paraplegin; Pseudodominant inheritance
    DOI:  https://doi.org/10.1007/s10048-026-00955-7
  32. Adv Sci (Weinh). 2026 Oct 25. pii: e78392. [Epub ahead of print]
    Donor-Cell Senescence Redirects PINK1-Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3-Stabilized HSPA9.
    Zixuan Ou, Mingke Zhao, Zhiwei Ling, Lianqi Peng, Bide Tong, Huaizhen Liang, Hongchuan Wang, Di Wu, Yifan Du, Zhi Du, Shihao Zhang, Yuyuan Jia, Yifan Qian, Gan Xu, Liuliang He, Gang Li, Shun Zhang, Lei Tan, Kun Wang, Xiaobo Feng, Cao Yang, Zhiwei Liao.
      Extracellular vesicle therapies have been developed for tissue repair, but how donor-cell senescence reshapes vesicle-mediated mitochondrial transfer remains unclear. Here, we show that senescent adipose-derived stem cells (ADSCs) redirect damaged mitochondria into microvesicles (MVs), converting protective vesicles into pro-degenerative carriers. Senescent ADSC-derived MVs are enriched in PINK1-marked, oxidatively damaged mitochondrial cargo. After transfer to nucleus pulposus cells (NPCs), this cargo disrupts recipient mitochondrial homeostasis, activates the cGAS-STING-NLRP3 inflammatory axis, and aggravates intervertebral disc degeneration. Proteomic and functional analyses identify HSPA9 as a mitochondrial cargo-sorting adaptor. Senescent stress induces SUMO3 conjugation of HSPA9 at K612, stabilizing HSPA9 by limiting ubiquitin-proteasomal degradation. Stabilized HSPA9 uses its peptide-binding domain to engage the kinase domain of activated PINK1 and links PINK1-positive damaged mitochondria to Annexin A1-associated MV structures. This SUMO3-HSPA9-PINK1 module diverts damaged mitochondria from PINK1-Parkin mitophagy toward MV-mediated mitochondrial transfer. Donor-cell reprogramming that restrains the release of damaged mitochondria and reinforces mitophagic clearance restores the in vivo therapeutic efficacy of senescent ADSC-derived MVs. These findings identify mitochondrial cargo fate as a switch between vesicle-mediated repair and degeneration.
    Keywords:  SUMOylation; cellular senescence; intervertebral disc degeneration; microvesicles; mitochondrial transfer
    DOI:  https://doi.org/10.1002/advs.78392
  33. ArXiv. 2026 Oct 07. pii: arXiv:2610.09288v1. [Epub ahead of print]
    FaceKit: a Toolkit for Interpretable Facial Phenotyping, Synthetic Image Generation and Privacy Analysis in Rare Diseases.
    Hongzhuo Chen, Zhanliang Wang, Florent Pollet, Mian Umair Ahsan, Joshua Bie, Tzung-Chien Hsieh, Peter Krawitz, Cong Liu, Wendy K Chung, Chunhua Weng, Gamze Gürsoy, Kai Wang.
      Many rare genetic diseases are associated with recognizable craniofacial features. However, traditional approaches for describing facial morphology rely largely on qualitative clinical observation and free-text descriptions, which are often subjective, non-standardized, and difficult to reproduce across observers and institutions. Although the Human Phenotype Ontology (HPO) provides controlled terms for describing facial features, these terms are typically categorical rather than quantitative and may vary depending on examiner experience and interpretation. Here, we present FaceKit, a computational framework for quantitative facial phenotyping from frontal facial photographs. FaceKit extracts standardized measurements of facial landmarks and derived 120 morphological features, then reports feature-level z-scores representing deviation from population reference distributions. The reference distributions are built from the FairFace dataset spanning diverse ancestral groups. We evaluated FaceKit on a curated subset of the GestaltMatcher Database covering 50 rare-disease cohorts. In addition to quantitative facial analysis, FaceKit includes synthetic facial image generation to support rare disease model development and data augmentation. We also performed privacy evaluation to assess whether synthetic images reveal identifiable information from real patient photographs and could compromise patient privacy. Across disease case studies, FaceKit-derived quantitative measurements captured known facial features associated with rare genetic disorders and provided objective support for clinical phenotyping. Together, these results establish FaceKit as a useful tool for quantitative phenotyping, and has the potential to improve rare disease diagnosis, support genotype-phenotype studies, and enable more reproducible clinical characterization across diverse patient populations.
    Keywords:  facial phenotyping; facial photo; landmarking; privacy evaluation; rare disease
  34. Life (Basel). 2026 Sep 23. pii: 1590. [Epub ahead of print]16(10):
    Mitochondrial Genomic Variation in Rare and Metabolic Diseases: From Heteroplasmy to Precision Medicine.
    Arijahir Alexis Mancio-Cárdenas, Humberto García-Ortiz, Francisco Barajas-Olmos, Cecilia Contreras-Cubas, Ximena Luna-González, Diego Ramírez-Martínez, Federico Centeno-Cruz, José Rafael Villafán-Bernal, Montserrat Ivonne Morales-Rivera, Beth Mitchell Gamez-Rangel, Angélica González-Oliver, Lorena Orozco, Angélica Martínez-Hernández.
      Mitochondrial DNA (mtDNA) variation has traditionally been investigated in the context of human evolution and rare mitochondrial diseases; however, growing evidence suggests that it may also contribute to susceptibility to common metabolic disorders. This review integrates current knowledge of mitochondrial biology, mtDNA genetics, heteroplasmy, and the global distribution of mitochondrial haplogroups to examine their roles in health and disease. In this narrative review, we synthesized English-language studies identified through PubMed, Scopus, and Web of Science from January 1988 to May 2026, prioritizing evidence according to relevance, scientific contribution, recency, and historical significance. We summarize evidence showing how pathogenic variants (PVs) in mtDNA genes impair oxidative phosphorylation (OXPHOS), increase reactive oxygen species (ROS) production, and disrupt cellular bioenergetics, thereby contributing to the multisystem manifestations of mitochondrial diseases. We further discuss population-specific mitochondrial haplogroups and their reported population-specific associations with metabolic phenotypes, including obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD). Finally, we review recent advances in next-generation sequencing technologies and their contributions to the molecular diagnosis of mitochondrial diseases and the characterization of genotype-phenotype relationships. Collectively, current evidence supports a well-established pathogenic role for specific mtDNA variants in primary mitochondrial disorders, whereas the contributions of common polymorphisms and haplogroups to complex metabolic disease remain largely associative and require further replication and functional validation.
    Keywords:  bioenergetics; heteroplasmy; metabolic disorders; mitochondrial disease; next-generation sequencing; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/life16101590
  35. Sci Adv. 2026 Oct 30. 12(44): eaef8069
    Photosynthetic chimeric stem cells function as mitochondrial batteries.
    Zhengtai Chen, Hanxiao Sun, Yuanyang Zheng, Xuan Jiang, Yan He, Kai Ye, Yufan Zhang, Zhengwei Mao, Ziyi Zhou, Xiaoxi Lin, Chenggang Yi, Wei Wang.
      Therapies built on mitochondrial transfer hold promise for repairing dysfunctional, energy-deficient cells. Still, mesenchymal stem cells used as mitochondrial donors are limited by poor engraftment, risk of aberrant differentiation, and low transfer efficiency. Herein, we constructed photosynthesis-empowered cross-kingdom chimeric stem cells (PCSs; "mitochondrial battery") by introducing plant-derived thylakoid-based artificial nuclei plus FGF21-encoding messenger RNA (mRNA) into enucleated bone marrow mesenchymal stem cells. Photosynthetic activity enhances mitochondrial transfer to restore metabolism in damaged cells and elevates anabolism to increase FGF21 production. Sustained FGF21 release promotes mitochondrial biogenesis and sustains long-term cellular energy homeostasis. Mouse and porcine wound healing models demonstrate that PCSs recharge cellular energy to accelerate wound repair. This light-activated cellular photosynthetic platform supports modular mRNA programmability, shows no engraftment or aberrant differentiation, and allows repeated administration for diverse therapeutic applications.
    DOI:  https://doi.org/10.1126/sciadv.aef8069
  36. Diabetes Metab Syndr Obes. 2026 ;19 639810
    Mitochondrial Copper Homeostasis in Diabetic Kidney Disease: Emerging Links Between Metabolic Stress, Respiratory Chain Dysfunction, and Renal Injury.
    Bo Hou, Jiahao Liang, Xingrui Li.
      Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease and kidney failure despite major therapeutic advances. Current disease-modifying therapies reduce, but do not abolish, residual risk, indicating that additional cell-intrinsic mechanisms convert diabetic metabolic stress into progressive renal injury. Mitochondrial dysfunction has emerged as a central node in this process because renal tubular cells, podocytes, endothelial cells, and mesangial cells rely on mitochondrial oxidative phosphorylation to sustain transport, filtration-barrier integrity, redox control, and adaptive repair. Copper is an essential metal cofactor for cytochrome c oxidase (COX; respiratory chain complex IV), and mitochondrial copper delivery is required for COX assembly, electron transfer, proton-pumping capacity, and ATP generation. This review integrates established evidence from DKD pathobiology, mitochondrial biology, and copper homeostasis with emerging and indirect evidence to examine mitochondrial copper dyshomeostasis as a potential mechanistic link in DKD. Established findings support mitochondrial dysfunction in DKD and the essential role of copper in COX/complex IV assembly and respiratory-chain function. We further propose that diabetic metabolic stress may disturb copper uptake, intracellular trafficking, mitochondrial copper delivery, or copper use by COX, resulting in functional mitochondrial copper depletion or misallocation. Such disturbances could contribute to COX dysfunction, oxidative phosphorylation failure, ATP depletion, mtROS amplification, impaired mitochondrial quality control, and subsequent renal injury. However, direct DKD-specific evidence demonstrating impaired mitochondrial copper trafficking or functional mitochondrial copper depletion remains limited, and this mechanism should therefore be regarded as a testable hypothesis rather than an established pathogenic pathway. We also distinguish this mechanism from cuproptosis, examine intersections with ferroptosis, and outline biomarker, multi-omics, metallomics, and therapeutic opportunities.
    Keywords:  copper trafficking; cytochrome c oxidase; diabetic kidney disease; mitochondrial copper homeostasis; oxidative stress; renal injury; respiratory chain dysfunction
    DOI:  https://doi.org/10.2147/DMSO.S639810
  37. Adv Healthc Mater. 2026 Oct 26. pii: e71902. [Epub ahead of print]
    Biomaterials Targeting Mitochondrial NAD+ Metabolism for Tissue Regeneration.
    Xinyu Ma, Mengying Li, Tingyu Ren, Yuchao Li, Yufang Zhu, Yuxin Wang, Lei Han.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) has emerged as a pivotal regulator in tissue regeneration, central to cellular energy metabolism and redox homeostasis. It regulates key mitochondrial processes-including energy production, reactive oxygen species (ROS) scavenging, and cell death-primarily through the tricarboxylic acid cycle (TAC), oxidative phosphorylation, and sirtuin deacetylase activity. This coordinated regulation fosters a favorable metabolic and immune microenvironment conducive to tissue repair. Strategies to increase mitochondrial NAD+ levels, such as delivery, precursor supplementation (e.g., NR or NMN), catalytic conversion, and inhibition of NAD+-consuming enzymes, have demonstrated significant efficacy in promoting regeneration across diverse tissues, including bone, cartilage, tooth, skin, myocardium, muscle, nerve, and vascular. There is no review that systematically addresses the latest progress in the advances of biomaterials targeting mitochondrial NAD+ metabolism for tissue regeneration. This review fills the gap by outlining the central role of biomaterials targeting mitochondrial NAD+ in tissue regeneration. We introduce the biological functions and regulatory mechanisms of mitochondrial NAD+, highlight the intervention strategies to boost NAD+ levels, and summarize the applications across diverse regenerative contexts. Finally, we discuss prevailing challenges and future prospects, providing new theoretical and interventional insights for regenerative medicine.
    Keywords:  NAD+; biomaterials; metabolic homeostasis; mitochondrial; tissue regeneration
    DOI:  https://doi.org/10.1002/adhm.71902
  38. J Neurol. 2026 Oct 28. pii: 690. [Epub ahead of print]273(11):
    Visual acuity changes in idebenone treatment‑naïve patients with Leber hereditary optic neuropathy: insights from the CRS-2 study.
    Maciej R Krawczynski, Judith van Everdingen, Bart P Leroy, Christophe Verny, Nöel J C Bauer, Cécile Andris, Birgit Lorenz, Marcela Votruba, Claudia Priglinger, Neringa Jurkute, Xavier Llòria, Magda Silva, Valerio Carelli, Patrick Yu-Wai-Man, Thomas Klopstock.
       OBJECTIVE: Case Record Survey (CRS)-2 was an international, multicenter, retrospective study designed to characterize the natural history of vision loss and spontaneous recovery in patients with Leber hereditary optic neuropathy (LHON).
    METHODS: Case records of idebenone treatment-naïve patients aged ≥12 years, with mitochondrial DNA (mtDNA) variants m.3460G>A, m.11778G>A or m.14484 T>C, onset of symptoms (OoS) after 1999, and ≥2 visual acuity (VA) assessments within 5 years of OoS were analyzed. Disease phases were subacute/dynamic (≤1 year) or chronic (>1 year from OoS). Separate analyses were performed for eyes with VA assessments within 12 or 24±3 months from baseline (first VA assessment after OoS in each eye). Outcomes included: spontaneous clinically relevant recovery (sCRR; improvement from off-chart to ≤1.6 logMAR, or ≥0.2 logMAR if on-chart), sCR stabilization (sCRS; maintenance of VA <1.0 logMAR), sCR benefit (sCRB; eyes with a sCRR and/or sCRS), and sCR worsening (sCRW; worsening to off-chart, or loss of ≥0.2 logMAR if on-chart). The primary endpoint was the proportion of subacute/dynamic eyes 12 months from baseline with sCRB.
    RESULTS: Of 402 eligible eyes, 385 were subacute/dynamic at baseline, with 96 included in the 12-month analysis. Most patients were male (79.9%), with the m.11778G>A variant (71.7%). The primary endpoint was observed in 20.8% (n=20/96) of eyes. Spontaneous visual outcomes varied by disease phase, mtDNA variant, sex, and age at OoS.
    CONCLUSIONS: CRS-2 provides insights into LHON natural history and suggests the disease course may be more dynamic than previously reported, with spontaneous VA changes occurring well into the chronic phase.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT02796274, May 2016.
    Keywords:  Disease progression; Leber hereditary optic neuropathy; Mitochondrial disease; Natural history; Optic neuropathy
    DOI:  https://doi.org/10.1007/s00415-026-14181-6
  39. Pharmacol Res. 2026 Oct 27. pii: S1043-6618(26)01623-3. [Epub ahead of print]234 109708
    Mitochondrial transplantation as a therapeutic strategy: From energy replacement to metabolic and immune reprogramming.
    Chuli Zhu, Meng Xu, Yanan Ji, Jie Wang, Xinlei Yao, Hualin Sun.
      Mitochondrial dysfunction drives diseases, including ischemia-reperfusion injury, neurodegenerative disorders, cardiovascular disease, metabolic syndrome, and inflammation. Conventional mitochondria-targeted strategies offer only partial rescue and are insufficient for severe, irreversible damage. Mitochondrial transplantation (MT)-the delivery of exogenously isolated functional mitochondria to injured cells-has emerged as a promising therapeutic strategy that directly restores mitochondrial bioenergetic function and may subsequently modify the tissue microenvironment. This Review examines the entire MT pipeline, from mitochondrial source selection, isolation and preservation, to in vivo delivery strategies. We critically examine the multiple mechanisms underlying MT's therapeutic efficacy, including cellular uptake and intracellular integration, energy restoration and metabolic reprogramming, redox rebalancing, remodeling of mitochondrial quality control (fusion/fission, mitophagy, biogenesis), and immunomodulation. We summarize preclinical and clinical applications across multiple organ systems-heart, nervous system, liver, kidney, lung, skeletal muscle, retina-as well as in oncology and aging. We analyze five major translational bottlenecks: the lack of standardized manufacturing protocols, undefined dose-response relationships, immunogenicity and long-term safety uncertainties, the decisive impact of mitochondrial heterogeneity, and regulatory ambiguity. We outline future directions-mechanistic deepening, engineered target delivery, individualized mitochondrial medicine, combinatorial regimens, and a phased clinical roadmap. MT is not merely energy supplementation; it may reshape cellular metabolism, quality control networks, and immune microenvironments, representing a shift from pharmacological modulation of mitochondrial function toward organelle replacement strategies. Despite challenges, these advances may facilitate individualized mitochondrial therapies as a proposed future direction.
    Keywords:  Clinical translation; Individualized mitochondrial medicine; Metabolic reprogramming; Mitochondrial dysfunction; Mitochondrial quality control; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.phrs.2026.109708
  40. Methods Mol Biol. 2027 ;3093 3-9
    Optimized Dissociation of Skeletal Muscle Tissue to Recover Muscle Stem Cells.
    Teoman Ozturk, Julien Mignot, Nathalie Didier.
      Adult skeletal muscle regenerative potential mainly relies on resident muscle stem cells (MuSC), tightly anchored in a specialized niche. These cells are widely used for mechanistic in vitro assays and are promising candidates for cell-based therapies. However, muscle tissue enzymatic dissociation required to isolate MuSC remains a critical step that can deeply alter their viability and functionality. Here, we provide a step-by-step method to dissociate skeletal muscle tissue, optimized to preserve the viability of MuSC and improve their purification yield.
    Keywords:  Dissociation; Muscle stem cells; Skeletal muscle tissue
    DOI:  https://doi.org/10.1007/978-1-0716-5643-3_1
  41. Front Mol Biosci. 2026 ;13 1861051
    Disrupted valine metabolism and SCPC-mediated neurological toxicity in ECHS1 deficiency.
    Meghan M Eller, Madison A Bunce, Mamta Verma, Raegan M Adams, Xiaorong Fu, Alina P Montalbano, Felix Nitschke, Shawn C Burgess, Rachel M Bailey.
       Background: ECHS1 Deficiency (ECHS1D) is a rare neurometabolic disorder caused by loss of function in the mitochondrial enzyme short-chain enoyl-CoA hydratase (ECHS1), leading to developmental delay, dystonia, seizures, and early mortality. Impaired ECHS1 activity disrupts valine catabolism, resulting in accumulation of reactive valine-derived intermediates associated with disease severity, though direct experimental evidence of neuronal toxicity and therapeutic modifiability remains limited. This study aimed to define the consequences of impaired ECHS1 activity, focusing on valine-derived intermediates and their impact on neuronal mitochondrial function.
    Methods: Wild-type and Echs1-deficient (Echs1D) mouse neuroblastoma (N2A) cells were utilized to investigate effects of patient-relevant valine intermediates S-(2-carboxypropyl)cysteine (SCPC), S-(2-carboxyethyl)cysteine (SCEC), and 2,3-dihydroxy-2-methylbutyric (DHMB) on mitochondrial function, oxidative stress, and cell viability. ECHS1D mice were used to quantify valine intermediates, evaluate pyruvate dehydrogenase complex (PDC) function, and assess seizure susceptibility under typical, excess, or restricted dietary valine intake.
    Results: In wild-type N2A cells, SCPC exposure induced dose-dependent cell toxicity and impaired mitochondrial respiration, while SCEC and DHMB exerted distinct mitochondrial effects. In contrast, Echs1D N2A cells displayed preserved mitochondrial fitness with premature neuronal differentiation, indicating cell-type-specific metabolic adaptations. ECHS1D mice accumulated SCPC, which was exacerbated by excess dietary valine and associated with reduced pyruvate dehydrogenase complex activity, and worsened seizure susceptibility. Valine restriction initiated during adolescence failed to reduce SCPC or improve seizure outcomes and instead increased SCEC levels.
    Conclusion: These studies demonstrate that accumulation of ECHS1D-specific valine intermediates, particularly SCPC, contributes to mitochondrial dysfunction and disease severity in ECHS1D. Dietary valine modulation during adolescence showed limited therapeutic benefit and induced broader metabolic perturbations, underscoring the need for improved therapeutic strategies.
    Keywords:  ECHS1; epilepsy; mitochondrial disease; neurodevelopment; valine metabolism
    DOI:  https://doi.org/10.3389/fmolb.2026.1861051
  42. J Biol Chem. 2026 Oct 26. pii: S0021-9258(26)02568-8. [Epub ahead of print] 113696
    Snapshots of ATP-driven substrate translocation by the mitochondrial AAA+ protease AFG3L2.
    Yunjia Dai, Sixing Hong, Yan Wu, Renyi Xiong, Zeyuan Guan, Delin Zhang, Qiang Wang, Ping Yin.
      AFG3L2, located in the mitochondrial inner membrane, is an ATP-fueled protease responsible for protein degradation, and its dysfunction has been implicated in multiple neurodegenerative disorders. However, the structural basis underlying its ATP-driven substrate translocation remains incompletely understood. Here, we purified full-length human AFG3L2 and determined its cryo-EM structures in four distinct conformational states (Con1-Con4), revealing substrate engagement in the core catalytic domain despite weak EM density for its transmembrane domain. These structures display an asymmetric spiral-staircase architecture in which the six protomers are arranged around a central pore that accommodates a polypeptide substrate. The four conformational states jointly reveal a substrate translocation mechanism in which ATP binding by the uppermost protomer promotes substrate engagement, whereas ATP hydrolysis by the lowermost ATP-bound protomer leads to substrate release. Our findings provide snapshots of ATP-driven substrate translocation by AFG3L2 and refine the hand-over-hand translocation mechanism by revealing substrate capture and release during an ordered ATPase cycle.
    Keywords:  AAA+ protease; AFG3L2; ATP-driven substrate translocation; Cryo-electron microscopy; Mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.113696
  43. J Neurochem. 2026 Oct;pii: e70561. [Epub ahead of print]170(10):
    PINK1 and PARKIN Deficiency Increases Neuronal Vulnerability to Autoimmune Neuroinflammation Through Mitochondrial Fragmentation in Aged Mice.
    Davide Cossu, Sachiko Noda, Shigeto Sato, Kazumasa Yokoyama, Yuji Tomizawa, Ruochen Wang, Sarah Vascellari, Leonardo Antonio Sechi, Taku Hatano, Nobutaka Hattori.
      PINK1 and Parkin regulate mitochondrial quality control in both neuronal and immune-cell populations, but their roles during autoimmune neuroinflammation in aging remain incompletely understood. We investigated the association of PINK1 or Parkin deficiency with clinical disease, peripheral immune responses, CNS inflammation, and neuronal mitochondrial morphology during experimental autoimmune encephalomyelitis (EAE). EAE was induced in aged PINK1-/- and PARK2-/- mice and age-matched controls. Clinical disease was assessed longitudinally, while independent cohorts were analyzed at peak disease using flow cytometry, spinal cord histology, transmission electron microscopy, and Western blotting of mitochondrial fractions. PINK1-/- and PARK2-/- showed greater cumulative disease burden and incomplete clinical recovery, most prominently in PARK2-/- mice. At peak disease, knockout mice exhibited increased dendritic cells, monocytes, and CD8+ T cells, while aged knockouts showed more IFN-γ-producing CD4+ and CD8+ T cells following ex vivo stimulation. Increased spinal cord inflammation was not accompanied by genotype-dependent differences in myelin staining. Ultrastructural analysis revealed more numerous, smaller mitochondria in substantia nigra pars compacta and motor cortex neurons, accompanied by selective alterations in OPA1 and DRP1, but not MFN2. These findings demonstrate that PINK1 or Parkin deficiency is associated with enhanced inflammation, greater EAE disease burden, and altered neuronal mitochondrial morphology in aging. These results support an association between immune dysregulation and altered mitochondrial homeostasis without establishing impaired mitophagy or a direct causal relationship.
    Keywords:  EAE; PARKIN; PINK1; aging; mitochondrial fragmentation; mitophagy; neuroinflammation; substantia nigra
    DOI:  https://doi.org/10.1111/jnc.70561
  44. Antioxidants (Basel). 2026 Oct 05. pii: 1295. [Epub ahead of print]15(10):
    Mitochondrial Remodeling and Impaired Bioenergetics Define Neuronal Vulnerability in Fragile X-Related Disorders.
    Benedetta Niccolini, Martina Grandi, Veronica Nobile, Cecilia Pucci, Francesco Boldrin, Maria Elisabetta Clementi, Patrizia Bottoni, Alessia Riente, Pietro Chiurazzi, Giovanni Neri, Maurizio Genuardi, Alessandra Baracca, Giuseppe Maulucci, Elisabetta Tabolacci, Valentina Giorgio.
      Fragile X syndrome (FXS) and related conditions associated with FMR1 gene alterations have increasingly been linked to mitochondrial dysfunction, although most available evidence derives from peripheral cell models. Whether these abnormalities also occur in disease-relevant neuronal populations remains largely unknown. Building on our previous observations in patient-derived fibroblasts, we investigated mitochondrial structure and function in neurons differentiated from induced pluripotent stem cells (iPSCs) generated from individuals with FXS and carriers of unmethylated full mutations, using matched healthy control lines. Mitochondrial integrity, bioenergetic properties, and network organization were evaluated to determine whether FMR1-associated mitochondrial defects are preserved in a neuronal context. Mitochondrial abnormalities previously identified in fibroblasts were recapitulated in iPSC-derived neurons. These findings demonstrate that impaired mitochondrial dynamics and function are conserved across different cell types, indicating that mitochondrial dysfunction represents a relevant cellular feature of FXS and related FMR1-associated conditions. Our results indicate that mitochondrial dysfunction is a shared feature of FMR1-related neuronal models, while the underlying patterns of mitochondrial remodeling are influenced by the specific FMR1-associated condition. These results support a role for mitochondrial alterations in FMR1-related neuronal dysfunction and provide a basis for the further investigation of the mechanisms linking mitochondrial homeostasis to the pathophysiology of FXS and related conditions.
    Keywords:  FMR1 gene; cyclophilin D; fragile X syndrome; fragile X-related conditions; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/antiox15101295
  45. J Transl Med. 2026 Oct 17. pii: 1354. [Epub ahead of print]24(1):
    Mitochondrial dysfunction in diabetic neuropathy: a core pathogenic hub and therapeutic implications.
    Xiaotong Wu, Xiaobo Li, Nengjun Lou, Xianghua Zhuang, Shihong Chen.
       BACKGROUND: Diabetic neuropathy is a heterogeneous complication of diabetes in which sensory loss, neuropathic pain, autonomic dysfunction and distal axonal degeneration cannot be fully explained by hyperglycaemia alone. Because peripheral axons, Schwann cells and autonomic neurons depend on sustained bioenergetic support, mitochondrial injury has emerged as a central link between metabolic overload, neuroinflammation and progressive nerve dysfunction.
    MAIN BODY: This review synthesizes evidence that hyperglycaemia, lipotoxicity and microvascular stress impair electron transport, oxidative phosphorylation and mitochondrial DNA stability, leading to excessive reactive oxygen species generation, calcium dyshomeostasis, mitochondrial permeability transition pore opening and maladaptive metabolic reprogramming. Disrupted fission-fusion balance, defective axonal transport, impaired mitophagy and abnormal mitochondria-associated endoplasmic reticulum membranes further weaken mitochondrial quality control in long peripheral axons. These changes engage SARM1-related NAD+ depletion, inflammasome activation, cGAS-STING signalling, apoptosis and glial-neuronal metabolic failure, thereby connecting bioenergetic collapse with pain sensitisation, distal axonal degeneration and autonomic dysfunction. Across painful and painless diabetic peripheral neuropathy, corneal small-fibre neuropathy, autonomic neuropathy and diabetes-related central nervous system injury, mitochondrial mechanisms appear shared, but endpoints and dominant cell types differ. Translationally, exercise and dietary strategies, metabolic regulators, SARM1 and calcium-pathway targeting, mitophagy modulation, mitochondria-directed antioxidants, and traditional Chinese medicine or natural products are discussed as metabolism-oriented interventions. Current evidence supports target engagement in experimental systems, but human validation, tissue exposure data, structural nerve endpoints and high-quality disease-modifying trials remain insufficient.
    CONCLUSION: Mitochondrial dysfunction functions as a core pathogenic hub-rather than the sole cause-linking substrate overload, redox imbalance, calcium stress, organelle quality-control failure, inflammatory signalling, and axonal degeneration in diabetic neuropathy. The most actionable translational path is not symptomatic antioxidant use alone but biomarker-guided, mechanism-stratified trials that connect mitochondrial target modulation with small-fibre structure, nerve function, safety, and patient-centred outcomes.
    SEARCH STRATEGY AND EVIDENCE SELECTION: For this narrative review, PubMed was searched from database inception to 1 August 2026, supplemented by backward reference screening of relevant original studies and recent reviews. Search terms included "diabetic neuropathy", "diabetic peripheral neuropathy", "mitochondria", "oxidative phosphorylation", "oxidative stress", "mitophagy", "SARM1", "NLRP3", "cGAS-STING", and "mitochondria-associated endoplasmic reticulum membranes", alone and in combination. English-language original mechanistic, translational, observational, and interventional studies were prioritised; recent high-quality reviews were used for context and to identify primary studies. Evidence from other neurological disorders was retained only when direct DN evidence was limited and the study clarified biological plausibility. Because this is a narrative review, no formal risk-of-bias tool or GRADE assessment was applied; human, animal, and cellular evidence and major translational limitations are instead distinguished explicitly.
    Keywords:  Diabetic neuropathy; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1186/s12967-026-09015-y
  46. Am J Physiol Cell Physiol. 2026 Oct 29.
    Beyond Mitochondrial Fission: Emerging Roles of Drp1 in Skeletal Muscle Physiology and Disease.
    Kai Zou, Nicolas J Berger, Zhenqi Zhou, Benjamin A Kugler.
      Dynamin-related protein 1 (Drp1) is best recognized as the primary regulator of mitochondrial fission. However, emerging evidence indicates that Drp1 is a multifaceted regulator of skeletal muscle physiology whose functions extend well beyond its canonical role in mitochondrial fission. Recent studies have identified novel roles of Drp1 in regulating substrate utilization, calcium homeostasis, reactive oxygen species signaling, respiratory complex assembly, and mitochondrial-to-nuclear signaling, including mechanisms independent of its canonical fission activity. Importantly, Drp1 regulation in skeletal muscle is highly context-dependent, as both excessive and insufficient Drp1 activity can disrupt skeletal muscle homeostasis. For example, excessive Drp1 activation and mitochondrial fragmentation are associated with insulin resistance, type 2 diabetes, and neuromuscular diseases, whereas severe or prolonged Drp1 deficiency impairs mitochondrial quality control, bioenergetics, induce muscle atrophy, and compromise the exercise training adaptations. Therefore, the biological consequences of Drp1 modulation are highly context dependent and influenced by the metabolic and physiological state of skeletal muscle. In this review, we summarize the molecular regulation and emerging functions of Drp1 in skeletal muscle, with particular emphasis on fission-independent mechanisms and Drp1 dysregulation in metabolic and neuromuscular diseases. We further discuss pharmacological and non-pharmacological strategies for modulating Drp1 signaling and highlight emerging approaches for skeletal muscle-specific targeting. Collectively, current evidence supports a paradigm in which skeletal muscle Drp1 functions as a multifaceted regulator of mitochondrial and skeletal muscle homeostasis, highlighting the therapeutic potential of modulating Drp1 activity to optimize mitochondrial and muscle health across different physiological and pathological contexts.
    Keywords:  DYNAMIN-RELATED PROTEIN 1; MITOCHONDRIA DYNAMICS; SKELETAL MUSCLE
    DOI:  https://doi.org/10.1152/ajpcell.90065.2026
  47. Mitochondrion. 2026 Oct 25. pii: S1567-7249(26)00120-0. [Epub ahead of print]92 102230
    Paraganglioma and childhood-onset optic atrophy in a SDHA compound heterozygous patient: an example of dual dominant and recessive inheritance.
    Catherine Vincent Delorme, Catherine Cardot Bauters, Caroline Girardot, Isabelle Bouvet Drumare, Sabine Defoort Dhellemmes, Patrizia Amati-Bonneau, Lucie Coppin, Claire-Marie Dhaenens, Marie-Francoise Odou, Pascal Pigny.
      SDHA pathogenic variants cause moderate to severe complex II deficiency, which manifests as a mitochondrial disorder in a homozygous/compound heterozygous child, or as hereditary cancer, mostly paraganglioma or pheochromocytoma, in a heterozygous adult. Here, we report the first composite heterozygous SDHA patient (hypomorphic allele p.(Thr508Ile) × null allele p.(Arg451His)) who developed complete congenital optic atrophy and a paraganglioma at the age of 36 yrs. No other germline variants were identified by sequencing panels of genes involved in these two disorders. This raises the question of whether paraganglioma screening should be implemented for carriers of a null SDHA variant.
    Keywords:  Complex II; Functional testing; Genetic disease; Mitochondria; Paraganglioma; SDHA
    DOI:  https://doi.org/10.1016/j.mito.2026.102230
  48. Am J Physiol Cell Physiol. 2026 Nov 01. 331(5): C1542-C1554
    Exposure to airborne PM2.5 suppresses mitochondrial associated membranes and MAM-associated metabolic regulators in mouse liver.
    Qi Chen, Hyunbae Kim, Lucynda Pham, Qinghua Sun, Ren Zhang, Maik Hüttemann, Siddhesh Aras, Lawrence I Grossman, Kezhong Zhang.
      Airborne fine particulate matter ≤2.5 μm in diameter (PM2.5) poses a significant threat to human health due to its capacity to penetrate deep into the respiratory tract and enter the systemic circulation. Mitochondria-associated membranes (MAMs), specialized contact sites between the endoplasmic reticulum (ER) and mitochondria, are central regulators of calcium signaling, stress responses, and energy metabolism. In this study, we reveal that exposure to environmentally relevant PM2.5 disrupts hepatic MAM integrity through an oxidative stress-dependent mechanism. Upon PM2.5 exposure, macrophages take up PM2.5 particles, which can be prevented by treatment with antioxidants or cellular calcium chelators. Transmission electron microscopy examination of MAM structure indicated that PM2.5 inhalation markedly reduces MAM abundance and the proportion of MAM-forming mitochondria in mouse livers. Direct exposure of hepatocytes to PM2.5 particles suppresses both basal and glucagon-induced MAM formation, as visualized using an MAM-specific bimolecular fluorescence complementation sensor. Mechanistically, PM2.5 exposure represses MAM-associated transcriptional programs controlling the mitochondrial unfolded protein response and fatty acid oxidation by downregulation of the cyclic AMP-responsive element-binding protein hepatic-specific/peroxisome proliferator-activated receptor-α regulatory axis. In summary, our studies identify disruption of ER-mitochondria communication as a pivotal mechanism by which PM2.5 impairs mitochondrial homeostasis and metabolic resilience, providing new insight into the pathogenesis of air pollution-associated metabolic disorders.NEW & NOTEWORTHY This study identifies mitochondria-associated membranes (MAMs) as a previously unrecognized target of airborne particulate matter PM2.5 in the liver. We demonstrate that environmentally relevant PM2.5 exposure disrupts endoplasmic reticulum-mitochondria contact sites through an oxidative stress-dependent mechanism. PM2.5 suppresses hepatic MAM formation and thereby impairs mitochondrial unfolded protein response and fatty acid oxidation programs. These findings establish loss of MAM integrity as a major mechanism linking air pollution exposure to mitochondrial dysfunction and metabolic vulnerability.
    Keywords:  airborne particulate matter; fatty acid oxidation; metabolic disorders; mitochondria-associated membrane; mitochondrial UPR
    DOI:  https://doi.org/10.1152/ajpcell.00103.2026
  49. Biochemistry (Mosc). 2026 Oct;91(10): 1798-1821
    Mitochondria, Cell Death, and Neurodegeneration.
    Andrey Yu Vinokurov, Artyom Yu Baev, Elena V Potapova, Andrey Yu Abramov.
      Mitochondria, acquired during the evolution of eukaryotic cells, have become essential organelles for cellular life. Beyond their well-established role in energy production, mitochondria are key regulators of intracellular signaling, acting as modulators of Ca2+ transport and major sources of reactive oxygen species. Mitochondrial metabolism is also closely linked to the metabolism of signaling molecules, including glutamate and monoamines. Another vital role of mitochondria is their involvement in the regulation of cell death. Disruption of mitochondrial functions contributes to the development of multiple pathological conditions, including neurodegenerative diseases. Here, we discuss how impairments in major mitochondrial processes contribute to neuronal death in neurodegenerative diseases and highlight the principal mitochondrial targets with potential pharmacological relevance.
    Keywords:  bioenergetics; calcium homeostasis; cell death; mitochondria; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.1134/S0006297926601826
  50. Cell Death Discov. 2026 Jul 29. pii: 426. [Epub ahead of print]12(1):
    Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis.
    Ayesha Kiran Mendes, Stijn L M In 't Groen, Vicky De Winter, Vincent Timmerman.
      Small Heat Shock Protein Family B (HSPB) members are ATP-independent chaperones essential for maintaining cellular proteostasis. Together with chaperones and co-chaperones such as HSP70 and BAG3, they prevent aberrant protein folding and suppress protein aggregation, particularly under proteotoxic stress. HSPBs have also been extensively linked to neurodegenerative disease and in promoting chemoresistance in cancer. We previously showed that members of the HSPB family can reside within the mitochondrial intermembrane space where they contribute to the maintenance of proteostasis, and that acute cytotoxic stress leads to HSPB sequestration to the outer mitochondrial membrane. Here, we further elucidate this mechanism, demonstrating that HSPB1 is selectively enriched within mitochondria under milder thermal stress condition, exhibiting a pronounced association with the outer mitochondrial membrane. We also observed distinct stress-dependent mitochondrial recruitment profiles across HSPB paralogs, revealing a similar behaviour for HSPB8, whereby HSPB1 responded at a comparatively lower stress threshold, indicating functional specialization within the HSPB family. Inducing this mechanism enhances cell survival during hyperthermic stress, preventing Cytochrome c release, and raising the apoptotic activation threshold in our experimental system. These findings indicate that HSPBs, particularly HSPB1 may contribute to mitochondrial stress adaptation prior to Cytochrome c release. This underexplored mechanism may underlie the modulation of stress-related and degenerative disease progression and contribute to the chemoresistance associated with cancer, which have been attributed to HSPBs.
    DOI:  https://doi.org/10.1038/s41420-026-03268-8
  51. bioRxiv. 2026 Sep 03. pii: 2026.09.01.748636. [Epub ahead of print]
    Integrated map of somatic mosaicism across human tissues in 25 individuals.
    Somatic Mosaicism across Human Tissues Network
      Although all cells in the body descend from one genome, they accumulate distinct genetic and epigenetic changes over a lifetime, producing a mosaic of somatic variation that can shape development, aging, and disease. This mosaicism is often studied in isolation, leaving unclear how these forms relate within and between individuals. Here, we present the first integrated analysis of the Somatic Mosaicism across Human Tissues (SMaHT) Network's production resource, profiling up to 20 tissues from 25 donors using short- and long-read, duplex, single-cell, transcriptomic, and epigenomic sequencing, alongside donor-specific near-telomere-to-telomere assemblies. Somatic mutation burden cannot be captured by a single data type or metric, as tissues accumulate distinct variant classes largely independently of one another. Long-read and single-cell data resolved cell-type-specific mutational processes, traced mobile element insertions to source loci, and revealed the developmental timing and functional consequences of individual mutations. Donor-specific assemblies uncovered elevated mutation rates within centromeres and segmental duplications inaccessible to standard reference genomes, while haplotype-resolved chromatin and methylation data showed that nongenetically-deterministic epigenetic states are pervasive across tissues. Together, these findings provide an integrated, multi-scale portrait of somatic mosaicism across the human body, establishing a baseline against which its contributions to aging and disease can be measured.
    DOI:  https://doi.org/10.64898/2026.09.01.748636
  52. Nucleic Acids Res. 2026 Oct 29. pii: gkag1070. [Epub ahead of print]
    MitImpact 4: a genome-wide resource for the interpretation of coding and non-coding mitochondrial DNA variants.
    Agnese Giovannetti, Alessandro Napoli, Niccolò Liorni, Francesco Petrizzelli, Tommaso Biagini, Antonio Gasbarrini, Viviana Caputo, Tommaso Mazza.
      Mitochondrial DNA variants are a frequent cause of inherited disease, yet their computational interpretation has focused almost exclusively on the 13 protein-coding genes. Variants in tRNA and rRNA genes, which carry a disproportionate share of the known pathogenic alleles, have remained a diagnostic blind spot, because their effect depends on RNA structure rather than on protein sequence and few dedicated predictors exist. MitImpact 4 removes this asymmetry. The database now covers all 49 704 single-nucleotide variants that can occur in the mitochondrial genome and reports their functional consequence, phylogenetic conservation, local mutational constraint, and population frequency in gnomAD, HelixMTdb, and ToMMo. Missense variants are annotated with APOGEE 2 and with newly added predictors, including AlphaMissense, ESM1b, VARITY, and LIST-S2, while tRNA and rRNA variants receive predictions from nAPOGEE, our RNA-specific model, alongside MitoTIP and PON-mt-tRNA. For both classes, scores are accompanied by posterior probabilities of pathogenicity that can be used within the ACMG/AMP framework for mitochondrial DNA. Clinical annotation from ClinVar and MITOMAP, including ClinGen expert-panel classifications, is integrated in a redesigned interface that also annotates user-submitted VCF files. MitImpact 4 is freely available at https://mitimpact.mcb2lab.org.
    DOI:  https://doi.org/10.1093/nar/gkag1070
  53. Cell Rep. 2026 Oct 26. pii: S2211-1247(26)01303-3. [Epub ahead of print]45(11): 118224
    Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability.
    Jasmine Phan, Lincoln Gay, Ladislav Dokládal, Claudio De Virgilio, Leonardo Salcedo, Suprim Tha, Caitlyn Wandvik, Markus Babst.
      How cells integrate nutrient availability to coordinate metabolism and growth remains poorly understood. Here, we identify branched-chain amino acid (BCAA) synthesis as a metabolic sensing system linking mitochondrial activity to translational and transcriptional control. Yeast limits Leu and Val import and instead relies on their synthesis, allowing BCAA production to reflect mitochondrial anabolic capacity. Reduced Val synthesis activates Gcn2, whereas reduced Leu synthesis inhibits TORC1, together decreasing translation efficiency and restricting growth. This response lowers levels of the transcriptional repressor Mig1, suppressing the Warburg/Crabtree effect and promoting alternative carbon source utilization. Remarkably, pharmacological inhibition of Leu/Val synthesis induces this metabolic reprogramming even in nutrient-rich medium, indicating that mitochondrial BCAA synthesis can partially override other nutrient-sensing pathways. Thus, BCAA synthesis couples mitochondrial anabolic capacity to Gcn2 and TORC1 activity and, through translational control of transcription factor abundance, shapes cellular metabolism.
    Keywords:  CP: metabolism; Gcn2; TORC1; Warburg effect; amino acid synthesis; diauxic shift; mitochondria; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2026.118224
  54. Science. 2026 Oct 29. 394(6823): eaed2525
    Stimulated protein degradation to promote mitochondrial function and neuronal survival.
    Srividya Chandrasekhar, Rachael McMinimy, Andrew G Manford, Eddie Wehri, Christine L Gee, Caitlyn Miller, Baris Bingol, John Kuriyan, Julia Schaletzky, Michael Rapé.
      Targeted protein degradation is a promising modality to treat cancer or inflammation, but whether it can provide a similar benefit for disorders caused by pervasive protein dysregulation is unclear. We describe stimulated protein degradation (SPD) as a strategy that leverages agonists of stress-responsive E3 ubiquitin ligases to simultaneously eliminate multiple pathogenic factors. Specifically, we show that activators of the reductive stress response E3 CUL2FEM1B boost degradation of multiple physiological substrates to improve mitochondrial import and electron transport chain assembly. In this manner, CUL2FEM1B agonists preserve mitochondrial function and neuronal survival in models of neurodegenerative COX deficiency syndrome and Friedreich's ataxia. By activating E3 ligases that evolved to safeguard cellular integrity, SPD expands the use of compound-induced protein degradation to complex pathologies of high unmet need.
    DOI:  https://doi.org/10.1126/science.aed2525
  55. BMC Neurol. 2026 Aug 03. pii: 680. [Epub ahead of print]26(1):
    Recombinant human growth hormone exposure preceding multisystem manifestations in a patient with MT-TL1 m.3243 A > G-related mitochondrial disease: a ten-year case report.
    Yinhong Xie, Lizhen Wang, Shuangfeng Yang, Pei Wang, Junhao Zhang, Chengcheng He, Hongyu Lin, Yang Li, Shanfeng Qiu, Shunxian Wang, Shengxiong Pu, Lei Zhang, Jian Chen, Yang Peng, Yun Liu, Ying Ma.
       BACKGROUND: Mitochondrial encephalomyopathy (ME) is clinically heterogeneous and frequently misdiagnosed as a single-organ disease. While recombinant human growth hormone (rhGH) is commonly used to treat short stature in children, its safety in patients with undiagnosed ME remains uncertain, with theoretical concerns that it may exacerbate multisystem disease progression.
    CASE PRESENTATION: We described a genetically confirmed case of ME in a 24-year-old male patient over a decade. After receiving rhGH therapy at age 14 in 2015 for childhood short stature, he developed a cascade of multisystem manifestations: ptosis and cognitive decline emerged in 2017, followed by an acute metabolic crisis resembling heatstroke in 2018. Over the following years, he was diagnosed with a succession of conditions, including chronic sinusitis, sensorineural hearing loss, diabetes (HbA1c 7.25%), myocardial hypertrophy with elevated troponin (0.016 ng/L), and marked cerebellar atrophy. Laboratory studies consistently showed hyperlactatemia (3.72 mmol/L), and neuropsychological testing indicated mild to moderate cognitive impairment (MMSE 21, MoCA 13).
    CONCLUSIONS: The chronological correlation observed in this case suggested a possible temporal association between rhGH exposure and subsequent multisystem disease expression. However, this single case observation does not establish causality; the observed timeline may, in part, reflect the natural history of MELAS-spectrum disease, which often manifests multisystem involvement during adolescence and early adulthood. Nonetheless, this report highlights the importance of clinical vigilance and thorough evaluation for underlying mitochondrial disorders prior to initiating rhGH treatment, especially in children with short stature and subtle neurological symptoms.
    Keywords:  Case report; Metabolic stress; Mitochondrial encephalomyopathy; Multisystem disease; Recombinant human growth hormone; m.3243A>G mutation
    DOI:  https://doi.org/10.1186/s12883-026-05197-6
  56. Nat Cardiovasc Res. 2026 Oct 27.
    Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.
    Joshua L Axelrod, Zuzana Nichtová, Timothy Schneider, Jaehoon Lee, Ryan Pekson, Dongze Qin, Madeeha Ghazi, Vinay Kumar, Victoria Margulets, Lorrie A Kirshenbaum, Gaetano Santulli, György Csordás, John W Calvert, Richard N Kitsis.
      Mitofusin (MFN) 1 and MFN2 are large outer mitochondrial membrane GTPases. Dimerization of MFNs on adjacent mitochondria mediates mitochondrial fusion. MFN2, but not MFN1, also resides at the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane, and dimerization of MFNs on ER/SR and mitochondria tethers the two organelles. Here we report that cell-permeable peptides that perturb MFN conformations regulate myocardial infarct size by impacting ER/SR-mitochondria interactions and Ca2+ transfer independently of changes in mitochondrial fusion. MFN activators increase ER/SR-mitochondria proximity, promote ER/SR to mitochondria Ca2+ transfer and exacerbate infarct size in mice, with effects dependent on MFN2, but not MFN1, and on mitochondrial calcium uniporter, which transports Ca2+ into the mitochondrial matrix. Conversely, although ER/SR-mitochondria proximity is not affected, MFN inhibitors reduce mitochondrial Ca2+ transfer and infarct size, even when their administration is delayed until reperfusion. These findings demonstrate the feasibility of acutely modulating ER/SR-mitochondria interactions and Ca2+ dynamics and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction.
    DOI:  https://doi.org/10.1038/s44161-026-00903-6
  57. Neurogenetics. 2026 Oct 29. pii: 85. [Epub ahead of print]27(1):
    Expanding the genetic spectrum of inherited peripheral neuropathies in complex neurogenetic disorders using whole-exome sequencing.
    Paria Najarzadeh Torbati, Reza Boostani, Mojtaba Safi, Najmeh Ahangari, Mohammad Doosti, Hasan Badpar, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Barbara Vona.
      Inherited peripheral neuropathies (IPNs) represent a clinically and genetically heterogeneous group of disorders affecting sensory, motor, autonomic functions, and can also present as a part of complex neurogenetic syndromes. Charcot-Marie-Tooth disease (CMT) is the most prevalent type of IPN. Despite advances in genetic testing, the diagnostic process remains challenging due to genetic heterogeneity and overlapping clinical phenotypes. We performed a comprehensive genetic evaluation of 126 patients presenting with symptoms of IPN. Nineteen patients with a typical CMT phenotype were initially screened for PMP22 copy number variations using Multiplex Ligation-dependent Probe Amplification (MLPA). Whole-exome sequencing (WES) was subsequently performed in 107 patients. Of these, 72 (63.7%) were classified as pathogenic or likely pathogenic, including 36 novel variants (50.0%), yielding an overall WES diagnostic rate of 62.6% (67/107). CMT-spectrum disorders identified by MLPA (n = 19 patients) and WES (n = 33 patients) accounted for 41.3% (52/126) of the study cohort. Additional diagnoses included hereditary sensory neuropathy 3.97% (5/126), distal hereditary motor neuropathy 4.76% (6/126), spastic paraplegia 3.97% (5/126), spinocerebellar ataxia 5.56% (7/126), spastic ataxia 8.73% (11/126), mitochondrial disease 7.94% (10/126), and other complex neurogenetic disorders 23.81% (30/126). Our findings highlight the utility of genomic sequencing approaches for resolving clinically heterogeneous neuropathy presentations and demonstrate the value of WES in a highly consanguineous Iranian cohort. These results support the role of WES in advancing precision medicine approaches for inherited neuropathies.
    Keywords:  Hereditary sensory and motor neuropathy; Inherited peripheral neuropathy; Peripheral nervous system diseases; Whole exome sequencing
    DOI:  https://doi.org/10.1007/s10048-026-00952-w
  58. Immunity. 2026 Oct 30. pii: S1074-7613(26)00429-2. [Epub ahead of print]
    Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.
    Kosuke Tanaka, Yasuki Adachi, Takuma Irie, Tomoko Yamamori-Morita, Kazuhiro Kumagai, Takuya Owari, Genki Okumura, Yoshihisa Kobayashi, Hideaki Bando, Yuichiro Tsukada, Shogo Kumagai, Kota Itahashi, Eri Sugiyama, Hiroki Izumi, Yuji Shibata, Koichi Goto, Akihiro Ohashi, Susumu S Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa.
      Cells experiencing mitochondrial stress can undergo apoptosis or cell death that triggers innate immune activation. We examined the mechanisms determining these distinct outcomes in cancer. Abundant mitochondrial DNA (mtDNA) and high expression of the cGAS-STING pathway were features of KRAS-mutant cancers. In a pharmacological screen, MEK inhibitor (MEKi) effectively induced mtDNA release into the cytosol in KRAS-mutant cancer cells. However, MEKi also induced PRKN-mediated mitophagy, which limited mtDNA release by eliminating damaged mitochondria. Inhibition of mitophagy sustained mtDNA efflux and amplified cGAS-STING signaling. Mechanistically, PRKN-mediated mitophagy restrained mitochondrial outer membrane permeabilization (MOMP) to limit mtDNA efflux. The balance between mtDNA and cytochrome c (cyt.c) release defined two immunologically distinct outcomes: immunogenic cell death (ICD) and apoptosis. In preclinical models, combined inhibition of MEK and mitophagy induced robust dendritic cell (DC) activation and promoted CD8+ T cell-mediated antitumor immunity. Consistently, PRKN expression negatively correlated with immune infiltration in human cancers. Collectively, these findings provide a rationale for combination strategies targeting mitochondrial dynamics to augment antitumor immunity.
    Keywords:  KRAS-mutant cancer; TWINKLE; cGAS-STING; immunogenic cell death; mitochondrial DNA; mitophagy; molecularly targeted therapy; subapoptotic MOMP; type I interferon
    DOI:  https://doi.org/10.1016/j.immuni.2026.10.002
  59. Signal Transduct Target Ther. 2026 Oct 26. pii: 469. [Epub ahead of print]11(1):
    Encapsulated mitochondrial transplantation: Advancing organelle therapeutics.
    Hae-Jun Yang, Pil-Soo Jeong, Sun-Uk Kim.
      
    DOI:  https://doi.org/10.1038/s41392-026-02959-z
  60. Cell Biol Toxicol. 2026 Aug 03. pii: 125. [Epub ahead of print]42(1):
    Mitochondrial remodeling with mitochondrial fusion promoter M1 for osteoarthritis therapy.
    Xiangqian Zou, Yibo Ma, Zhi Yang, Renjie Zhang, Christine Tao, Guohua Zhang, Chenyue Xu, Bingxin Liu, Changjian Chen, Liang Yang.
      Osteoarthritis (OA) is closely associated with mitochondrial dysfunction, but whether mitochondrial dynamics restoration can serve as an effective therapeutic entry point remains unclear. This study investigated the mitochondrial fusion promoter M1 (MFPM1) as a modulator of mitochondrial dynamics in OA and explored its target-associated mechanism. Bioinformatic and transcriptomic analyses linked OA progression and MFPM1 activity to mitochondrial dynamics, oxidative stress, inflammatory activation, apoptosis, and extracellular matrix (ECM) homeostasis. In OA-like chondrocytes, MFPM1 restored the balance between DNM1L/DRP1-associated fission signaling and MFN2/OPA1-associated fusion machinery, accompanied by recovery of mitochondrial energy metabolism and redox homeostasis and attenuation of inflammatory and apoptotic injury. Target prediction, molecular docking, molecular dynamics simulation, and CETSA identified GSK3B as a prioritized MFPM1 target, while GSK3B overexpression weakened the mitochondrial and cartilage-protective effects of MFPM1, supporting its functional involvement. MFPM1 further preserved ECM homeostasis and alleviated OA progression. These findings identify mitochondrial dynamics remodeling as a mechanistic entry point for OA intervention and support MFPM1 as a mitochondria-centered therapeutic candidate.
    Keywords:  Extracellular matrix; Mitochondrial dynamics; Mitochondrial fusion promoter M1; Mitochondrial remodeling; Osteoarthritis
    DOI:  https://doi.org/10.1007/s10565-026-10242-8
  61. J Fluoresc. 2026 Oct 27.
    Mitochondria-Targeted Polymer-Lipid Hybrid Nanoprobes for Imaging of K+ and O2 Dynamics in Living Cells.
    Tingting Pan, Jiahui Mai, Huili Li, Jianxiang Liao, Yanqing Tian.
      Mitochondrial potassium ion (K+) homeostasis and oxygen (O2) level are closely involved in diverse cellular physiological and pathological processes. However, imaging these two parameters within the same subcellular remains challenging because combination of different probes often suffers from spectral crosstalk and mismatched cellular internalization kinetics. Herein, we constructed mitochondria-targeted polymer-lipid hybrid nanoparticles, TPP-KO NPs, for dual-responsive imaging of K+ and O2 dynamics. The nanoprobes were fabricated by a facile self-assembly strategy and were designed with a spatially isolated core-shell architecture to separate the K+- and O2-sensing moieties. In aqueous solution, TPP-KO NPs exhibited concentration-dependent responses to K+ and O2, rapid response kinetics, good colloidal stability, and favorable photostability. Cellular evaluations confirmed their favorable biocompatibility and mitochondrial localization. In living cells, TPP-KO NPs provided distinguishable optical signals of mitochondrial K+ fluctuations and O2 dynamics under the specific excitation and emission ranges after K+-modulating or hypoxic treatments. This dual-responsive nanoprobe system provides an imaging platform for monitoring of mitochondrial K+ and O2 dynamics in living cells, which holds great potential for exploring the mitochondrial K+-O2 microenvironment.
    Keywords:  Dual-responsive nanoprobe; Live-cell imaging; Mitochondrial-targeting; Oxygen sensing; Potassium ion sensing
    DOI:  https://doi.org/10.1007/s10895-026-04982-3
  62. J Cell Sci. 2026 Oct 28. pii: jcs.264850. [Epub ahead of print]
    Suppressing the SREBP-mediated lipogenic pathway rescues pink1 deficiency in Drosophila and influences mitochondrial morphology.
    Jenny Zhe Liao, Christopher Tam, Esther M Verheyen.
      Sterol-regulatory element binding proteins (SREBP) are master transcriptional factors controlling lipogenesis. In Drosophila, the SREBP-mediated lipogenic pathway is essential for development. Homozygous SREBP mutants are lipid deficient and larval lethal, whereas excessive lipids in flies are often associated with neurodegeneration. Since SREBP has previously been identified as a risk factor for Parkinson's disease, we further investigated the role of SREBP-mediated lipogenesis in a pink1 deficient Drosophila parkinsonism model. We found that expressing either dominant negative SREBP or knocking down its downstream target rescues pink1 mutant phenotypes including thorax indentation and impaired locomotion. Investigation of the indirect flight muscles reveals that suppression of the lipogenic pathway restores defective muscle morphology and mitochondrial defects, and reduces ectopic ROS associated with the pink1 null allele. Interestingly, we found altered mitochondrial morphologies when the lipogenic pathway was manipulated under physiological condition, suggesting the SREBP-mediated lipogenic pathway plays a role in regulating mitochondrial shapes. Our findings highlight the tight connection between lipid metabolism and mitochondria in both disease and physiological setting.
    Keywords:  Lipids; Mitochondrial dynamics; Parkinsonism; Pink1; SREBP
    DOI:  https://doi.org/10.1242/jcs.264850
  63. Nucleic Acids Res. 2026 Oct 31. pii: gkag1102. [Epub ahead of print]
    MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains.
    Laurens Wiel, Federico Ferraro, Jay Yu, Jimmy Zhen, Daniel Nachun, Rodrigo Mendez, Chloe M Reuter, Jason L Cui, Devon E Bonner, Jennefer N Carter, Shruti Marwaha, Maartje van de Vorst, Sara Emami, Elijah Kravets, Matthew B Neu, Tjakko J van Ham, Tjitske Kleefstra, Euan A Ashley, Jonathan A Bernstein, Stephen B Montgomery, Christian Gilissen, Matthew T Wheeler.
      The interpretation of missense variants remains a major challenge in clinical genetics. "Meta-domains" aggregate population and pathogenic variation across homologous Pfam domain instances in the human proteome, providing per-residue context for interpreting variants of uncertain significance (VUS). Our 2019 implementation, MetaDome, is widely used and named in clinical variant-classification guidelines. Here, we present the MetaDome 2027 update, featuring a comprehensively updated dataset and GRCh38 support. The redesigned pipeline enables incremental updates of GENCODE, UniProtKB/Swiss-Prot, Pfam, gnomAD, and ClinVar while maintaining 100% sequence-identity gene-to-protein mapping. Annotated Pfam domain instances grew 14.9% from 71 419 to 82 069 and meta-domain-eligible Pfam families (≥2 human occurrences) by 73.3% from 3334 to 5778; Pfam domains are annotated to 92% of human proteins. Approximately 43% of mapped protein-coding nucleotides (14.3 million in GRCh38, 13.8 million in GRCh37) are in a meta-domain; in GRCh38, 67.9% (37 692 of 55 548) of pathogenic or likely pathogenic ClinVar missense variants fall at such a position. We show how MetaDome helped reclassify a de novo missense VUS in RALA and identify 52 463 ClinVar missense VUS for which meta-domains supply otherwise unavailable pathogenic evidence. MetaDome is freely available at www.metadome.app.
    DOI:  https://doi.org/10.1093/nar/gkag1102
  64. Nat Chem Biol. 2026 Oct 28.
    ADP-ribose induces neuronal ferroptosis through ENT2-mediated nucleotide rewiring.
    Haoqi Ni, Yingying He, Qiao Ye, Peng Cui, Jieyuan Yuan, Guoqing Lv, Huiyan Lei, Qian Wang, Feng Wang, Qichuan ZhuGe, Baodong Chen, Ling Liang, Yong Zhang, Lin Yuan.
      Excessive nicotinamide adenine dinucleotide (NAD+) consumption fuels neurological pathogenesis, yet the limited benefit of NAD+ supplementation hints at unresolved toxicity from its catabolism. Here, we identify ADP-ribose, a neglected NAD+ catabolite generated by poly(ADP-ribose) polymerase 1 (PARP1) and poly(ADP-ribose) glycohydrolase, as an inducer of neuronal ferroptosis through nucleotide metabolic rewiring. We discovered that extracellular ADP-ribose directly binds and inhibits the nucleoside transporter equilibrative nucleoside transporter 2 (ENT2; SLC29A2), suppressing nucleotide salvage and driving compensatory hyperactivation of de novo purine and pyrimidine biosynthesis. This metabolic rerouting engages xanthine oxidase (XO) and dihydroorotate dehydrogenase (DHODH) to unleash superoxide bursts, triggering lipid peroxidation and ferroptotic neuronal death. ADP-ribose accumulates across neurological disease models and its acute administration recapitulates ferroptotic neurodegeneration in vivo. Targeting ADP-ribose signaling through PARP1 knockdown, NUDT9-mediated hydrolysis or dual XO/DHODH inhibition rescues delayed cognitive deficits in intracerebral hemorrhage models. These findings define the ADP-ribose-ENT2 axis as a metabolic driver of neuronal ferroptosis and reveal a druggable vulnerability in disorders marked by NAD+ hyperconsumption.
    DOI:  https://doi.org/10.1038/s41589-026-02355-2
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