bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–02–01
77 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mito-nuclear communication: From cellular responses to organismal health.
  2. Mitochondria as sources and targets of cellular signaling.
  3. Impaired mitochondrial morphology and respiratory dysfunction in human induced pluripotent stem cells with mitochondrial tRNA mutations (m.3243A>G and m.14739G>A).
  4. Systematic evaluation of mitochondrial morphology regulators for amelioration of neuronal α-synucleinopathy.
  5. Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease.
  6. Bioenergetic Signatures of DLD Deficiency: Dissecting PDHc- and α-KGDHc-Linked Defects.
  7. Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.
  8. Mitochondria and Epigenetic Regulation: Bidirectional Crosstalk and Emerging Mitochondria-Targeted Degron Tools.
  9. Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
  10. Drivers of Diagnostic Delay in Mitochondrial Disease: Missed Recognition of Canonical Features.
  11. Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
  12. Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
  13. ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
  14. Mitochondrial Myopathy, Lactic Acidosis, and Stroke-Like Episodes Combined with Diabetes: A Case Report.
  15. Coordination of cell organelles to promote metabolon formation.
  16. [Super-refractory status epilepticus caused by hereditary mitochondrial disease].
  17. Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
  18. Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
  19. Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
  20. Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Aging: Current Insights and Therapeutic Advances.
  21. A TFAP4-UBC9-SUMO1 axis orchestrates pathological mitochondrial hyperfission in diabetic complications.
  22. Myo-Inositol modulates AKT signalling, mitochondrial protein expression and intracellular Ca²⁺dynamics in human dermal fibroblasts.
  23. Unveiling a Novel MT-TS1 m.7479G>A in Mitochondrial Diabetes: The Critical Role of mtDNA Sequencing in Atypical Cases.
  24. PHB2 mitigates intervertebral disc degeneration by modulating mitophagy to inhibit necroptosis in nucleus pulposus cells.
  25. Disruption of ATP Synthase Spatiotemporal Organization, Ca2+ Dynamics, and Contractile Function in Senescent Cardiomyocytes.
  26. Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
  27. Mitochondrial succinate transport is required for cardiac ischemia/reperfusion injury.
  28. Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
  29. HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.
  30. BAP31 Modulates Mitochondrial Homeostasis Through PINK1/Parkin Pathway in MPTP Parkinsonism Mouse Models.
  31. Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes.
  32. Genome-wide methylation detection and episignature analysis using PacBio long-read sequencing.
  33. Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study.
  34. In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.
  35. Optical and Microdialysis Monitoring of Succinate Prodrug Treatment in a Rotenone-Induced Model of Mitochondrial Dysfunction in Swine.
  36. Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.
  37. TRPM8 Regulates Mitochondrial Ca2+-Dynamics, Temperature and Endoplasmic Reticulum-Mitochondrial Contact Points in T Cell.
  38. From isolation to insights: mitochondrial complex I in the diatom Phaeodactylum tricornutum.
  39. Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.
  40. Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
  41. Hereditary Polyneuropathies in the Era of Precision Medicine: Genetic Complexity and Emerging Strategies.
  42. Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure.
  43. Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.
  44. Spatiotemporally regulated mitochondrial genome editing via enzyme and NIR-activated CRISPR/Cas9 nanoplatform.
  45. Collapsin Response Mediator Protein 2 (CRMP2) Modulates Induction of the Mitochondrial Permeability Transition Pore in a Knock-In Mouse Model of Alzheimer's Disease.
  46. Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
  47. The LncRNA11-hnRNPA1 functional axis maintains adipose tissue metabolic homeostasis by promoting mitochondrial respiration and lipid utilization.
  48. Genetic evidence for a functional association between Parkinson's disease proteins leucine-rich repeat kinase 2 and α-synuclein during axonal transport.
  49. A Non-Mitophagy Activity of BNIP3L/NIX in Amygdala Glutamatergic Neurons is Essential for Contextual Fear Memory Formation.
  50. A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
  51. Novel Clinical Insights From a Swedish RFC1 Spectrum Disorder Cohort.
  52. Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function.
  53. Off-target effects of mitochondrial oxidative phosphorylation inhibitors are common and can compromise the viability of cultured cells.
  54. UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment.
  55. Protocol for the generation and xenotransplantation of human induced pluripotent stem cell-derived neural progenitor cells into the mouse forebrain.
  56. Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.
  57. Hemoglobin alpha regulates T-lymphocyte activation and mitochondrial function.
  58. Methylation, acetylation and cell fate.
  59. A step towards building miniature human livers.
  60. Cryo-EM structure of bixafen-bound S. cerevisiae complex II unravels SDHI specificity against pathogenic fungi.
  61. Exogenous mitochondrial transfer alleviates neurodegeneration in Parkinson's disease model by improving mitochondrial function.
  62. Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
  63. Fighting Parkinson's disease: a neurologist-patient journey.
  64. Tachycardiomyopathy-Like Presentation in Neonatal MCAD Deficiency: A Novel Cardiac Phenotype.
  65. Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors.
  66. RTN4IP1 Mutation and Endocrine Failure: Clinical Features and Possible Benefits of Coenzyme Q10.
  67. Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review.
  68. Mitochondria-targeted antioxidant AntiOxBEN2 prevents metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing fatty acid oxidation and mitochondrial bioenergetics.
  69. Meiotic purification of dysfunctional mitochondria in mouse oocytes.
  70. Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
  71. Cholinergic Phenotypes of Acetyl-CoA with ATP-Citrate Lyase Link.
  72. Proliferation of activated hepatic stellate cells requires REST.
  73. Mitochondria transfer from myocytes to endothelial cells Promotes angiogenesis in skeletal muscle.
  74. The influence of cellular energy status, microtubules, and crowding on mitochondrial motion.
  75. Rapid targeted analysis of the genome: Rapid genomic sequencing in critically ill infants.
  76. Lysosomes as hubs of metabolic sensing and cellular homeostasis.
  77. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
  1. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00021-3. [Epub ahead of print]
    Mito-nuclear communication: From cellular responses to organismal health.
    Guanyu Chen, Hangyu Dong, Ye Tian.
      The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations activate retrograde pathways such as the mitochondrial unfolded protein response (UPRmt) and the mitochondrial integrated stress response (ISRmt), which couple organelle dysfunction to nuclear transcriptional programs, thereby promoting mitochondrial function and preserving cellular integrity. Importantly, this communication is not confined to individual cells but extends across tissues to coordinate systemic adaptations. Stress signals can be sensed, broadcasted through secreted mitokines and neural circuits, and then interpreted by distal organs to coordinate systemic adaptations. These systemic responses integrate metabolism, immunity, and behavior, conferring resilience to stress and shaping the trajectory of aging. Understanding this multi-layered communication, from the organelle to the organism and its microbial ecosystem, promises new therapeutic strategies to enhance mitochondrial function, promote resilience, and extend healthspan.
    Keywords:  ISRmt; UPRmt; aging; mito-nuclear communication; mitokine; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.001
  2. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]
    Mitochondria as sources and targets of cellular signaling.
    Anna Meichsner, Verian Bader, Konstanze F Winklhofer.
      Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
    Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
  3. Orphanet J Rare Dis. 2026 Jan 29.
    Impaired mitochondrial morphology and respiratory dysfunction in human induced pluripotent stem cells with mitochondrial tRNA mutations (m.3243A>G and m.14739G>A).
    Fibi Meshrkey, Kelly M Scheulin, Bibhuti Saikia, Joshua Stabach, Raj R Rao, Franklin D West, Shilpa Iyer.
      
    Keywords:  Bioenergetics; Mitochondrial disease; Mitochondrial dynamics; Mitochondrial morphology; Pluripotent stem cell; Reprogramming; Respiration; hiPSC; tRNA mutation
    DOI:  https://doi.org/10.1186/s13023-026-04201-z
  4. NPJ Parkinsons Dis. 2026 Jan 27.
    Systematic evaluation of mitochondrial morphology regulators for amelioration of neuronal α-synucleinopathy.
    Su Yeon Kim, JunYoung Choi, Dong Cheol Jang, Pa Reum Lee, Gyu-Sang Hong, Jinkuk Kim, Won-Ki Jeong, Kihoon Han, Seok-Kyu Kwon.
      Neuronal mitochondria display distinct morphologies across compartments, with dendritic mitochondria being elongated and axonal ones shorter, and their morphologies are dynamically changed via fusion and fission machineries. Mitochondrial structural abnormalities are common in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, yet systematic evaluation of therapeutic targets remains limited. Here, we tested key mitochondrial shape regulators, mitofusin 1/2 for fusion and Mff/Fis1 for fission, in an α-synucleinopathy model. Using MitoVis, a deep learning-based neuronal mitochondrial image analysis tool, we achieved rapid, compartment-specific analysis of mitochondrial morphologies. Among all interventions, Fis1 knockdown most effectively protected mitochondrial structure to control levels without inducing over-elongation of axonal mitochondria, which was linked to abnormal Ca2+ dynamics. While all manipulations preserved dendritic spine loss, Fis1 optimally maintained axonal mitochondrial function. These findings demonstrate a high-throughput screening approach for mitochondrial regulators and highlight Fis1 as a promising preventive/therapeutic target. Our results support targeting mitochondrial morphology as a viable strategy for treating α-synucleinopathy and potentially other mitochondria-related neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41531-026-01277-z
  5. Cells. 2026 Jan 10. pii: 127. [Epub ahead of print]15(2):
    Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease.
    Beatrisa Rimskaya, Ekaterina Kropocheva, Elza Shchukina, Egor Ulashchik, Daria Gelfenbein, Lidiya Lisitskaya, Vadim Shmanai, Svetlana Smirnikhina, Andrey Kulbachinskiy, Ilya Mazunin.
      Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report the first successful mitochondrial import of a catalytically active RNA-guided prokaryotic Argonaute protein from the mesophilic bacterium Alteromonas macleodii (AmAgo). By guiding AmAgo to the single-stranded D- or R-loop region of mtDNA using synthetic RNA guides, we observed a nearly threefold reduction in mtDNA copy number in human cell lines. This proof of concept study demonstrates that a bacterial Argonaute can remain active within the mitochondrial environment and influence mtDNA levels. These findings establish a foundational framework for further development of programmable systems for mitochondrial genome manipulation.
    Keywords:  DNA editing; mitochondria; mtDNA copy number; prokaryotic Argonaute proteins
    DOI:  https://doi.org/10.3390/cells15020127
  6. Antioxidants (Basel). 2025 Dec 22. pii: 19. [Epub ahead of print]15(1):
    Bioenergetic Signatures of DLD Deficiency: Dissecting PDHc- and α-KGDHc-Linked Defects.
    Yarden Haham Zarbib, Shira Huri Ohev-Shalom, Shani Kassia Lyskov, Yuval Mazor, Mika Anekstein-Spigel, Nechama Shalva, Ronen Spiegel, Orna Staretz-Chacham, Joshua Manor, Ann Saada, Rachel Rock, Yair Anikster, Tal Yardeni.
      Dihydrolipoamide dehydrogenase (DLD) deficiency (MIM #246900) is a rare autosomal recessive mitochondrial disorder caused by pathogenic variants in the DLD gene, which encodes the E3 subunit common to multiple mitochondrial enzyme complexes, including pyruvate dehydrogenase (PDHc) and α-ketoglutarate dehydrogenase (αKGDHc). Although genotype-phenotype correlations have been described, the precise bioenergetic consequences of DLD dysfunction remain poorly defined. Here, we applied high-resolution respirometry using a novel single-run protocol that allows simultaneous assessment of mitochondrial respiratory capacity and, critically, distinguishing between PDHc- and αKGDHc-linked respiration within the same assay. Fibroblasts from six genetically confirmed DLD-deficient patients with distinct pathogenic variants and clinical severities exhibited a consistent reduction in maximal and complex I-linked respiration. The most severe cases (c.1436A>T; p.D479V) showed combined PDHc and αKGDHc impairment, whereas milder genotypes displayed isolated PDHc dysfunction. This mechanistic distinction likely underlies the variable clinical response to ketogenic therapy, which depends on intact αKGDHc function. Analysis of the mitochondrial mass and mtDNA copy number revealed no global reduction, indicating intrinsic enzymatic dysfunction as the primary defect. Collectively, this study defines a reproducible bioenergetic signature of DLD deficiency and introduces an integrated one-run diagnostic strategy for delineating enzyme-specific mitochondrial defects, providing a framework for mechanistic and therapeutic investigations.
    Keywords:  complex I dysfunction; diagnostic assay; dihydrolipoamide dehydrogenase deficiency; high-resolution respirometry; mitochondrial bioenergetics; pyruvate dehydrogenase complex; α-ketoglutarate dehydrogenase complex
    DOI:  https://doi.org/10.3390/antiox15010019
  7. Genes (Basel). 2026 Jan 13. pii: 82. [Epub ahead of print]17(1):
    Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.
    Magan N Pittman, Mary Beth Nelsen, Marlo K Thompson, Aishwarya Prakash.
      Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP production by OXPHOS generates reactive oxygen species (ROS) that pose a significant threat to the nearby mtDNA. To counter these insults, neurons rely on base excision repair (BER), the principal mechanism for removing oxidative and other small, non-bulky base lesions in nuclear and mtDNA. BER involves a coordinated enzymatic pathway that excises damaged bases and restores DNA integrity, helping maintain mitochondrial genome stability, which is vital for neuronal bioenergetics and survival. When mitochondrial BER is impaired, mtDNA becomes unstable, leading to ETC dysfunction and a self-perpetuating cycle of bioenergetic failure, elevated ROS levels, and continued mtDNA damage. Damaged mtDNA fragments can escape into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways and inflammasome complexes. Chronic activation of these pathways drives sustained neuroinflammation, exacerbating mitochondrial dysfunction and neuronal loss, and functionally links genome instability to innate immune signaling in neurodegenerative diseases. This review summarizes recent advancements in understanding how BER preserves mitochondrial genome stability, affects neuronal health when dysfunctional, and contributes to damage-driven neuroinflammation and neurodegenerative disease progression. We also explore emerging therapeutic strategies to enhance mtDNA repair, optimize its mitochondrial environment, and modulate neuroimmune pathways to counteract neurodegeneration.
    Keywords:  base excision repair; damage associated molecular patterns; mitochondrial DNA; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3390/genes17010082
  8. Cells. 2026 Jan 06. pii: 95. [Epub ahead of print]15(2):
    Mitochondria and Epigenetic Regulation: Bidirectional Crosstalk and Emerging Mitochondria-Targeted Degron Tools.
    Yingwei Xu, Xiaokun Jian, Lei Shi, Lisa S Shock, Lanming Chen, Louise T Chow, Hengbin Wang.
      Mitochondria not only generate ATP and metabolites essential for nuclear and cytoplasmic processes but also actively shape nuclear epigenetic regulation. Conversely, the nucleus encodes most of the proteins required for mitochondrial functions, and intriguingly, certain nuclear-encoded epigenetic factors-such as DNA and histone modifiers-also localize to mitochondria, where they modulate mitochondria genome stability, gene expression, metabolic flux, and organelle integrity. This reciprocal interplay defines mitochondria as both a source and a target of epigenetic regulation, integrating energy metabolism with gene expression and cellular homeostasis. This review highlights emerging mechanisms that link mitochondrial metabolism to chromatin remodeling, DNA and histone modifications, and transcriptional control, as well as how nuclear epigenetic enzymes translocate into mitochondria and regulates their functions. We also briefly introduce recent methodological advances that enable spatially selective depletion of mitochondrial proteins, offering new tools to dissect this bidirectional communication. Together, these insights underscore mitochondria's central role as an energetic and epigenetic hub coordinating nuclear function, development, and disease.
    Keywords:  epigenetics; gene expression; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cells15020095
  9. Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13
    Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
    Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.
      Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.
    Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome
    DOI:  https://doi.org/10.7554/eLife.95576
  10. JIMD Rep. 2026 Jan;67(1): e70068
    Drivers of Diagnostic Delay in Mitochondrial Disease: Missed Recognition of Canonical Features.
    Rory J Tinker, Neil Jacob, Mohammad Ghouse Syed, Janhawi Kelkar, Colleen Donnelly, Ibrahim Elsharkawi, Jaya Ganesh, Bruce D Gelb, Vikas Pejaver, Tamas Kozicz, Eva Morava.
      Diagnostic delay is common in mitochondrial disease, and its drivers remain unclear despite advances in molecular diagnostics. We retrospectively analyzed 61 individuals with molecularly confirmed mitochondrial disease at the Mount Sinai Mitochondrial Disease Clinic, diagnosed after 2016. Diagnostic delay was partitioned into intervals from symptom onset to clinical suspicion, and from suspicion to molecular diagnosis. Demographic, phenotypic, and genetic data were abstracted from health records, and Human Phenotype Ontology terms were compared before and after diagnosis using ClinPhen. Most delays occurred between symptom onset and clinical suspicion (mean 8.17 years) rather than after suspicion (mean 1.28 years), yielding a mean total delay of 8.22 years (median 3.0). Delay decreased sharply by year of birth (r = -0.99, p < 49.92 × 10-39) and symptom onset (r = -0.96, p < 8.14 × 10-27), but showed no meaningful trend with year of diagnosis. Canonical features such as seizures, hypotonia, and stroke were frequently documented years before suspicion, underscoring missed opportunities. Diagnostic delay may reflect missed recognition rather than testing limitations. Systematic capture of early phenotypes and AI/NLP-based mining of electronic health records could proactively flag patients for reflexive sequencing, shortening diagnostic delay.
    Keywords:  diagnostic delay; electronic health records (EHR); genotype‐first diagnosis; human phenotype ontology (HPO); missed diagnostic opportunities; mitochondrial disease; natural language processing (NLP); phenotype recognition
    DOI:  https://doi.org/10.1002/jmd2.70068
  11. Biomolecules. 2026 Jan 20. pii: 171. [Epub ahead of print]16(1):
    Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
    Mariagrazia Mancuso, Federico Mezzalira, Beatrice Vignoli, Elisa Greotti.
      Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca2+ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca2+-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca2+ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca2+-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca2+ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca2+-centered mitochondria-glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer's disease.
    Keywords:  Alzheimer’s disease; astrocyte–neuron communication; excitotoxicity; glutamate homeostasis; glutamatergic synapse; metabolic coupling; mitochondrial Ca2+ signaling; mitochondrial signaling; neuronal hyperexcitability; synaptic vulnerability
    DOI:  https://doi.org/10.3390/biom16010171
  12. J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):
    Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
    Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.
      Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.
    DOI:  https://doi.org/10.1083/jcb.202501023
  13. Nat Commun. 2026 Jan 29.
    ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
    Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.
      Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.
    DOI:  https://doi.org/10.1038/s41467-026-68813-6
  14. Endocr Metab Immune Disord Drug Targets. 2026 Jan 15.
    Mitochondrial Myopathy, Lactic Acidosis, and Stroke-Like Episodes Combined with Diabetes: A Case Report.
    Shumin Zhou, Yongjun Tian, Fengying Liu, EnZhu Wu, Xiaodan Feng.
       INTRODUCTION: Mitochondrial diseases refer to a group of hereditary disorders involving damage to high-energy-consuming tissues, such as muscles, nerves, and the heart. Mitochondrial DNA (mtDNA) mutations account for most cases, but the timely identification and treatment of these conditions remain challenging.
    CASE PRESENTATION: This report describes a case of a 36-year-old male patient who was diagnosed with diabetes in 2017 and subsequently experienced recurrent diabetic ketoacidosis and seizures. On May 20, 2022, he presented with cognitive impairment, unsteady gait, and an elevated blood lactate level. Brain MRI and mitochondrial gene sequencing on peripheral blood cells revealed destructive neuronal lesions and a mutation of m.3243A>G in the MT-TL1 gene with a ratio of 6.04%, which supported the diagnosis of mitochondrial encephalomyopathy associated with lactic acidosis and stroke-like episodes (MELAS) and mitochondrial diabetes mellitus (MDM). Treatment with insulin, fluid replacement, ketoacidosis correction, diazepam, and phenobarbital relieved most symptoms. However, his blood glucose was poorly controlled. Four months after discharge, the patient suffered a relapse. Although therapies to combat infection, reduce blood glucose, and correct ketoacidosis improved his condition, the patient died in 2023 due to cerebral infarction.
    CONCLUSION: This case embodies the typical manifestations of mitochondrial diseases, emphasizing the urgency of prompt diagnosis and symptom management, which largely depends on effective genetic screening.
    Keywords:  Mitochondrial diabetes; mitochondrial DNA.; mitochondrial encephalomyopathy associated with lactic acidosis and stroke-like episodes (MELAS)
    DOI:  https://doi.org/10.2174/0118715303419754251125093050
  15. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123
    Coordination of cell organelles to promote metabolon formation.
    Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.
      The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.
    Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine
    DOI:  https://doi.org/10.1073/pnas.2532504123
  16. Ugeskr Laeger. 2026 Jan 26. pii: V07250609. [Epub ahead of print]188(5):
    [Super-refractory status epilepticus caused by hereditary mitochondrial disease].
    Niels Bach Sørensen, Kristina Stamenkovic, Ellen Hollands Steffensen, Inge Ring Kofoed.
      In this case report, we present an 11-year-old girl who developed super-refractory status epilepticus (SRSE) after focal seizures. Initial investigations, including MRI, CSF analysis, and autoimmune panels, were normal. Despite extensive treatment with several anti-seizure medications, immunotherapy, attempt of treatment with ketogenic diet and anesthetic infusions targeting burst-suppression, no improvement occurred. Trio whole genome sequencing revealed compound heterozygous pathogenic variants in POLG, confirming mitochondrial disease. Due to poor prognosis and deterioration, treatment was withdrawn, and she died in ICU.
    DOI:  https://doi.org/10.61409/V07250609
  17. Acta Pharm Sin B. 2026 Jan;16(1): 1-12
    Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
    Joshua Kramer, Eric Rohwer, Palaniappan Sethu, Min Xie, Timmy Lee, Victor Darley-Usmar, Jianhua Zhang.
      Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia-reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell-cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.
    Keywords:  Cardiomyocytes; Exophers; Fibroblasts; Macrophages; Migrasomes; Mitophagy; TNTs; Transmitophagy
    DOI:  https://doi.org/10.1016/j.apsb.2025.11.030
  18. Pharmacol Rep. 2026 Jan 26.
    Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
    Brígida R Pinho, Vasco Martins, Anitta R Chacko, Célia Nogueira, Michael R Duchen, Jorge M A Oliveira.
      
    Keywords:  ATP synthase; Autophagy; Cybrid; Mitochondrial DNA; Mitochondrion; Ubiquitin
    DOI:  https://doi.org/10.1007/s43440-026-00829-7
  19. Nat Commun. 2026 Jan 27. 17(1): 1064
    Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
    Wenqian Chen, Gabriel C Lander, Jie Yang.
      The human ClpXP complex (hClpXP) orchestrates mitochondrial protein quality control through targeted degradation of misfolded and unnecessary proteins. While bacterial ClpXP systems are well characterized, the assembly and regulation of human ClpXP remain poorly understood. In this study, we elucidate the complete assembly pathway of hClpXP through high-resolution cryo-electron microscopy (cryo-EM) structures. Our findings confirm that hClpP exists as a single-ring heptamer in isolation and reveal a previously undocumented initial assembly complex in which hexameric hClpX first engages with heptameric hClpP. We further demonstrate how this interaction drives substantial conformational rearrangements that facilitate the formation of tetradecameric hClpP within the fully assembled complex. Notably, we characterize a unique eukaryotic sequence in hClpX, termed the E-loop, which plays a critical role in stabilizing hexamer assembly and maintaining ATPase activity. Additionally, we show that peptide binding at the hClpP active site triggers further structural changes essential for achieving full proteolytic competence. Together, these structures provide unprecedented mechanistic insights into the stepwise assembly and activation of hClpXP, significantly advancing our understanding of this essential mitochondrial protein degradation machinery.
    DOI:  https://doi.org/10.1038/s41467-025-67010-1
  20. Biomedicines. 2026 Jan 03. pii: 100. [Epub ahead of print]14(1):
    Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Aging: Current Insights and Therapeutic Advances.
    Nabila Izzati Nur Azan, Norwahidah Abdul Karim, Nadiah Sulaiman, Min Hwei Ng, Asyraff Md Najib, Haniza Hassan, Ekram Alias.
      Mitochondrial dysfunction plays a central role in cardiac aging. Damaged mitochondria release excessive free radicals from the electron transport chain (ETC), leading to an increased production of reactive oxygen species (ROS). The accumulation of ROS, together with impaired ROS clearance mechanisms, results in oxidative stress, further disrupts mitochondrial dynamics, and diminishes bioenergetic capacity. Furthermore, the dysfunctional mitochondria exhibit an impaired endogenous antioxidant system, exacerbating this imbalance. These alterations drive the structural and functional deterioration of the aging heart, positioning mitochondria at the center of mechanisms underlying age-associated cardiovascular decline. In this review, we summarize the current evidence on how mitochondrial oxidative stress, mutations on mitochondrial DNA (mtDNA), and disruptions in the fission-fusion balance contribute to cardiomyocyte aging. This review also explores ways to mitigate oxidative stress, particularly with mitochondria-targeted antioxidants, and discusses the emerging potential of mitochondrial transplantation to replace dysfunctional mitochondria.
    Keywords:  ROS; cardiovascular aging; mitochondria dynamics; mitochondria-targeted antioxidants; mitochondrial dysfunction; mitochondrial transplantation; oxidative stress
    DOI:  https://doi.org/10.3390/biomedicines14010100
  21. Acta Diabetol. 2026 Jan 28.
    A TFAP4-UBC9-SUMO1 axis orchestrates pathological mitochondrial hyperfission in diabetic complications.
    Zhiyu Jin, Ying Jiang, Dayun Tao, Zunyan Li, Xiuling He, Hao Zhou, Hang Zhu, Lina Ren.
       BACKGROUND: Mitochondrial failure is a cornerstone of diabetic organ damage. While it is well understood that shattered mitochondria (excessive fission) and aggressive cleanup (mitophagy) drive this deterioration, the upstream genetic "switches" that trigger these processes remain unclear. This study investigates whether a specific regulatory chain the TFAP4-UBC9-SUMO1 axis orchestrates this mitochondrial breakdown in diabetic tissues.
    METHODS: We analyzed transcriptomic data from four independent cohorts (GEO datasets: GSE1009, GSE4745, GSE6880, and GSE133598) covering diabetic renal and cardiac tissues. By integrating differential expression analysis with functional enrichment tools (GO, KEGG, and GSEA), we mapped the molecular landscape connecting cellular stress to mitochondrial dynamics and metabolic remodeling.
    RESULTS: Our analysis revealed a synchronized stress response across all datasets rather than isolated gene changes. Diabetic tissues exhibited a distinct upregulation of pathways related to protein SUMOylation, mitochondrial organization, and ER stress. Specifically, the data showed a convergence of signals indicating chronic "Protein processing in the endoplasmic reticulum" and sustained "Mitophagy," accompanied by broad shifts in lipid and energy metabolism. These signatures suggest that the machinery responsible for SUMO-modifying proteins is hyperactive and tightly linked to mitochondrial clearance programs.
    CONCLUSION: The transcriptomic evidence supports a model where TFAP4 acts as a transcriptional driver that boosts UBC9 and SUMO1 expression. This upregulation likely fuels the SUMO-dependent modification of DRP1, locking mitochondria in a state of hyper-fission and forcing the cell into excessive self-eating (mitophagy). The TFAP4-UBC9-SUMO1 axis thus represents a critical, yet overlooked, engine of mitochondrial depletion and offers a promising new target for halting diabetic complications.
    Keywords:  DRP1; Diabetic complications; Mitochondrial dysfunction; Mitochondrial fission; Mitophagy; SUMOylation; Transcriptomic analysis
    DOI:  https://doi.org/10.1007/s00592-026-02645-0
  22. Sci Rep. 2026 Jan 28.
    Myo-Inositol modulates AKT signalling, mitochondrial protein expression and intracellular Ca²⁺dynamics in human dermal fibroblasts.
    Paola Zanfardino, Alessandro Amati, Domenico Iacobellis, Matilde Colella, Vittoria Petruzzella.
      
    Keywords:  AKT; Calcium; Mitochondria; Myoinositol; Oxidative phosphorylation; Phosphoinositides
    DOI:  https://doi.org/10.1038/s41598-026-37423-z
  23. JCEM Case Rep. 2026 Feb;4(2): luaf341
    Unveiling a Novel MT-TS1 m.7479G>A in Mitochondrial Diabetes: The Critical Role of mtDNA Sequencing in Atypical Cases.
    Eleanor Danek, Felicity Pyrlis, Aleena Shujaat Ali, Elif I Ekinci.
      Mitochondrial diabetes is a rare form of diabetes mellitus caused by mitochondrial DNA (mtDNA) mutations, often presenting with atypical features and maternal inheritance. We report a 71-year-old white female presenting with diabetes diagnosed at age 50, managed with oral therapy, who exhibited significant weight loss and a strong maternal family history of diabetes. Glutamic acid decarboxylase and insulinoma-associated-2 antibodies were negative with normal C-peptide, and genetic testing revealed a heteroplasmic MT-TS1 m.7479G>A variant (13.90%). Glycemic management was achieved with metformin and gliclazide, and at 21 years post diagnosis, the patient maintained stable glycemic control with a glycated hemoglobin A1c of 6.5% (SI: 48 mmol/mol) (reference range, 4.0%-6.0% [SI 20-42 mmol/mol]) without insulin. The MT-TS1 m.7479G>A variant is implicated as a pathogenic cause of mitochondrial diabetes, highlighting the importance of mtDNA sequencing in atypical cases with maternal inheritance, the potential for milder phenotypes with low-heteroplasmy variants, and the critical role of genetic counseling.
    Keywords:  MT-TS1; atypical diabetes; genetic testing; m.7479G>A; maternal inheritance; mitochondrial diabetes
    DOI:  https://doi.org/10.1210/jcemcr/luaf341
  24. iScience. 2026 Feb 20. 29(2): 114365
    PHB2 mitigates intervertebral disc degeneration by modulating mitophagy to inhibit necroptosis in nucleus pulposus cells.
    Zhenyu Zhu, Yongcheng Liang, Xiaowen Liu, Fanqi Kong, Kaiqiang Sun, Ximing Xu, Jiangang Shi.
      Intervertebral disc degeneration involves loss of nucleus pulposus (NP) cells driven by inflammatory and mitochondrial stress-related death pathways. Because mitophagy maintains mitochondrial quality, its disruption may influence cell fate during degeneration. Using human tissues, a mouse lumbar instability model, a rat disc puncture model, and human NP cells stimulated with TNF-α, SM-164, and Z-VAD-FMK (TSZ), we examined how mitochondrial quality control shapes necroptotic signaling. Necroptotic cells displayed mitochondrial damage and reduced mitophagy, while mitophagy activation limited necroptosis and preserved extracellular matrix components. We identified the mitochondrial protein PHB2 as a key regulator linking mitophagy to suppression of necroptosis. PHB2 loss impaired mitophagy, disrupted mitochondrial function, and intensified necroptotic death, whereas PHB2 overexpression restored mitophagy, maintained mitochondrial membrane potential, and reduced degeneration. In vivo PHB2 delivery mitigated necroptosis and protected disc structure. These findings highlight a mitochondria-centered mechanism that shapes cell survival during disc degeneration.
    Keywords:  Biological sciences; Cell biology; Health sciences; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.114365
  25. Aging Cell. 2026 Feb;25(2): e70388
    Disruption of ATP Synthase Spatiotemporal Organization, Ca2+ Dynamics, and Contractile Function in Senescent Cardiomyocytes.
    Silke Morris, Nico Marx, Gonzalo Barrientos, Isidora Molina-Riquelme, Frank Schmelter, Hugo E Verdejo, Stefan Peischard, Guiscard Seebohm, Verónica Eisner, Karin B Busch.
      Heart disease is the leading cause of death in the elderly population. Age-related heart failure is frequently associated with energy deficits in cardiomyocytes. These cells rely on their abundant, cristae-rich mitochondria for ATP production. ATP synthase, localized along the cristae rims, is central to this process. It is presumed that its function is tightly bound to its spatial organization, but details remain unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent human iPSC-derived CM in conjunction with its functions. We found changes in the stoichiometry of F1 and FO subunits in senescent CM. The ratio of FO-SU c to F1-SU β increased. The oligomeric organization of the complex was weakened. Using single-molecule localization and tracking microscopy, we observed an increased enzyme mobility within cristae that displayed increased fenestrations. This coincided with decreased mitochondrial ATP level, increased ATP hydrolysis capacity, and a moderate increase in mitochondrial transition pore opening. Disturbed ATP production was correlated with dysregulated calcium dynamics, characterized by heightened spikes and slower cytosolic clearance. Consequently, senescent cardiomyocytes exhibited irregular autonomous and paced beating patterns. These findings indicate that, in senescent cardiomyocytes, functional decline is closely linked to disrupted ATP metabolism, driven by the aberrant organization, dynamics, and activity of ATP synthase within remodeled cristae.
    Keywords:  ATP hydrolysis; ATP synthase organization; calcium dynamics; cardiomyocytes; contractility; cristae architecture; human induced pluripotent stem cells; mitochondrial permeability transition pore (mPTP); senescence; single molecule dynamics
    DOI:  https://doi.org/10.1111/acel.70388
  26. Immunology. 2026 Jan 29.
    Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
    Woo Hyun Park.
      Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin-1β (IL-1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K+) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox-mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)-mediated mtDNA synthesis. The profound involvement of the mtDNA-inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.
    Keywords:  immunogenic cell death; inflammasome; innate immunity; mitochondrial DNA; pyroptosis; sterile inflammation
    DOI:  https://doi.org/10.1111/imm.70111
  27. Cardiovasc Res. 2026 Jan 28. pii: cvag031. [Epub ahead of print]
    Mitochondrial succinate transport is required for cardiac ischemia/reperfusion injury.
    Laura Pala, María Torres-López, Stuart T Caldwell, Joyce Valadares, Emily M Smith, Katherine L Hammond, Olga Sauchanka, Jiro Abe, Thomas Krieg, Richard C Hartley, Michael P Murphy, Hiran A Prag.
       BACKGROUND: Succinate accumulates significantly during myocardial ischemia, and its rapid oxidation upon reperfusion is a critical driver of ischemia/reperfusion (I/R) injury. The transport of succinate across the mitochondrial inner membrane, particularly by the dicarboxylate carrier (DIC; SLC25A10), is hypothesized to play a crucial role in mediating these pathological succinate dynamics. However, tools to test this hypothesis by modulating mitochondrial succinate transport in biological systems are lacking.
    METHODS AND RESULTS: C57BL/6J mice, isolated Wistar Rat heart mitochondria, bovine heart mitochondrial membranes, C2C12 mouse myoblasts and primary adult cardiomyocytes were used as in vitro and in vivo models. Butylmalonate prodrugs were synthesized and tested. Isolated mitochondria were used to assess succinate-dependent respiration and reactive oxygen species (ROS) production. Cells were treated with succinate dehydrogenase (SDH) inhibitors or exposed to anoxia and butylmalonate esters. Mouse hearts were subjected to in vivo left anterior descending coronary artery ligation. Succinate and butylmalonate levels were measured by targeted liquid chromatography-tandem mass spectrometry, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.Knockdown of DIC, but not of the oxoglutarate carrier OGC, in C2C12 cells prevented succinate accumulation by SDH inhibition and anoxia. The only extant DIC inhibitor butylmalonate, is limited by poor cell permeability. We synthesized diacetoxymethyl butylmalonate (DAB), which efficiently delivers butylmalonate intramitochondrially in isolated heart mitochondria and cells. DAB inhibited succinate-dependent respiration and ROS production. DAB prevented succinate accumulation in cells treated with SDH inhibitors. DAB delivered butylmalonate to cardiac mitochondria when administered to mice in vivo and reduced infarct size by perturbing mitochondrial succinate transport.
    CONCLUSIONS: The DIC is a key node in the cellular distribution of succinate, controlling its transport between mitochondria and the cytosol. These findings highlight the potential of DIC as a promising therapeutic target for conditions where succinate elevation contributes to pathogenesis, such as cardiac I/R injury.
    Keywords:  SLC25A10; Succinate; butylmalonate; ischemia/reperfusion injury; mitochondrial dicarboxylate carrier; mitochondrial transport; myocardial infarction
    DOI:  https://doi.org/10.1093/cvr/cvag031
  28. Biomedicines. 2026 Jan 20. pii: 222. [Epub ahead of print]14(1):
    Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
    Yudong Wang, Gregory Varga, Meicheng Wang, Johan Palmfeldt, Shakuntala Basu, Erik Koppes, Andrew Jeffrey, Robert James Hannan, Grant Sykuta, Jerry Vockley.
      Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.
    Keywords:  VLCAD deficiency; fatty acid oxidation; mitochondrial electron transfer chain supercomplex (ETC-SC); very-long-chain acyl-CoA dehydrogenase (VLCAD)
    DOI:  https://doi.org/10.3390/biomedicines14010222
  29. Front Pharmacol. 2026 ;17 1705666
    HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.
    Liting Xu, Min Zeng.
      High temperature requirement protein A2 (HtrA2/Omi), a key regulator of mitochondrial quality control, plays a pivotal role in determining cell fate through its subcellular localization, whether mitochondrial or cytosolic. Growing evidence links the absence or dysfunction of HtrA2 to the pathogenesis of neurodegenerative diseases. This review examines the structure and function of HtrA2, highlights its transcriptional regulators, explores its involvement in neurodegeneration, and outlines the currently identified agonists and inhibitors, offering new insights for developing HtrA2/Omi as a potential therapeutic target for neurodegenerative disorders.
    Keywords:  HtrA2; UCF-101; apoptosis; mitochondria; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fphar.2026.1705666
  30. Cells. 2026 Jan 12. pii: 137. [Epub ahead of print]15(2):
    BAP31 Modulates Mitochondrial Homeostasis Through PINK1/Parkin Pathway in MPTP Parkinsonism Mouse Models.
    Wanting Zhang, Shihao Meng, Zhenzhen Hao, Xiaoshuang Zhu, Lingwei Cao, Qing Yuan, Bing Wang.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31-an endoplasmic reticulum protein critical for protein trafficking and degradation-has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31fl/fl controls, Slc6a3cre-BAP31fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1-Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders.
    Keywords:  BAP31; EN1; PINK1–Parkin pathway; Parkinson’s disease; mitochondrial homeostasis
    DOI:  https://doi.org/10.3390/cells15020137
  31. Mol Genet Metab. 2026 Jan 07. pii: S1096-7192(26)00014-4. [Epub ahead of print]147(3): 109731
    Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes.
    Steven H Lang, Naiga Cottingham, Colleen Donnelly, Sarah Risen, Rossana Malatesta Muncher, Eileen D Brewer, Jeffery M Saland, Corrine Benchimol, Fernando Scaglia, Jaya Ganesh.
      Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1-2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.
    Keywords:  CKD (chronic kidney disease); Kearns-Sayre syndrome (KSS); Kidney transplant; Mitochondrial disease; Pearson marrow-pancreas syndrome (PMP); Progressive external ophthalmoplegia (PEO); Single large scale mitochondrial DNA deletion syndromes (SLSMDS)
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109731
  32. Genome Med. 2026 Jan 26. 18(1): 11
    Genome-wide methylation detection and episignature analysis using PacBio long-read sequencing.
    Véronique Ivashchenko, Michelle de Groot, Ronny Derks, Amber den Ouden, Gelana Khazeeva, Simone van den Heuvel, Raoul Timmermans, Jordi Corominas Galbany, Rolph Pfundt, Tom Hofste, Helger Yntema, Lisenka Vissers, Alexander Hoischen, Juliet Hampstead, Christian Gilissen.
       BACKGROUND: The detection of 5-methylcytosine (5mC) patterns in the human genome is relevant for the diagnosis of various genetic conditions. Genome-wide methylation episignatures provide a new approach for resolving variants of uncertain significance. Whole-genome DNA methylation detection is usually performed using short-read bisulfite sequencing procedures or methylation arrays. Pacific Biosciences (PacBio) long-read sequencing (LRS) is a technology that can detect 5mC on native DNA. Here we assessed the ability of PacBio HiFi LRS to robustly identify genome-wide methylation for medical purposes. We assessed the ability to identify differentially methylated imprinted regions and genome-wide epigenetic signatures for genetic disorders.
    METHODS: PacBio LRS methylation detection was compared to two conventional genome-wide DNA methylation sequencing techniques. We used 30 PacBio LRS samples (10 trios at ~ 30× coverage) and assessed the ability to detect differential methylation using 25 known parentally imprinted regions with different genome-wide sequence coverage. Finally, we evaluated two published epigenetic signatures for KMT2A gene defects using PacBio LRS data from 12 KMT2A patients, 2 patients with a variant of uncertain significance, and 39 control samples.
    RESULTS: PacBio methylation calls on the HG002 cell line were highly comparable to short-read protocols, providing 5% additional calls, predominantly in regions that are difficult to assess using short-read technologies. Among the 10 trios, correct haplotype-resolved methylation patterns were found for 24 out of 25 (96%) imprinted regions and all of the methylated alleles showed the expected parental origin. Downsampling analysis showed that these imprinted regions can robustly be detected using a minimum of 15× genome-wide coverage. Finally, we found that although the two published KMT2A episignatures are significantly different, both are successfully able to distinguish KMT2A patients from controls and classify the two KMT2A VUS samples as control samples.
    CONCLUSIONS: Overall, our results indicate that PacBio LRS can reliably detect specific medically relevant methylation changes as well as genome-wide episignatures in rare disease patients.
    Keywords:  Episignature; Genomic imprinting; Methylation; PacBio long-read sequencing
    DOI:  https://doi.org/10.1186/s13073-025-01506-9
  33. Antioxidants (Basel). 2025 Dec 28. pii: 40. [Epub ahead of print]15(1):
    Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study.
    Claudia R Oliva, Susanne Flor, Corinne E Griguer.
      Ferroptosis is an iron-dependent, oxidative form of regulated cell death that has emerged as a therapeutic vulnerability in glioblastoma; however, the mitochondrial determinants that govern ferroptotic sensitivity remain poorly defined. Cytochrome c oxidase (CcO/Complex IV), a key regulator of mitochondrial respiration, contains two isoforms of subunit IV (COX4): COX4-1, a housekeeping isoform, and COX4-2, a stress-inducible variant. We previously found that COX4-1 expression protects glioma cells from erastin-induced ferroptosis, suggesting that mitochondria influence cell-death decisions independently of canonical ferroptotic regulators. Here, we used CRISPR-generated POLG-knockout ρ0 cells and transmitochondrial cybrids to isolate mitochondrial from nuclear contributions to ferroptosis sensitivity. Cybrids reconstituted with COX4-1-containing mitochondria restored CcO activity and recapitulated the ferroptosis-resistant phenotype, whereas COX4-2 cybrids remained insensitive to erastin. COX4-1 cybrids exhibited reduced labile iron, diminished cystine uptake, and low expression of SLC7A11 and GPX4, yet underwent apoptosis rather than ferroptosis upon erastin treatment. These findings demonstrate that mitochondrial COX4-1 rewires redox metabolism and diverts cell-death signaling away from ferroptosis toward apoptosis. Our results identify isoform-specific mitochondrial composition as a previously unrecognized determinant of regulated cell death and highlight COX4-1-driven mitochondrial remodeling as a potential mechanism of therapeutic resistance in glioblastoma.
    Keywords:  COX4-1 isoform; apoptosis; erastin; ferroptosis; glioma; transmitochondrial cybrids
    DOI:  https://doi.org/10.3390/antiox15010040
  34. Aging Cell. 2026 Feb;25(2): e70390
    In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.
    Wayne Mitchell, Cecília G de Magalhães, Alexander Tyshkovskiy, Yushi Uchida, Ludger J E Goeminne, Takaharu Ichimura, Emery L Ng, Alibek Moldakozhayev, Joseph V Bonventre, Vadim N Gladyshev.
      Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight necessitating euthanasia. In the livers and kidneys of these animals, we observe significant increases in lipid droplet accumulation, as well as changes in mitochondrial morphology in the livers that are associated with mitochondrial stress. Thus, partial chemical reprogramming may induce mitochondrial stress and lead to significant lipid accumulation, which may cause toxicity and hinder the rejuvenation of cells and tissues in aged mammals.
    Keywords:  aging; aging biomarkers; chemical reprogramming; lipid droplets; mitochondria; mitochondrial morphology; oxidative phosphorylation; rejuvenation; reprogramming
    DOI:  https://doi.org/10.1111/acel.70390
  35. Metabolites. 2026 Jan 11. pii: 65. [Epub ahead of print]16(1):
    Optical and Microdialysis Monitoring of Succinate Prodrug Treatment in a Rotenone-Induced Model of Mitochondrial Dysfunction in Swine.
    Alistair Lewis, Rodrigo M Forti, Tiffany S Ko, Eskil Elmér, Meagan J McManus, Arjun G Yodh, Todd J Kilbaugh, Wesley B Baker.
       BACKGROUND/OBJECTIVES: Mitochondrial dysfunction is a major cause of brain injury in patients with primary mitochondrial disease. New mitochondrial therapeutics and non-invasive tools for efficacy monitoring are urgently needed. To these ends, succinate prodrug NV354 (methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate) and diffuse optical techniques are promising. In this proof-of-concept study, we characterize NV354's effects on microdialysis metrics of cerebral metabolism in a swine model of mitochondrial dysfunction and assess the associations of diffuse optical metrics with mitochondrial dysfunction and metabolic improvement.
    METHODS: One-month-old swine received a four-hour co-infusion of rotenone with either the succinate prodrug NV354 (n = 5) or placebo (n = 5). Rotenone is a mitochondrial complex I inhibitor. Before and during co-infusion, cerebral metabolism was probed with microdialysis and diffuse optics. Microdialysis acquired interstitial lactate and pyruvate levels invasively, while diffuse optics measured changes in oxygen extraction fraction (OEF) and oxidized cytochrome-c-oxidase concentration (oxCCO).
    RESULTS: Interstitial lactate continually increased in the placebo group (p < 0.01), but lactate levels plateaued in the NV354 group (p = 0.90). oxCCO also increased in the placebo group (p = 0.05), but OEF remained constant (p = 0.80). In the NV354 group, oxCCO increased (p < 0.01) while OEF decreased (p < 0.01).
    CONCLUSIONS: Microdialysis results suggest that NV354 treatment can increase oxygen metabolism in large animals with mitochondrial dysfunction. The optical oxCCO metric was also sensitive to metabolic changes induced by rotenone and NV354 administration.
    Keywords:  cerebral oxygen metabolism; complex I dysfunction; cytochrome-c-oxidase; diffuse optical spectroscopy; primary mitochondrial disease
    DOI:  https://doi.org/10.3390/metabo16010065
  36. Mitochondrion. 2026 Jan 23. pii: S1567-7249(26)00002-4. [Epub ahead of print]87 102112
    Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.
    Svetlana Pecheritsyna, Melisa Emel Ermert, Emina Podhumljak, Bas Pennings, Ruth Zondag, Eligio F Iannetti, Herma Renkema, Jan Smeitink.
      Primary mitochondrial diseases (PMDs) are directly linked to oxidative phosphorylation (OXPHOS) dysfunction. Here, we investigated the selective sensitivity of PMD patient fibroblasts compared to healthy control primary human skin fibroblasts (PHSF) to ferroptosis, and the role of iron in this cell death mechanism. To address this, we investigated sensitivity to ferroptosis inducers, the effects of iron supplementation, and intracellular iron pools. The selectivity of PMD fibroblasts ferroptotic cell death was found to be more pronounced with class 1 ferroptosis inducers (FINs) that deplete GSH than upon direct GPX4 inhibitors. Notably, exogenous iron discriminatory triggered ferroptosis in patient fibroblasts and enhanced BSO-induced cell death in both patient and control cells. Further study revealed elevated basal levels of labile iron in patient fibroblasts, but mRNA analysis of iron-regulating genes did not reveal major expression differences. These findings suggest that increased labile iron predisposes PMD fibroblasts to ferroptosis. Complementation of defective OXPHOS restored ferroptosis sensitivity and LIP levels in a cell line with an NDUFS7 mutation, indicating a functional relationship caused by OXPHOS deficiency. Further understanding this interplay may provide insights into therapeutic strategies targeting iron homeostasis to mitigate ferroptotic cell death in PMDs.
    Keywords:  Ferroptosis; Labile iron pool; Primary mitochondrial disease
    DOI:  https://doi.org/10.1016/j.mito.2026.102112
  37. J Cell Mol Med. 2026 Feb;30(3): e71014
    TRPM8 Regulates Mitochondrial Ca2+-Dynamics, Temperature and Endoplasmic Reticulum-Mitochondrial Contact Points in T Cell.
    Tusar Kanta Acharya, Shamit Kumar, Tejas Pravin Rokade, Parnasree Mahapatra, Young Tae Chang, Chandan Goswami.
      TRPM8 is a cold temperature-sensitive and non-selective Ca2+-channel. Previously we have observed that TRPM8 is endogenously expressed and affects T cell activation process. Now, we report that TRPM8 regulates functions of mitochondria and ER, two important sub-cellular compartments. Pharmacological modulation of TRPM8 and/or due to TCR-treatment regulates mitochondrial Ca2+, ATP, membrane potential, cardiolipin level and mitochondrial temperature in a context-dependent manner. In addition, TRPM8 alters the relative temperature of mitochondria and ER, ER-mitochondrial contact points, mainly at the immunological synapse (IS), and thus TRPM8 has the potential to affect the overall cellular functions. Our data suggests both, i.e., the presence and enrichment of TRPM8 in the IS of T cells. We suggest that TRPM8 is a crucial regulator of Ca2+-signalling in T cells and significantly contributes to Ca2+-buffering by modulating cellular and sub-cellular organelle functions. These findings are useful to understand the functions of T cells in different pathological conditions.
    Keywords:  Ca2+‐buffering; T‐cell activation; immune regulation; immune synapse; metabolism; mitochondria; sub‐cellular organelle temperature
    DOI:  https://doi.org/10.1111/jcmm.71014
  38. Plant J. 2026 Feb;125(3): e70706
    From isolation to insights: mitochondrial complex I in the diatom Phaeodactylum tricornutum.
    Federico Berdun, Jennifer Senkler, Michael Senkler, Noah Ditz, Eva Plönnigs, Thomas Reinard, Eduardo Zabaleta, Hans-Peter Braun.
      Diatoms are among the most ecologically successful microalgae, contributing significantly to marine primary production and global carbon cycling. Their distinctive metabolic architecture, shaped by a complex evolutionary history involving secondary endosymbiosis, includes a highly compartmentalized cell organization and unique metabolic pathways. In Phaeodactylum tricornutum, a model pennate diatom, chloroplasts with four membranes and mitochondria of likely exosymbiotic origin exhibit intricate physical and metabolic interactions that support integrated carbon and nitrogen metabolism. The mitochondrial electron transport chain, essential for ATP synthesis, shows clade-specific structural and compositional adaptations. Despite its importance, detailed proteomic characterization has remained limited. Here, we report a method for the isolation of mitochondrial complex I from P. tricornutum and present a comprehensive proteomic analysis. Our results confirm the presence of carbonic anhydrase and bridge modules, both previously proposed as ancestral features of mitochondrial complex I, and identify at least one novel, clade-specific subunit that resembles NAD(P)H-dependent trans-2-enoyl-CoA/ACP reductases (TER) from other species. The subunit is similar to proteins involved in mitochondrial fatty acid biosynthesis. Our findings provide new insights into the composition, evolutionary conservation, and potential biotechnological relevance of this essential respiratory protein complex in diatoms.
    Keywords:  NADH dehydrogenase; Phaeodactylum tricornutum; carbonic anhydrase; carbonic anhydrase module; complex I; diatoms; ferredoxin bridge; mitochondria; respiration; respiratory chain
    DOI:  https://doi.org/10.1111/tpj.70706
  39. Redox Biol. 2026 Jan 16. pii: S2213-2317(26)00036-4. [Epub ahead of print]90 104038
    Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.
    Shadi Al-Mesitef, Daisuke Ando, Tomoya Saigasaki, Yuki Sakaguchi, Shunya Akagi, Abdulrahman Mousa, Sherif Rashad, Kuniyasu Niizuma.
      Transfer RNA-derived small RNAs (tDRs) are emerging regulators of cellular stress response, yet their biogenesis and activities during mitochondrial dysfunction remain poorly understood. Here we profiled tDRs generated in HEK293T cells exposed to inhibitors of respiratory complexes I-V (rotenone, TTFA, antimycin A, KCN, oligomycin) or to arsenite and assessed the impact of CRISPR-mediated angiogenin (ANG) knockout, ANG over-expression and recombinant ANG supplementation on the stress response and tDRs production. tDR-seq revealed stress-specific, highly ordered tDR repertoires: rotenone and antimycin predominantly induced internal (i-tRF) and 3' tRNA (tRF3) fragments, whereas arsenite induced anticodon-cleaved tRNA halves (tiRNAs). mito-tDRs were mostly internal fragments and antimycin induced the strongest mitochondrial tDRs expression. ANG deletion markedly impaired stress-induced tDR biogenesis and sensitized cells to antimycin and oligomycin stress, whereas its overexpression selectively enhanced tDR biogenesis and conferred protection against these mitochondrial stressor. Synthetic tDR mimics failed to rescue viability, implying that native modification patterns or cooperative tDR pools are required. tDR motif enrichment analysis identified YBX1-binding sites among antimycin-induced tDRs, and genetic perturbation of YBX1 phenocopied aspects of enhanced mitochondrial bioenergetics and stress resistance. Together, these findings demonstrate that context-specific, ANG-directed tDR biogenesis forms a crucial arm of the mitochondrial stress response.
    Keywords:  Angiogenin; Mitochondrial stress; RNA binding proteins; YBX1; tRNA; tRNA derived fragments
    DOI:  https://doi.org/10.1016/j.redox.2026.104038
  40. Autophagy. 2026 Jan 28.
    Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
    Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.
      Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.
    Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2026.2623988
  41. Genes (Basel). 2026 Jan 03. pii: 56. [Epub ahead of print]17(1):
    Hereditary Polyneuropathies in the Era of Precision Medicine: Genetic Complexity and Emerging Strategies.
    Maria Chrysostomaki, Despoina Chatzi, Stella Aikaterini Kyriakoudi, Soultana Meditskou, Maria Eleni Manthou, Sofia Gargani, Paschalis Theotokis, Iasonas Dermitzakis.
      Hereditary polyneuropathies represent a genetically and clinically heterogeneous group of disorders affecting the peripheral nervous system, characterized by progressive motor, sensory, and autonomic impairment. Advances in molecular genetics have identified key causative genes, including PMP22, MPZ, MFN2, TTR, EGR2, and CX32 (GJB1), which are implicated in Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and related neuropathies. These conditions display substantial allelic and locus heterogeneity. Pathogenetically, mechanisms involve impaired myelin maintenance, disrupted axonal transport, mitochondrial dysfunction, and aberrant Schwann cell biology. Despite these insights, therapeutic options remain limited, and there is a pressing need to translate genetic findings into effective interventions. This review aims to provide a comprehensive synthesis of current knowledge compiling all known mutations resulting in hereditary polyneuropathies. In addition, it underscores the molecular pathomechanisms of hereditary polyneuropathies and evaluates emerging therapeutic strategies, including adeno-associated virus mediated RNA interference, CRISPR-based gene editing, antisense oligonucleotide therapy, and small-molecule modulators of axonal degeneration. Furthermore, the integration of precision diagnostics, such as next-generation sequencing and functional genomic approaches, is discussed in the context of personalized disease management. Collectively, this review underscores the need for patient-centered approaches in advancing care for individuals with hereditary polyneuropathies.
    Keywords:  Schwann cell; gene therapy; genetics; hereditary polyneuropathies; peripheral nerve; precision medicine
    DOI:  https://doi.org/10.3390/genes17010056
  42. J Biol Chem. 2026 Jan 22. pii: S0021-9258(26)00038-4. [Epub ahead of print] 111168
    Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure.
    Xiao He, Qinghai Zhang, Chao Chen, Yutao Wu, Kai Wang, Shihao Yao, Haiyan Sun, Min-Xin Guan.
      Posttranscriptional nucleotide modifications of tRNAs play the critical roles in their structure and function. Deficient τm5s2U modifications of mitochondrial tRNAGlu, tRNAGln and tRNALys arising from TRMU mutations primarily manifest the liver failure. However, mechanisms of tissue specificity in TRMU-induced deficiencies remain largely elusive. In this report, we demonstrated that the loss of τm5s2U in mitochondrial tRNAs due to TRMU-deficiency caused the tissue-specific manifestation that contributed to pathogenesis of liver failures in the zebrafish. A wide range levels of τm5s2U in tRNALys, tRNAGlu, and tRNAGln occurred across the zebrafish brain, muscle, eye, liver and ovum tissues. Striking differences in tissue-specific effects of conformation, stability and aminoacylation of tRNAGlu, tRNALys and tRNAGln were observed among five tissues of trmu knockout (KO) zebrafish. Notably, livers are vulnerable to the loss of τm5s2U of tRNAs, evidenced by more severe failures in these tRNA metabolisms including conformation, instability and aminoacylation in liver than those in other four tissues of trmuKO zebrafish. These aberrant tRNA metabolisms altered the assembly, stability, and activities of complexes I, III and IV, especially pronounced in the liver of trmuKO zebrafish. Notably, livers displayed the highest ratios in the levels and activities of complex I to complex II in across five tissues, indicating the liver-specific electron flow preferences through complex I to coenzyme Q to complex III. These tissue-specific complex I deficiencies manifested the liver failures including hepatic steatosis and enlargement. Our findings provide new insights into the mechanism of liver-specific defects arising from the aberrant nucleotide modification of mitochondrial tRNAs.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111168
  43. Geroscience. 2026 Jan 28.
    Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.
    Malte Schmücker, Cathrine Tranberg, Jacob Borch, Mette Killerup Kaae, Michelle Damgaard, Mathias Flensted-Jensen, Ida Blom, Marco Morosetti, Sara Barbarossa, Patrick Orlando, Luca Tiano, Flemming Dela, Jørn Wulff Helge, Steen Larsen.
      Mitochondrial function is important to healthy aging, as it influences energy metabolism, oxidative stress, and physical performance. With age, mitochondrial function and biosynthesis of coenzyme Q10 (CoQ10) may change. CoQ10 serves as a key antioxidant and component of the electron transport system. Supplementation with CoQ10 may help preserve mitochondrial function and support healthy aging. Forty older community-dwelling adults (74 ± 4 years) received either daily oral CoQ10 supplementation (400 mg daily) or a placebo in a 12-week double-blinded, randomized, placebo-controlled design. Before and after the supplementation period, muscle biopsies were obtained. Subsequently, oral glucose tolerance tests (OGTT) and VO2max tests were conducted. Mitochondrial respiratory capacity (MRC), mitochondrial H2O2 emission, and mitochondrial content were assessed in both isolated mitochondria and permeabilized muscle fibers. Levels and redox status of CoQ10 were measured in plasma, muscle tissue, and isolated skeletal muscle mitochondria. Additionally, resting metabolic rate, cognitive function, and body composition were investigated. Plasma levels of CoQ10 increased significantly without changes in redox status after the intervention. No changes between groups or time were observed in muscle and isolated mitochondria regarding MRC, H2O2 emission, mitochondrial content, and levels of CoQ10. Glucose homeostasis, VO2max, and body composition were also unchanged. Twelve weeks of supplementation led to increased plasma levels of CoQ10, with unchanged levels in muscle tissue and isolated mitochondria. No differences in mitochondrial function, glucose homeostasis, and physical performance were found in a cohort of robust older adults.
    Keywords:  Antioxidant; Healthy aging; Mitochondrial function; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11357-025-02068-9
  44. Chem Sci. 2026 Jan 13.
    Spatiotemporally regulated mitochondrial genome editing via enzyme and NIR-activated CRISPR/Cas9 nanoplatform.
    Fei Yang, Qianqin Ran, Jiahui Chen, Guochen Bao, Yuezhong Xian, Cuiling Zhang.
      Mitochondrial DNA (mtDNA) mutations play critical roles in tumor progression and metabolic reprogramming. Controllable gene editing within tumor cell mitochondria remains a challenge due to the double-membrane barrier and the lack of tumor-selective activation. Herein, we report a dual-responsive CRISPR/Cas delivery platform (UCRP-TPP) that enables spatiotemporally regulated mtDNA editing for targeted tumor therapy. This nanoplatform integrates near infrared light-responsive upconversion nanoparticle (UCNP), an apurinic endonuclease 1 (APE-1)-responsive DNA complex, and a mitochondrial-targeting ligand (TPP), ensuring selective activation and mitochondrial release of Cas9/sgRNA complexes. Upon activation by endogenous APE-1 enzyme and exogenous NIR light, UCRP-TPP induces mtDNA editing by CRISPR/Cas, which leads to mtDNA copy number reduction, mitochondrial membrane depolarization, reactive oxygen species generation, and tumor cell apoptosis. In vivo studies further confirm the robust antitumor efficacy of the UCRP-TPP-based nanoplatform. This work presents a versatile and controllable mitochondrial gene-editing strategy.
    DOI:  https://doi.org/10.1039/d5sc07976d
  45. Cells. 2026 Jan 19. pii: 179. [Epub ahead of print]15(2):
    Collapsin Response Mediator Protein 2 (CRMP2) Modulates Induction of the Mitochondrial Permeability Transition Pore in a Knock-In Mouse Model of Alzheimer's Disease.
    Tatiana Brustovetsky, Rajesh Khanna, Nickolay Brustovetsky.
      Hyperphosphorylated collapsin response mediator protein 2 (CRMP2) is elevated in the cerebral cortex of an APP-SAA knock-in mouse model of Alzheimer's disease and binds the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. We propose that, in Alzheimer's disease (AD) mitochondria, dissociation of hyperphosphorylated CRMP2 from ANT promotes opening of the permeability transition pore (PTP). We showed that purified ANT, when reconstituted into giant liposomes, forms large calcium-dependent channels resembling the PTP, which are effectively blocked by recombinant, unphosphorylated CRMP2. In synaptic mitochondria isolated from the cortices of APP-SAA knock-in mice and control B6J hAbeta mice, we observed an increased susceptibility to permeability transition pore (PTP) induction in AD mitochondria, accompanied by reduced viability of cultured cortical neurons. Pre-treatment of AD mice with the CRMP2-binding small molecule (S)-lacosamide ((S)-LCM), which prevents CRMP2 hyperphosphorylation and restores its interaction with ANT, attenuated PTP induction and improved neuronal viability. Interestingly, direct application of (S)-LCM to isolated mitochondria failed to suppress PTP induction, indicating that its protective effect requires upstream cellular mechanisms. These findings support a phosphorylation-dependent role for CRMP2 in regulating PTP induction in AD mitochondria and highlight (S)-LCM as a promising therapeutic candidate for mitigating mitochondrial dysfunction and enhancing neuronal viability in AD.
    Keywords:  (S)-lacosamide; Alzheimer’s disease; CRMP2; adenine nucleotide translocase; cortical neurons; mitochondria; permeability transition pore
    DOI:  https://doi.org/10.3390/cells15020179
  46. Biology (Basel). 2026 Jan 13. pii: 139. [Epub ahead of print]15(2):
    Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
    Jessica Ábalos-Martínez, Francisco Visiedo, María Victoria Cascajo-Almenara, Celeste Santos-Rosendo, Victoria Melero-Jiménez, Carlos Santos-Ocaña, Luis Vázquez-Fonseca, Fernando Bugatto.
      Preeclampsia is a serious pregnancy disorder of unknown etiology. One of its cellular hallmarks is increased mitochondrial dysfunction in placental tissue. Further investigation into this aspect may help elucidate the molecular basis of preeclampsia. A total of 24 pregnant women who delivered by cesarean section participated in the study: n = 13 controls and n = 11 diagnosed with preeclampsia. Maternal blood samples were collected to assess the biochemical profile, and demographic and clinical data were recorded. Placental trophoblast samples were processed to isolate mitochondria and perform molecular biology assays. Women with preeclampsia exhibited the characteristic clinical features of the disease, along with biochemical alterations consistent with an inflammatory process. A significant decrease (73%) in mitochondrial DNA (mtDNA) copy number in trophoblastic tissue and a reduction in citrate synthase (CS) activity (-51%) in cytotrophoblast mitochondria-enriched fractions were observed in preeclampsia, indicating mitochondrial dysfunction accompanied by a loss of functional mitochondrial mass. In addition, we detected a marked decrease in MnSOD levels (-32%), together with an increase in the LC3II/LC3I ratio (47%) in cytotrophoblast mitochondria-enriched fractions, supporting the presence of mitochondrial alterations and suggesting the possible activation of mitophagy specifically in this cell type. Moreover, coenzyme Q10 (CoQ10) levels were elevated by 31% in trophoblastic villi. A pronounced 2.5-fold increase in CoQ10 normalized to CS activity (CoQ10/CS) was detected specifically in cytotrophoblasts from preeclamptic placentas. Importantly, we did not observe these alterations in the syncytiotrophoblast. In conclusion, preeclampsia is associated with mitochondrial dysfunction and increased CoQ10 levels normalized to CS activity, specifically in cytotrophoblast mitochondria, with findings being consistent with a possible involvement of mitophagy in this cell type. These findings suggest that cytotrophoblast mitochondrial metabolism may be more affected in preeclampsia compared with syncytiotrophoblasts, and that CoQ10 accumulation together with the possible activation of mitophagy may represent cellular defense mechanisms. Due to the limitations of the study, it should be considered exploratory and hypothesis-generating, and its results should be regarded as preliminary.
    Keywords:  coenzyme Q10; cytotrophoblast; mitochondria; mitophagy; preeclampsia
    DOI:  https://doi.org/10.3390/biology15020139
  47. Int J Biol Macromol. 2026 Jan 25. pii: S0141-8130(26)00453-8. [Epub ahead of print] 150527
    The LncRNA11-hnRNPA1 functional axis maintains adipose tissue metabolic homeostasis by promoting mitochondrial respiration and lipid utilization.
    Fan Wang, Saijun Xu, Yudie Zhang, Qilong Wang, Bin Zhang, Xiaobo Sun.
      Long noncoding RNAs (lncRNAs) are emerging as critical regulators of metabolic homeostasis and obesity pathogenesis. Mitochondrial dysfunction is a key driver of metabolic disorders, yet the underlying regulatory mechanisms remain incompletely understood. In this study, we unveil the metabolic function of a novel lncRNA GM44386 (LncRNA11), which is abundantly expressed in brown adipose tissue and functions as a protective molecule against obesity-related energy imbalance. Genetic deletion of LncRNA11 in mice led to exacerbated adipocyte hypertrophy, insulin resistance, and severe hepatic lipid accumulation under both normal and high-fat diet (HFD) conditions. Functionally, LncRNA11 deficiency compromised mitochondrial structure, quality, and oxidative phosphorylation capacity in adipocytes, resulting in defective fatty acid oxidation and impaired thermogenesis. Mechanistically, LncRNA11 forms a complex with Heterogeneous Nuclear Ribonucleoprotein A1 (hnRNPA1) to potentiate mitochondrial glycolysis in adipose tissue by upregulating pyruvate kinase M (PKM) expression. This enhancement supplies ATP required for UCP1-mediated uncoupling, thereby helping to maintain mitochondrial integrity and adaptive thermogenesis. Collectively, our findings identify LncRNA11 as a crucial upstream regulator that coordinates thermogenic capacity and mitochondrial stability, presenting a potential therapeutic target for combating obesity.
    Keywords:  Adipose tissue; Glycolysis; Long noncoding RNA; Mitochondria metabolism; Obesity; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150527
  48. Front Mol Neurosci. 2025 ;18 1667839
    Genetic evidence for a functional association between Parkinson's disease proteins leucine-rich repeat kinase 2 and α-synuclein during axonal transport.
    Piyali Chakraborty, Pratima Bajgain, Jing Huang, Rakibul Islam, Rupkatha Banerjee, Shermali Gunawardena.
      Mutations in α-synuclein (α-syn) and LRRK2 cause familial Parkinson's disease (fPD), yet how these proteins functionally interact remain ambiguous. We previously showed that α-syn undergoes bi-directional transport within axons and influences mitochondrial health, while other studies suggested that LRRK2-G2019S disrupts the axonal transport of autophagic vesicles and mitochondria. Here we tested the hypothesis that α-syn and LRRK2 are functionally linked during axonal transport. Expression of human LRRK2-WT in Drosophila larval nerves caused modest CSP-containing axonal blockages whereas no defects were seen in LRRK2 loss of function mutants in contrast to other proteins directly involved in axonal transport. Surprisingly, fPD mutations in the GTPase (LRRK2-Y1699C) and WD40 (LRRK2-G2385R) domains suppressed axonal blocks compared to LRRK2-WT, while kinase-domain mutant G2019S enhanced them. Reducing kinesin-1 had no effect with LRRK2-WT, but increased axonal transport defects with LRRK2-G2385R suggesting a functional interaction between the LRRK2 WD40 domain and the anterograde transport machinery. Further, co-expression of α-syn with either the GTPase domain or WD40 domain LRRK2 fPD mutants significantly suppressed α-syn-mediated axonal transport defects, decreased stalled α-syn-vesicles, but did not alter α-syn-mediated neuronal cell death. Taken together, these results suggest that while LRRK2 itself may not play an independent role in axonal transport, its GTPase and WD40 domains likely associate functionally with α-syn during transport within axons.
    Keywords:  Drosophila; LRRK2; Parkinson’s disease; WD40 domain; axonal transport; α-syn
    DOI:  https://doi.org/10.3389/fnmol.2025.1667839
  49. Adv Sci (Weinh). 2026 Jan 25. e17585
    A Non-Mitophagy Activity of BNIP3L/NIX in Amygdala Glutamatergic Neurons is Essential for Contextual Fear Memory Formation.
    Xingxian Zhang, Xinlei Mo, Xinyu Zhou, Xiaoliang Liu, Guizhi Li, Songhui Hu, Yangyang Lu, Chenze Zhu, Jinxi Feng, Zhitong Chen, Weiwei Hu, Yihui Cui, Zhong Chen, Xiangnan Zhang.
      Mitochondrial quality is crucial for maintaining brain homeostasis. BNIP3L/NIX, a mitophagy receptor, has been linked to neurological disorders, yet its specific function in the brain remains unclear. We found BNIP3L highly expressed in basolateral amygdala (BLA) neurons. Selective deletion of bnip3l in BLA glutamatergic neurons (BLAGLU) impaired contextual fear memory, accompanied by reduced neuronal excitation and mitochondrial respiration. Notably, fear conditioning did not invariably activate mitophagy in BLAGLU neurons. Overexpression of both wild-type and a mitophagy-deficient mutant (BNIP3LΔLIR) in BLAGLU neurons was sufficient to rescue the contextual fear memory deficits in bnip3l-/- mice, suggesting a non-mitophagy role. Instead, we detected a prompt mitochondrial fission in BLAGLU neurons after foot-shock conditioning, an effect abolished by bnip3l deletion. Inhibition of Drp1 with Mdivi-1 disrupted memory formation, whereas optogenetic activation of Drp1 restored neuronal excitation and rescued memory deficits in bnip3l-/- mice. These data indicated an essential role of BNIP3L-mediated mitochondrial fission in modulating contextual fear memory. Mechanistically, BNIP3L and Drp1 competitively interact with AMPK, leading to reduced Drp1 phosphorylation and increased Drp1 accumulation on mitochondria, thereby promoting mitochondrial fission. Taken together, the present study revealed a previously uncharacterized, non-mitophagy-dependent role for BNIP3L in contextual fear memory conditioning.
    Keywords:  AMPK‐Drp1; BNIP3L/NIX; basolateral amygdala; contextual fear memory; mitochondrial fission
    DOI:  https://doi.org/10.1002/advs.202517585
  50. Immunity. 2026 Jan 28. pii: S1074-7613(25)00566-7. [Epub ahead of print]
    A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
    Gillian Dunphy, Irene Adán-Barrientos, Irene Fernández-Delgado, Carolina Villarroya-Beltri, Ignacio Heras-Murillo, Elena Moya-Ruiz, Miguel Sánchez-Álvarez, Aitor Jarit-Cabanillas, Miguel A Del Pozo, Susana Guerra, Francisco Sánchez-Madrid, David Sancho.
      Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like receptor (TLR) stimulation, cytosolic nucleic acid sensing induced a decrease in mitochondrial membrane potential (MMP) while maintaining mitochondrial respiration. Interferon α/β (IFN-I) receptor (IFNAR) signaling was necessary and sufficient for this metabolic response. IFNAR signaling induced interferon-stimulated gene 15 (ISG15) expression and ISGylation of mitochondrial proteins, including subunits of mitochondrial complex V, increasing ATP production and decreasing MMP, thus enhancing macrophage efferocytic capacity. Moreover, the IFNAR-ISG15-mediated drop in MMP activated the mitochondrial protease OMA1, inducing mitochondrial fission and decreasing endoplasmic reticulum-mitochondria communication, thus dampening IFN-stimulated gene (ISG) induction. Loss of ISG15 or OMA1 enhanced histone acetylation and ISG induction upon IFN-I stimulation, in a manner dependent on mitochondrial calcium uptake. This increase in ISG induction provided protection against acute viral infections. These data indicate that IFNAR-ISG15 signaling boosts efferocytosis while limiting ISG induction, thereby promoting the resolution of inflammation.
    Keywords:  efferocytosis; interferon-stimulated genes; macrophage; metabolism; mitochondrial endoplasmic reticulum contacts; mitochondrial fission; mitochondrial membrane potential; oxidative phosphorylation; type I interferon; viral infection
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.010
  51. Eur J Neurol. 2026 Feb;33(2): e70488
    Novel Clinical Insights From a Swedish RFC1 Spectrum Disorder Cohort.
    Victor Alm, Linda Säll, Kristin Samuelsson, Rayomand Press, Snjolaug Arnardottir, Anna Lindstrand, Valter Niemelä, Lilia Terinte, Frida Nordin, Per Svenningsson, Daniel Nilsson, Luca Verrecchia, Martin Paucar.
       BACKGROUND: Biallelic pentanucleotide expansions in RFC1 cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and a growing spectrum of presentations. We aimed to clinically characterize a cohort of patients from Sweden with biallelic expansions in RFC1.
    METHODS: We retrospectively enrolled patients with homozygous expansions in RFC1 from a tertiary center in Sweden, evaluating clinical and genetic data. Assessments included nerve conduction studies (NCS, n = 27), electromyography (n = 7), quantitative sensory testing (n = 18), brain MRI (n = 27), and vestibular/eye motor tests (n = 18-21).
    RESULTS: Of the 30 patients enrolled, 28 were ethnic Swedish; 17/30 from smaller regions, including eight (27%) from Norrbotten. Twenty-two patients met the CANVAS criteria. Mean age of onset was 52 ± 12 years (range 20-70), and disease duration was 14 ± 12 years. Symptoms matched the CANVAS acronym with multisystemic features in 83%, including dysautonomia (77%), dyskinesia (36%), and bradykinesia (17%). Phenotypes overlapped with MSA-C (n = 2) and mitochondrial ataxias (n = 1). Notably, one symptomatic patient lacked neuropathy on NCS. Annual disease progression was slow (0.3 by spinocerebellar degeneration functional score, 1.2 by SARA). At vestibular testing, 47% showed a preserved caloric response and pathologic angular VOR with a nonsignificant trend among younger patients and milder ataxia; otolith function was largely preserved.
    DISCUSSION: Our findings expand the RFC1 spectrum, suggesting a founder effect in Sweden and extensive subclinical involvement. RFC1-spectrum disorder should also be considered in patients with cerebellar and vestibular dysfunction but lacking neuropathy. A discordant VOR pattern may represent an incipient sign of RFC1-spectrum disorder; interestingly, otolith pathways seem to be generally spared.
    Keywords:   RFC1 ; CANVAS; Ganglionopathy; Neuropathy; VEMP; bilateral vestibulopathy; cerebellar ataxia; vHIT; vestibular areflexia; vestibulo‐ocular reflex
    DOI:  https://doi.org/10.1111/ene.70488
  52. Elife. 2026 Jan 29. pii: RP99438. [Epub ahead of print]13
    Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function.
    Bei Zhang, Ting Cai, Esha Reddy, Yuanna Wu, Isha Mondal, Yinglu Tang, Adaeze Scholastical Gbufor, Jerry Wang, Yawei Shen, Qing Liu, Raymond Sun, Winson S Ho, Rongze Olivia Lu, Zhihao Wu.
      The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in human glioblastoma multiforme (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). The exogenous introduction of the mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein, accompanied by artificial CAT-tail mimicking sequences, enhanced mitochondrial membrane potential (ΔΨm) and inhibited the formation of the mitochondrial permeability transition pore (MPTP). These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth.
    Keywords:  cancer biology; carboxyl-terminal alanine and threonine tailing; cell biology; glioblastoma; human; mitochondria; ribosome-associated quality control
    DOI:  https://doi.org/10.7554/eLife.99438
  53. Mitochondrial Commun. 2025 ;3 99-108
    Off-target effects of mitochondrial oxidative phosphorylation inhibitors are common and can compromise the viability of cultured cells.
    Natalya Kozhukhar, Mikhail F Alexeyev.
      Mitochondrial respiratory chain inhibitors (MRCIs) are indispensable for studying cellular bioenergetics and its effects on various cellular processes. However, their off-target (those not mediated by respiratory chain inhibition) effects remain incompletely understood, even though their comprehension is crucial for the accurate interpretation of experimental outcomes. Here, we use four isogenic cell line pairs, which either have mitochondrial DNA (mtDNA) or lack it (ρ+ or ρ0 cells, respectively), to assess the possible off-target effects of widely used MRCIs antimycin A, oligomycin A, rotenone, and carbonyl cyanide m-chlorophenylhydrazone (CCCP). We examined clonogenic growth of ρ0 cells and ρ+ cells under conditions that either require the functional respiratory chain or do not. Unexpectedly, ρ0 cells were sensitive to rotenone and antimycin A, even though these cells lack functional complex I and complex III, respectively, suggesting a nonspecific effect of these drugs. Furthermore, ρ0 cells were more sensitive to CCCP than their ρ+ counterparts. Intriguingly, the loss of the clonogenic potential in ρ+ 143B cells could not be precisely correlated to the decrement of the mitochondrial inner membrane potential. These findings underscore the significance of off-target effects of MRCIs, which must be carefully considered when designing, conducting, and interpreting experiments involving these inhibitors.
    Keywords:  Antimycin A; Carbonyl cyanide m-chlorophenylhydrazone; Oligomycin A; Rho-0 cells; Rotenone
    DOI:  https://doi.org/10.1016/j.mitoco.2025.12.001
  54. Int J Mol Sci. 2026 Jan 22. pii: 1119. [Epub ahead of print]27(2):
    UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment.
    Bo Jin, Junyao Qu, Ke Xu, Yufei Zhang, Peng Xu, Xin Wang, Bo Zhao, Xianting Jiao.
      Mitophagy, as a critical form of selective autophagy, plays a central role in maintaining cellular homeostasis. While the canonical PTEN-Induced Kinase 1 (PINK1)-Parkin pathway is well established, mitophagy can still be effectively induced in Parkin-deficient cells such as HeLa, indicating the existence of Parkin-independent alternative pathways. The mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) acts as a key effector in such pathways, yet its regulatory mechanisms remain incompletely understood. Here, we identify Ubiquitination Factor E4B (UBE4B) as an E3 ubiquitin ligase for NIPSNAP1 and demonstrate that it catalyzes NIPSNAP1 ubiquitination in both Human Embryonic Kidney 293 cells (HEK293T) and HeLa cells. Under mitochondrial depolarization, UBE4B not only promotes NIPSNAP1 ubiquitination and subsequent lysosome-dependent degradation, but also significantly enhances its interaction with the autophagy adaptors Nuclear Dot Protein 52 kDa (NDP52) and Sequestosome 1 (p62/SQSTM1). Notably, while Parkin does not ubiquitinate NIPSNAP1, UBE4B-mediated ubiquitination facilitates mitophagy in Parkin-null HeLa cells by strengthening the binding between NIPSNAP1 and NDP52. Collectively, this study unveils a novel mitophagy pathway regulated by the UBE4B-NIPSNAP1 axis, offering new insights into mitochondrial quality control.
    Keywords:  HeLa cell; NIPSNAP1; UBE4B; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.3390/ijms27021119
  55. STAR Protoc. 2026 Jan 27. pii: S2666-1667(25)00711-7. [Epub ahead of print]7(1): 104305
    Protocol for the generation and xenotransplantation of human induced pluripotent stem cell-derived neural progenitor cells into the mouse forebrain.
    Julie J McInvale, Chloe E Ayers, Hemanta Sarmah, Kang Kim, Peter Reinhardt, Aayushi Mahajan, Nelson Humala, Barbara Corneo, Jared Sterneckert, Peter Canoll, Gunnar Hargus.
      Here, we present a protocol for the small-molecule-driven derivation of dopaminergic and GABAergic neurons from neural progenitor cells (NPCs) differentiated from human induced pluripotent stem cells and for stereotactic xenotransplantation of NPCs into the mouse forebrain. We also describe steps for perfusion of xenografted mice and microdissection of grafts for single-nucleus RNA sequencing analysis. This protocol can be used for various assays, including drug screening and toxicity assays, or for mechanistic studies on human neurons. For complete details on the use and execution of this protocol, please refer to Reinhardt et al.1 and Al-Dalahmah et al.2.
    Keywords:  cell differentiation; neuroscience; stem cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.104305
  56. Mol Syst Biol. 2026 Jan 29.
    Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.
    Duc Tung Vu, William Sibran, Andreas Metousis, Laurine Vandewynckel, Basak Eraslan, Liesel Goveas, Ericka Cm Itang, Claire Deldycke, Adriana Figueroa-Garcia, Réginald Lefèbvre, Johannes Bruno Müller-Reif, Sebastian Virreira Winter, Marie-Christine Chartier-Harlin, Jean-Marc Taymans, Matthias Mann, Ozge Karayel.
      Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD) and often increase kinase activity, making LRRK2 inhibitors promising treatment options. Although LRRK2 kinase inhibitors are advancing clinically, non-invasive readouts of LRRK2-linked pathway modulation remain limited. Profiling urinary proteomes from 1215 individuals across three cohorts and integrating whole-genome sequencing from >500 participants to map genotype-proteome associations, we identified 177 urinary proteins associated with pathogenic LRRK2, enriched for lysosomal/glycosphingolipid, immune, and membrane-trafficking pathways. Machine learning narrowed the features to a cohort-agnostic 30-protein panel that classified G2019S carriers with a mean ROC AUC of 0.91 across independent tests. To evaluate translation, we performed multi-organ and urinary proteomics in rat gain- and loss-of-function models (BAC-LRRK2G2019S and Lrrk2KO) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses-strongest in kidney-and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted LRRK2 mutation status in patients (AUC 0.75) and reversed with Lrrk2 inhibition, supporting their pharmacodynamic utility. Together, our findings establish urine as a scalable, non-invasive matrix that captures systemic and brain-relevant consequences of LRRK2 dysfunction and nominate candidate pharmacodynamic markers set to support LRRK2-directed trials.
    Keywords:  Biomarker; LRRK2; Parkinson’s Disease; Proteomics; Urine
    DOI:  https://doi.org/10.1038/s44320-026-00190-0
  57. Front Immunol. 2025 ;16 1725904
    Hemoglobin alpha regulates T-lymphocyte activation and mitochondrial function.
    Emily C Reed, Tatlock H Lauten, Tamara Natour, Lauren J Pitts, Caroline N Jojo, Brooke L Griffin, Sreeram Pasupuleti, Adam J Case.
      We have recently discovered hemoglobin alpha a1 (Hbα-a1 mRNA and Hbα protein) in T-lymphocytes and previously reported that its expression was sensitive to mitochondrial redox perturbations. However, outside of its occurrence and basic characterization, the functional role of Hbα in T-lymphocytes remained unknown. Herein, we identify Hbα in both CD4+ and CD8+ T-lymphocyte subsets, and found its expression is highly dynamic, differs between the two subtypes, and is dependent upon activation stage. Further, the loss of Hbα by use of a novel T-lymphocyte-specific Hbα knock-out mouse impairs mitochondrial function, dysregulates cytokine production, and lowers the activation threshold primarily in CD4+ T-lymphocytes, indicating a critical role for Hbα within this subset. While these data suggested the loss of Hbα in T-lymphocytes may promote aberrant activation of autoreactive T-lymphocytes, surprisingly, we discovered that mice lacking Hbα in T-lymphocytes exhibited reduced severity of experimental autoimmune encephalomyelitis (EAE) compared to wild-type control animals. Interestingly, T-lymphocytes lacking Hbα in vivo appeared to function identically to wild-type controls, which did not explain the protection against EAE. In contrast, T-lymphocyte Hbα knock-out mice displayed significantly reduced levels of circulating immunoglobulins and CD40L expression compared to their wild-type counterparts during EAE, suggesting possible impaired intercellular communication. These data elucidate a previously unrecognized role for Hbα in T-lymphocyte function, which may have implications for hemoglobin-related diseases (i.e., hemoglobinopathies).
    Keywords:  EAE; Inflammation; hemoglobinopathy; immune; redox
    DOI:  https://doi.org/10.3389/fimmu.2025.1725904
  58. Nat Metab. 2026 Jan 28.
    Methylation, acetylation and cell fate.
    Dan Huang, Ziwei Dai.
      
    DOI:  https://doi.org/10.1038/s42255-025-01449-w
  59. Nature. 2026 Jan 28.
    A step towards building miniature human livers.
      
    Keywords:  Biotechnology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-04012-5
  60. Commun Biol. 2026 Jan 28.
    Cryo-EM structure of bixafen-bound S. cerevisiae complex II unravels SDHI specificity against pathogenic fungi.
    Nikos Pinotsis, Claudia Burn-Leefe, Sarah Jones, Shu Chen, Natalya Lukoyanova, Brigitte Meunier, Edward A Berry, Amandine Maréchal.
      Respiratory complex II (CII), or succinate dehydrogenase, couples succinate oxidation in the Krebs cycle with electron transfer to the respiratory chain. Owing to this pivotal role, CII inhibitors are widely used fungicides globally; however, their development has largely proceeded without structural insights from fungal targets. Here, we report cryo-electron microscopy structures of the 128 kDa mitochondrial CII from Saccharomyces cerevisiae in two states: active, with endogenous ubiquinone-6 bound (3.15 Å), and inhibited with the fungicide bixafen (3.00 Å). Although closely related to the mammalian type C enzyme, our structures show that the yeast CII has lost the canonical heme cofactor. They also reveal how clade-specific sequence extensions of the membrane subunits Sdh3 and Sdh4 - conserved in pathogenic fungi - uniquely contribute to complex stability and fungicide binding. Our findings provide a foundation for rational design of next-generation CII inhibitors and combatting resistance, in both agriculture and human health.
    DOI:  https://doi.org/10.1038/s42003-026-09617-8
  61. Mitochondrion. 2026 Jan 26. pii: S1567-7249(26)00001-2. [Epub ahead of print]87 102111
    Exogenous mitochondrial transfer alleviates neurodegeneration in Parkinson's disease model by improving mitochondrial function.
    Yu Si, Muhammad Abid Hayat, Yingyin Ni, Jingwen Zhang, Tao Guo, Yudie Cao, Yancheng Hong, Hao Zuo, Xin Sun, Zheng Li, Bo Chen, Jia Wan, Yong Wang, Jiabo Hu.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder related to mitochondrial dysfunction. Recent studies have reported that mitochondrial transfer between cells occurred naturally and was effective for alleviating mitochondrial dysfunction. In the current study, functional exogenous mitochondria (Mito) were extracted and administered to both in vitro and in vivo PD models, exploring the therapeutic effects of Mito on damaged neurons. It was observed that in the in vitro PD model, Mito improved cell morphology and increased cell viability from 25.06% to 42.44% (p < 0.001), while enhancing mitochondrial activity within the cells by a 201% increase in the JC-1 red/green fluorescence ratio (p = 0.02). Further analysis suggests that Mito's neuroprotective effects are potentially mediated via integrated modulation of neuroinflammation and ferroptosis pathways. The findings of the in vivo PD model showed that Mito improved motor coordination in the rotational test by 71% (p < 0.01) and ameliorated depression-like behavior demonstrating a 13.4% enhancement in Sucrose preference (p < 0.001), accompanied by histological evidence of neuroprotection observed in Nissl-stained brain sections and the significant recovery in mitochondrial function by 31.6% (p = 0.01). This study is the first to demonstrate that Mito can enter a PD cell model and rescue neuronal and mitochondrial damage in both in vivo and in vitro settings, with transcriptomic analysis revealing the involvement of key molecular pathways related to neuroinflammation and ferroptosis. This offers new insights and prospectus therapeutic strategies for PD as well as a foundation for future research in clinical medicine.
    Keywords:  Mitochondria; Mitochondrial transplantation; Neurodegenerative diseases; Neurons; Parkinson’sdisease
    DOI:  https://doi.org/10.1016/j.mito.2026.102111
  62. Biology (Basel). 2026 Jan 20. pii: 189. [Epub ahead of print]15(2):
    Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
    Yanyu Bao, Guoying Miao, Nannan He, Xingting Bao, Zheng Shi, Cuilan Hu, Xiongxiong Liu, Bing Wang, Chao Sun.
      Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.
    Keywords:  melatonin; mitochondrial dysfunction; mitochondrial quality control; neurodegenerative diseases; oxidative stress
    DOI:  https://doi.org/10.3390/biology15020189
  63. Lancet Neurol. 2026 Feb;pii: S1474-4422(25)00489-2. [Epub ahead of print]25(2): 133
    Fighting Parkinson's disease: a neurologist-patient journey.
    Tissa Wijeratne.
      
    DOI:  https://doi.org/10.1016/S1474-4422(25)00489-2
  64. Eur J Med Genet. 2026 Jan 27. pii: S1769-7212(26)00004-2. [Epub ahead of print] 105070
    Tachycardiomyopathy-Like Presentation in Neonatal MCAD Deficiency: A Novel Cardiac Phenotype.
    Elisabetta Morana, Federico Baronio, Marcello Lanari, Egidio Candela, Rita Ortolano, Simone Bonetti, Gabriele Bronzetti, Giacomo Biasucci, Tammam Hasan, Luca Ragni, Andrea Donti.
       BACKGROUND: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia, while neonatal presentations are less common. Although the disorder classically manifests with metabolic decompensation, atypical cardiac involvement has occasionally been reported but remains exceedingly rare. MCADD is included in many newborn screening programs, enabling early detection and timely management.
    CASE PRESENTATION: We report a full-term female neonate who, at 3 days of life, developed severe metabolic decompensation with refractory supraventricular tachyarrhythmias, severe systolic dysfunction, and biventricular dilation requiring maximal inotropic support. Expanded newborn screening revealed a profile consistent with MCADD, and genetic testing identified a homozygous variant in the ACADM gene, described according to HGVS nomenclature as ACADM(NM_000016.6):c.985A>C p.(Lys329Gln). Disease-specific management, including high-rate intravenous glucose administration, carnitine supplementation, and a tailored low-fat diet, resulted in complete normalization of cardiac function within 48 hours.
    DISCUSSION: This case represents a tachycardiomyopathy-like presentation of neonatal-onset MCADD, a novel and rarely described cardiac phenotype. It emphasizes the importance of considering fatty acid oxidation disorders in the differential diagnosis of unexplained arrhythmias and cardiomyopathy in neonates, particularly before newborn screening results are available.
    CONCLUSIONS: Early diagnosis and prompt initiation of metabolic treatment are essential to reverse potentially life-threatening cardiac manifestations in MCADD. This report highlights a novel phenotype and expands the clinical spectrum of neonatal-onset MCADD.
    Keywords:  Fatty acid oxidation disorders; MCADD; Neonatal Newborn Screening; Neonatal Tachycardiomyopathy; dilated cardiomyopathy; medium chain acyl Co-A deficiency; neonatal metabolic emergencies
    DOI:  https://doi.org/10.1016/j.ejmg.2026.105070
  65. Mol Cell. 2026 Jan 27. pii: S1097-2765(25)01030-5. [Epub ahead of print]
    Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors.
    Martin Gamerdinger, Nicolas Burg, Elke Deuerling.
      Protein biogenesis requires the ribosome to collaborate with a diverse set of cotranslational factors that shape the fate of nascent chains. These interactions must be precisely choreographed: while cytonuclear proteins require immediate N-terminal maturation and folding, endoplasmic reticulum (ER) and mitochondrial proteins must be maintained in an unfolded state for targeting to their organelles. Reconciling these opposing demands requires a highly selective sorting mechanism operating at the ribosomal exit tunnel. Recent studies identify the conserved nascent polypeptide-associated complex (NAC) as a central coordinator of this process. By sensing nascent signals and dynamically modulating factor access to the ribosome, NAC directs substrates toward the appropriate maturation or targeting pathway. This emerging framework positions NAC as a molecular hub that organizes cotranslational interactions into efficient and orderly protein-biogenesis pathways. In this review, we discuss the mechanistic principles underlying NAC function and consider broader implications for how ribosome-associated networks enforce fidelity in protein biogenesis.
    Keywords:  ER; METAP; MTS; N-acetylation; N-myristoylation; N-myristoyltransferase; N-terminal acetyltransferase; N-terminal modification; NAC; NAT; NMT; NatA; NatD; NatE; SRP; SS; UBA; endoplasmic reticulum targeting; methionine aminopeptidase; methionine excision; mitochondrial targeting sequence; nascent polypeptide-associated complex; ribosome; signal recognition particle; signal sequence; ubiquitin-associated domain
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.031
  66. Endocr Connect. 2026 Jan 29. pii: EC-25-0768. [Epub ahead of print]
    RTN4IP1 Mutation and Endocrine Failure: Clinical Features and Possible Benefits of Coenzyme Q10.
    Telethon Undiagnosed Diseases Program Study Group
      RTN4IP1 encodes a mitochondrial oxidoreductase essential for Coenzyme Q biosynthesis; pathogenic variants have been reported mainly in optic neuropathy and encephalopathy. We describe a 30-year-old woman carrying three novel pathogenic RTN4IP1 variants by exome sequencing (c.1163G>A p.Arg388Gln, c.949A>C p.Met317Leu, c.1109T>C p.Phe370Ser), who presented with panhypopituitarism, optic-nerve hypoplasia, corpus callosum agenesis, bicuspid aortic valve disease, seizures, and muscle pain, already on conventional hormone replacement. Coenzyme Q10 (CoQ10) (200 mg) was administered orally for six months; outcomes were assessed using BPI, WOMAC, TUG, LEFS, grip-strength dynamometry, SF-36, CPK and LDH and after six months of daily 200 mg CoQ10 the patient showed marked reductions in pain (BPI 4 → 0.8; -80 %) and muscle-damage markers (CPK 254 → 110 U/L) together with gains in grip strength (+49 %) and lower-extremity function (LEFS 31 → 60; +94 %). SF-36 domains related to physical health showed marked gains, while emotional scores remained stable. This is the first report linking RTN4IP1 mutations to endocrine failure and suggesting a therapeutic role for CoQ10 in mitochondrial-related endocrine disease.
    Keywords:  CoQ10; Mitochondrial Disease; Optic Atrophy-10; Panhypopituitarism; RTN4IP1
    DOI:  https://doi.org/10.1530/EC-25-0768
  67. Biomolecules. 2026 Jan 08. pii: 117. [Epub ahead of print]16(1):
    Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review.
    Sakthipriyan Venkatesan, Cristoforo Comi, Fabiola De Marchi, Teresa Esposito, Carla Gramaglia, Carlo Smirne, Mohammad Mostafa Ola Pour, Mario Pirisi, Rosanna Vaschetto, Patrizia Zeppegno, Elena Grossini.
      Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind-body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care.
    Keywords:  allostatic load; mitochondrial dysfunction; psychosocial stress; reactive oxygen species; relationship trauma; systemic nervous system
    DOI:  https://doi.org/10.3390/biom16010117
  68. Biomed Pharmacother. 2026 Jan 28. pii: S0753-3322(26)00054-5. [Epub ahead of print] 119022
    Mitochondria-targeted antioxidant AntiOxBEN2 prevents metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing fatty acid oxidation and mitochondrial bioenergetics.
    Ricardo Amorim, Carina Magalhães, Ana I Duarte, Alexandra C de Lemos, Adriana-Marques Carvalho, Susana P Pereira, Luís F Grilo, Débora Mena, Heloísa Gerardo, Caroline Veloso, Diana Sousa, Armando Caseiro, Fernando Cagide, Fernanda Borges, Paulo Matafome, José Teixeira, Paulo J Oliveira.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. Its progression is commonly linked to excessive hepatic fat accumulation, elevated oxidative stress, and impaired mitochondrial function. Given the central role of mitochondria in cellular energy metabolism and redox balance, mitochondria-targeted bioactive molecules have emerged as a promising strategy for the prevention and treatment of MASLD. To this end, we develop AntiOxBEN2, a mitochondria-targeted compound generated by conjugating the antioxidant moiety of gallic acid with the lipophilic triphenylphosphonium cation. This design enables selective accumulation of AntiOxBEN2 in the mitochondrial matrix, taking advantage of the organelle's negative membrane potential. In multiple in vitro disease models, AntiOxBEN2 has demonstrated remarkable antioxidant properties, effectively mitigating oxidative stress and preserving mitochondrial function. However, effects on cellular and mitochondrial energy metabolism in vivo remain unexplored. In the present study, we tested whether chronic peripheral administration of AntiOxBEN2 (0.5 or 2.5 mg/kg, 3x/week) could prevent MASLD development in male and female C57BL/6 J mice fed with a 30 % high-fat, 30 % high-sucrose (Western Diet, WD) diet for 16 weeks. Our results demonstrate that AntiOxBEN2 treatment significantly reduced hepatic lipid accumulation in both sexes without affecting body weight. This reduction was accompanied by improvements in mitochondrial function, including enhanced fatty acid oxidation (FAO) and increased activities of mitochondrial electron transport chain (ETC) complexes. Moreover, AntiOxBEN2 administration lowered circulating levels of hepatic damage markers (ALT and AST), as well as insulin and leptin. Notably, a clear sexual dimorphism was observed, with female mice displaying a more pronounced improvement in mitochondrial parameters. Collectively, these findings highlight the therapeutic potential of AntiOxBEN2 for the prevention and/or treatment of MASLD.
    Keywords:  Fatty acid oxidation; Metabolic dysfunction-associated steatotic liver disease (MASLD); Mitochondria (dys)function; Mitochondria-targeted antioxidant AntiOxBEN(2); Oxidative stress; Western diet
    DOI:  https://doi.org/10.1016/j.biopha.2026.119022
  69. Reproduction. 2026 Jan 06. pii: xaaf008. [Epub ahead of print]171(1):
    Meiotic purification of dysfunctional mitochondria in mouse oocytes.
    Sanbao Shi, Zhunyuan Min, Yongqi Li, Jianxin Pan, Hongying Sha.
      Mitochondrial purification, including mitophagy, during oogenesis is critical for ensuring accurate mitochondrial DNA transmission, but it remains unclear whether meiosis plays a role in eliminating defective mitochondria. Here, we show that mitochondria in the first polar body (PB1) exhibit reduced membrane potential compared with those retained in oocytes. TUNEL and cytochrome c assays suggest that mitochondrial dysfunction in PB1 precedes nuclear fragmentation. Notably, the second polar body (PB2) exhibits heterogeneous membrane potentials, with both functional and dysfunctional populations present. By injecting dysfunctional and functional mitochondria, isolated respectively from the cytoplasts of the PB1and the oocyte, into germinal vesicle-stage mouse oocytes, we found that dysfunctional mitochondria were preferentially extruded into PB1, while functional mitochondria were retained after meiosis I. Interestingly, mitochondria from PB1 exhibit low membrane potential even after being transferred into a new, healthy oocyte, whereas oocyte-derived mitochondria maintain normal membrane potential following the same procedure. Immunofluorescence analysis further shows that PB1-derived mitochondria lack colocalization with motor protein Rho T1, in contrast to their oocyte-derived counterparts. Furthermore, PB1 transfer combined with mitochondrial probe and fast-NGS demonstrated that meiosis II also contributes to the extrusion of dysfunctional mitochondria into PB2. By comparison, spindle transfer revealed that most functional mitochondria were retained in the oocyte, with only minimal amounts detected in PB2. Predictably, PB2 and pronuclear transfer failed to extrude foreign mitochondria. Collectively, these findings identify meiosis as a distinctive safeguard for mitochondrial quality during oogenesis, with implications that warrant further investigation in humans.
    Keywords:  Cytochrome C; Meiosis; Mitochondria; oocyte; polar body
    DOI:  https://doi.org/10.1093/reprod/xaaf008
  70. Autophagy. 2026 Jan 29.
    Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
    Yang Qu, Shanhui Ren, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Chan Ding.
      Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy.
    Keywords:  Amino acid metabolism; MAVS; NDV, PINK1-PRKN; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2624746
  71. Int J Mol Sci. 2026 Jan 13. pii: 782. [Epub ahead of print]27(2):
    Cholinergic Phenotypes of Acetyl-CoA with ATP-Citrate Lyase Link.
    Sylwia Gul-Hinc, Agnieszka Jankowska-Kulawy, Andrzej Szutowicz.
      Glycolysis-derived pyruvate is the almost exclusive source of acetyl-CoA for energy production in mitochondrial compartments of all types of neuronal and glial cells. Neurons utilize several times more glucose than glial cells due to their neurotransmitter functions. Cholinergic neurons that are responsible for cognitive functions require additional amounts of acetyl-CoA for acetylcholine-transmitter synthesis in their cytoplasmic compartment. It may be assured by preferential localization of ATP-citrate lyase (ACLY) in the cytoplasm of cholinergic neurons' perikaryons and axonal terminals. This thesis is supported by the existence of strong regional and developmental correlations of ATP-citrate lyase and choline acetyltransferase (ChAT) activities and ACh levels in the brain. Electrolytic or chemical lesions of cholinergic nuclei cause proportional loss of the above parameters in the respective cortical target areas. On the other hand, the regional activity of mitochondrial pyruvate dehydrogenase complex (PDHC), which synthesizes nearly the whole pool of neuronal acetyl-CoA, displays no correlation with cholinergic innervation. It makes cholinergic neurons highly susceptible to brain pathologies impairing energy metabolism. Therefore, the ACLY pathway, which provides acetyl units directly to the site of acetylcholine synthesis in cholinergic nerve terminals, plays a key role in the maintenance of cholinergic neurotransmission. On the other hand, in cholinergic motor neurons, various ACLY-protein complexes are involved not only in neurotransmission but also in axonal transport of cholinergic elements from the perikaryon to cholinergic neuro-muscular junctions. This review presents findings supporting this thesis.
    Keywords:  ATP-citrate lyase; acetylcholine; choline acetyltransferase; cholinergic neuron; metabolic compartmentation; pyruvate dehydrogenase
    DOI:  https://doi.org/10.3390/ijms27020782
  72. Mol Med. 2026 Jan 28.
    Proliferation of activated hepatic stellate cells requires REST.
    Vladimir S Shavva, L Tarnawski, W Dai, N Moruzzi, A-S Haller, F Borg, S Hansson, Q Guo, M Cai, E Fekete, J J Vacquié, A Maestri, T Liu, R S Vimaladithan, S G Malin, P Saliba-Gustafsson, P-O Berggren, C E Hagberg, O Ahmed, Peder S Olofsson.
      
    Keywords:  Hepatic stellate cell activation; Mitochondrial metabolism.; Proliferation; REST
    DOI:  https://doi.org/10.1186/s10020-025-01406-z
  73. Mitochondrion. 2026 Jan 24. pii: S1567-7249(26)00006-1. [Epub ahead of print] 102116
    Mitochondria transfer from myocytes to endothelial cells Promotes angiogenesis in skeletal muscle.
    Yu-Feng Long, Ai-Jun Huang, Shuo Tang, Zhen Xu, Ming-Yue Wu, Kai Liu, Ze-Cai Chen, Lei Qin, Bing-Yang Dai, Cheng Dong, Wing-Hoi Cheung, Xin-Luan Wang, Da-Zhi Yang.
      Skeletal muscle and vascular health are closely interconnected, yet the mechanisms underlying their crosstalk remain poorly understood. This study investigates the role of mitochondria transfer from myocytes to endothelial cells. Using in vitro 2D and 3D coculture systems, combined with protein-level and functional analyses, we show that mitochondria are transferred via extracellular vesicles in a Rab7-dependent and cellular connection-independent manner. Connexin 43 (CX43) inhibition downregulating Growth-Associated Protein 43 (GAP43) but enhances mitochondria transfer, accompanied by increasing Rab7. Transferred mitochondria promote endothelial cells proliferation, migration, ATP production, and angiogenesis, which could be the key processes in preserving vascular integrity and muscle function. Our study indicated that the aging-associated decline in CX43 and mitochondrial quality exacerbates muscle atrophy by facilitating the transfer of dysfunctional mitochondria. These findings uncover a novel mechanism of muscle-vessel communication and highlight mitochondria transfer as a potential therapeutic target for aging-related muscular and vascular deterioration. New and Noteworthy. Mitochondria transfer is a way for cell communication. However, mitochondria transfer between myocyte and endothelial cell remains unknown. Here, we demonstrates that mitochondria transfer occurs between myocytes and endothelial cells. Interestingly, inhibition of CX43 leads to a decrease in GAP43 expression, while simultaneously upregulating Rab7 and enhancing mitochondria transfer from myocytes to endothelial cells. Furthermore, we reveal that Rab7-induced mechanism mediates the transfer of both functional and impaired mitochondria from myocytes to endothelial cells.
    Keywords:  Endothelial cells; Mitochondria transfer; Muscle; Myocytes; Vessel
    DOI:  https://doi.org/10.1016/j.mito.2026.102116
  74. Soft Matter. 2026 Jan 28.
    The influence of cellular energy status, microtubules, and crowding on mitochondrial motion.
    Beatrice Corci, Werner J H Koopman, Amalia M Dolga, Christoffer Åberg.
      Eukaryotic cells rely on a tightly regulated system to transport vesicles and organelles within the cell, as thermal diffusion becomes inefficient for larger cargo. This transport system is composed of the cytoskeleton, a polymer mesh extending throughout the cell, together with different types of motor proteins that attach to and walk along the cytoskeleton, thereby carrying the cargo along with them. Here we used mitochondria in human cells as a model system for cargo transported by motor proteins, followed their motion using microscopy, and analysed the trajectories. Consistent with previous studies, we observed that the mitochondria often remain within a limited region, rattling around, for long periods of time, before finally taking a longer jump. To elucidate the mechanisms behind this behaviour we subsequently perturbed the system. Depletion of cell energy substantially prolonged the waiting time before taking a jump, but also decreased the jump lengths and, to a lesser extent, the extent of the rattling. Disruption of the microtubule network showed a more modest effect on the motion, the largest effect being an approximate doubling of the waiting time before making a jump. Similarly, increasing intracellular crowding by osmotically compressing the cells also had a rather small effect on mitochondrial motion. Again, there was an approximate doubling of the waiting time before making a longer jump, coupled to a more modest decrease in the extent of the rattling. Overall, our data give quantitative insights into the mechanisms underlying motor protein-driven motion and, in particular, highlights the waiting time before making a longer jump as a key parameter.
    DOI:  https://doi.org/10.1039/d5sm01174d
  75. Genet Med Open. 2026 ;4 103476
    Rapid targeted analysis of the genome: Rapid genomic sequencing in critically ill infants.
    K Taylor Wild, Sara L Reichert, Matthew C Dulik, Alexandra Heck, Emma C Bedoukian, Kathleen H Wood, Katharine P Callahan, Jennifer A Hershey, David A Munson, Kieran B Pechter, Kelly Regan-Fendt, Anthony M Gacita, Francis Jeshira Reynoso Santos, Morgan L McManus, Natalie Burrill, Maria Alejandra Diaz-Miranda, Melissa A Gilbert, Ian D Krantz, Ramakrishnan Rajagopalan, Laura K Conlin, Nancy B Spinner.
       Purpose: We developed a genome sequencing-based test (Rapid Targeted Analysis of the Genome for Infants [rTAG-I]) to minimize turnaround time while maximizing diagnostic yield and access to rapid sequencing for critically ill infants. We sought to create a system of predicting which infants would have a molecular finding.
    Methods: We performed a prospective observational study of infants referred for genetics consult who received rTAG-I testing, which analyzes 3183 curated genes with phenotype-agnostic prioritization of pathogenic and likely pathogenic variants. Infants were stratified by perceived likelihood of a diagnostic result and divided into "Likely," "Uncertain," and "Not Likely." We also assessed whether reportable findings correlated with patient phenotypes.
    Results: We identified reportable findings in 133/400 (33%) infants. Access to rapid testing increased from 1% to 20% of all infants hospitalized in the neonatal/infant intensive care unit and cardiac intensive care unit, with a median turnaround time of 4.9 days. rTAG-I performed as well as exome/genome sequencing. Clinically associated results were identified in 59% of the "Likely" group and 9% of the "Not Likely" group.
    Conclusion: rTAG-I produced a high rate of reportable findings with a rapid turnaround time. Our ability to predict infants who would benefit most was imperfect, reinforcing that broad access to genome-based testing is still required.
    Keywords:  Genome sequencing; Infants; Neonatology; Rapid genomic testing; Targeted genomic analysis
    DOI:  https://doi.org/10.1016/j.gimo.2025.103476
  76. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]
    Lysosomes as hubs of metabolic sensing and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
    Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
  77. Nat Aging. 2026 Jan 29.
    Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
    Masahiro Wakita, Koyu Ito, Kaho Fujii, Dai Sakamoto, Takumi Mikawa, Sho Sugawara, Xiangyu Zhou, Jeong Hoon Park, Hideka Miyagawa, Daisuke Motooka, Emi Ogasawara, Naotada Ishihara, Akiko Takahashi, Hiroshi Kondoh, Eiji Hara.
      Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.
    DOI:  https://doi.org/10.1038/s43587-025-01057-z
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒01 at 12:04.