bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–12–14
77 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
  2. Identification of an uncharacterized gene as a mitochondrial methionine tRNA-synthetase in Caenorhabditis elegans.
  3. Activation of the integrated stress response contributes to developmental delay and seizures caused by mitochondrial prolyl-tRNA synthetase (PARS2) deficiency.
  4. Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.
  5. Letter to the Editor: CRISPR-based gene editing for cardiac protection in Barth syndrome.
  6. Loop-mediated regulation and base flipping drive RNA cleavage by human mitochondrial PNPase.
  7. Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.
  8. Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
  9. The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
  10. An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
  11. An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import.
  12. Serum neuronal, glial and mitochondrial markers in autosomal dominant optic atrophy and Leber hereditary optic neuropathy.
  13. Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
  14. Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
  15. Emerging dimensions of mitochondrial specialization.
  16. Respiratory complex I deficiency caused by a novel multi-exonic PUS1 deletion.
  17. Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.
  18. Integrated approaches for multiscale mitochondrial structure and function analysis.
  19. LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.
  20. Fatal Presentation of Leigh Syndrome in a Neonate: Comprehensive Neuroimaging Findings With MT-ND5 Mutation.
  21. Mitochondrial structure and function in OCRL depleted cells.
  22. HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.
  23. Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.
  24. FDA pitches new pathway for rare genetic diseases.
  25. Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
  26. Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.
  27. Elevated mtDNA copy number in older adults is linked to methylation of mitochondrial and nuclear regulatory regions.
  28. Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
  29. AKAP1 regulates mitochondrial and synaptic homeostasis to enable neuroprotection and repair in retinal ganglion cell degeneration.
  30. Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
  31. Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes.
  32. Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
  33. Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y Cells.
  34. Mitochondrial HMG-CoA Synthase Deficiency Presenting as Pediatric Metabolic Stroke: A Case Report of a Novel Homozygous HMGCS2 (p.Ile56Asn) Variant.
  35. A direct role for a mitochondrial targeting sequence in signalling stress.
  36. Transcellular mitochondrial transfer from hypermetabolic astrocytes to neurons during cocaine and HIV-1 exposure.
  37. Advances in Stimuli-Responsive Peptide-Polymer Carriers for Mitochondrial Therapeutics.
  38. The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons.
  39. Functional identification of two variants in unrelated Chinese patients with DNM1L-related mitochondrial disorders.
  40. Changes in nuclear and mitochondrial DNA methylation in cow blood associated with age and disease.
  41. Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis.
  42. Bio-friendly and high-precision super-resolution imaging through self-supervised reconstruction structured illumination microscopy.
  43. Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.
  44. Clinical insights into mitochondrial retinopathy: A case report on m.3243A>G mutation and macular dystrophy.
  45. Cell-Free DNA and Mitochondria in Parkinson's Disease.
  46. Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.
  47. Chemically Anchored Diamond with H3 Centers for Ratiometric Measurement of Isolated Mitochondria Temperature.
  48. Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial transfer via NLRP3 inflammasome activation.
  49. Mitochondrial Metabolomics Reveals the Mechanism of SCCP Induced Energy Metabolism Inhibition.
  50. Dynamic changes in mitochondria support phenotypic flexibility of microglia.
  51. A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease.
  52. 'Giant step forward' for Huntington's - the scientist behind the first gene therapy.
  53. The curious life of human mitochondrial SOD2.
  54. Rotenone-Induced Cellular Dysfunction in Human Blood Platelets: Unraveling Calcium Dysregulation, Mitochondrial Impairment, Oxidative Stress, and Apoptosis.
  55. PINK1/Parkin promotes liver regeneration via Sigma-1 ubiquitination to inhibit ER-Mitochondrial calcium transfer.
  56. Atypical GNAO1 variants in severe childhood speech disorders: clinical, genetic, and molecular insights.
  57. Editorial to the special issue on extracellular vesicles and mitochondria in CNS function and disease.
  58. Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.
  59. What will be the first AI-designed drug? These disease-fighting antibodies are top contenders.
  60. Integrated bioinformatic and in vivo analysis confirms the cardioprotective role of OPA1.
  61. Morphometric analysis of axonal ultrastructure: Coordinated scaling of organelles and myelin.
  62. Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
  63. Urinary Multi-Omics Profiling Reveals Systemic Molecular Alterations in Progressive External Ophthalmoplegia.
  64. Relationships of GDAP1 Mutations to Disease Phenotype and Mechanisms of Therapeutic Action of Oxidative Metabolism Activators in a Patient with Charcot-Marie-Tooth Neuropathy Type 2K.
  65. Causal modelling of gene effects from regulators to programs to traits.
  66. A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
  67. Anxiety-associated behaviors following ablation of Miro1 from cortical excitatory neurons.
  68. A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic interaction effects.
  69. Juvenile/adult-onset POLG-related disease unmasked by valproate-associated fulminant hepatic failure.
  70. GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
  71. Is your brain tired? Researchers are discovering the roots of mental fatigue.
  72. Autophagy-NAD+ axis: emerging insights into neuronal homeostasis and neurodegenerative diseases.
  73. A crucial role of KLF2-regulated mitochondrial oxidative phosphorylation in maintaining the stemness of mesenchymal stem cells derived from bone marrow.
  74. Assessing gene loss after gene editing.
  75. Imbalance in MICOS Proteins in Rat Liver Mitochondria in an Induced Hyperthyroidism Model.
  76. Human pluripotent stem cell-derived retinal ganglion cells: advances in differentiation and translational applications.
  77. Absence of the LRRK2 mutation in Emirati Parkinson's disease patients in contrast to other Arab populations.
  1. Mitochondrion. 2025 Dec 04. pii: S1567-7249(25)00104-7. [Epub ahead of print]87 102107
    Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
    Hélène Calais, Giulia Bertolin.
      Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.
    Keywords:  DELE1/HRI; ISR; Mitochondrial protein import; Pharmacological modulation; UPRam; UPRmt
    DOI:  https://doi.org/10.1016/j.mito.2025.102107
  2. G3 (Bethesda). 2025 Dec 08. pii: jkaf298. [Epub ahead of print]
    Identification of an uncharacterized gene as a mitochondrial methionine tRNA-synthetase in Caenorhabditis elegans.
    Bharat Vivan Thapa, Mohit Das, David I Taylor, James P Held, Maulik R Patel.
      Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPRmt) activators in C. elegans, we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes for a methionine tRNA synthetase (MetRS). Here, we characterize the UPRmt induction by Y105E8A.20, which we call mars-2, and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show that impaired mars-2 activity leads to reduced mitochondrial-encoded protein abundance, depletion of mitochondrial membrane potential, fragmented mitochondrial morphology, and mild developmental delay, although the animals remain viable. Hence, this hypomorphic mars-2(P447V) strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.
    Keywords:   Caenorhabditis elegans ; WormBase; mars-2; metionine tRNA-synthetase; mitochondria; mitochondrial unfolded protein response; mtDNA; tRNAs; translation
    DOI:  https://doi.org/10.1093/g3journal/jkaf298
  3. Redox Biol. 2025 Dec 09. pii: S2213-2317(25)00479-3. [Epub ahead of print]89 103966
    Activation of the integrated stress response contributes to developmental delay and seizures caused by mitochondrial prolyl-tRNA synthetase (PARS2) deficiency.
    Man Xu, Yuxin Liu, Runhua Ma, Wenlu Fan, Jingwei Duan, Huan Deng, Yanbin Ma, Wanzhong Ge.
      Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) causes mitochondrial defects and serious, progressive and usually lethal diseases with exceptional heterogeneous and tissue-specific clinical manifestations. However, the pathogenic mechanisms for specific mtARS related diseases are largely unknown and currently there is no highly effective treatment or cure for these diseases. In the present study, we generate Drosophila models with human mitochondrial prolyl-tRNA synthetase (PARS2) deficiency by knocking out or knocking down dPARS2, the Drosophila ortholog of human PARS2, and further characterize the disease-associated defects and explore the molecular basis of these phenotypes. Inactivation of dPARS2 in Drosophila causes developmental delay and seizure, two main clinical features in human PARS2 deficiency-associated patients. Biochemical analysis demonstrates that loss of dPARS2 activity results in reduced mitochondrial tRNAPro aminoacylation, decreased levels of OXPHOS complex proteins, defective assembly and altered enzyme activities of OXPHOS complexes. Interestingly, we discover that dPARS2 deficiency activates the integrated stress response (ISR), which reduces global protein translation and increases activity of ATF4 in our neuronal dPARS2 knockdown model. Importantly, blockade of ISR activation by genetic suppression of GCN2 kinase prevents developmental delay and seizure phenotypes in dPARS2-deficient flies. Furthermore, the genetic suppression of ATF4, the ISR key effector, also reverses these developmental and behavioral abnormalities associated with dPARS2 deficiency. Furthermore, a disease-associated PARS2 V95I variant causes mitochondrial dysfunction and ISR activation in human cells, verifying the findings in the Drosophila models. Together, these results not only provide evidence for PARS2 deficiency associated mitochondrial dysfunction, but also reveal a novel pathogenic mechanism involved in ISR activation in the PARS2 deficiency related disease, indicating a novel disease treatment approach by targeting ISR.
    Keywords:  Developmental delay; Integrated stress response; Mitochondrial aminoacyl-tRNA synthetases; PARS2; Seizures
    DOI:  https://doi.org/10.1016/j.redox.2025.103966
  4. J Biochem. 2025 Dec 10. pii: mvaf079. [Epub ahead of print]
    Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.
    Kei Okatsu, Shuya Fukai.
      Mitochondrial quality control plays a critical role in maintaining cellular homeostasis by eliminating dysfunctional mitochondria. The PINK1/Parkin-dependent mitophagy mediates the selective clearance of damaged mitochondria. Dysfunction of PINK1 and Parkin is closely linked to Parkinson's disease. Upon mitochondrial depolarization, PINK1 accumulates on the outer membrane and phosphorylates both ubiquitin and the UBL domain of Parkin to initiate a positive feedback loop of ubiquitination. Parkin catalyzes the assembly of heterogeneous ubiquitin chains on outer mitochondrial membrane proteins, which serve as signals for autophagy adaptors. These adaptors are regulated by kinases such as TANK-binding kinase (TBK1). Deubiquitinating enzymes such as USP30 act as negative regulators. Recent structural and biochemical studies have advanced our understanding of the PINK1/Parkin-dependent mitophagy. Nonetheless, important questions remain regarding the regulatory mechanisms of PINK1, the catalytic mechanism of ubiquitin chain formation by Parkin, and the recognition of ubiquitin chains by autophagy adaptors. Here, we review the current understanding and outstanding questions on the molecular mechanisms underlying the PINK1/Parkin-dependent mitophagy with a focus on ubiquitin signaling.
    Keywords:  autophagy; kinase; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1093/jb/mvaf079
  5. Ann Med Surg (Lond). 2025 Dec;87(12): 9163-9164
    Letter to the Editor: CRISPR-based gene editing for cardiac protection in Barth syndrome.
    Zain Ul Abedin, Anzah Imtiaz Waggan, Esha Khan, Muhammad Umer Suleman, Syeda Nafisa Tabassum.
      Barth syndrome is a rare X-linked mitochondrial disorder caused by mutations in the Tafazzin (TAZ) gene. These mutations make it hard for cardiolipin to remodel and mitochondria to work properly. This condition is characterized by growth retardation, neutropenia, skeletal myopathy, and dilated cardiomyopathy, frequently leading to significant morbidity and mortality, with numerous patients necessitating heart transplants. There are no treatments available at this time to fix the genetic problem. Recent progress in gene editing, especially CRISPR-based methods, holds great promise for fixing TAZ mutations. Research utilizing patient-derived cardiomyocytes has demonstrated that the rectification of TAZ mutations reinstates mitochondrial efficiency and enhances cellular functionality. Animal models, including TAZ-knockout mice, have exhibited substantial enhancements in cardiac function, survival rates, and diminished fibrosis subsequent to gene replacement therapy.
    Keywords:  adeno-associated virus vectors; barth syndrome; cardiolipins; cardiomyopathy, dilated; crispr-cas systems; gene editing; gene therapy; induced pluripotent stem cells; mitochondrial diseases; myopathy; neutropenia
    DOI:  https://doi.org/10.1097/MS9.0000000000004188
  6. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1296. [Epub ahead of print]53(22):
    Loop-mediated regulation and base flipping drive RNA cleavage by human mitochondrial PNPase.
    Ole Unseld, Hrishikesh Das, B Martin Hällberg.
      Human polynucleotide phosphorylase (hPNPase), a trimeric exoribonuclease, is crucial for maintaining mitochondrial RNA metabolism, including the regulated degradation of RNA. Mutations in hPNPase have been linked to mitochondrial pathologies, underscoring its importance in mitochondrial RNA homeostasis. Despite this significance, the molecular basis of its catalytic mechanism and the structural consequences of active-site mutations remain poorly understood. We employed high-resolution electron cryo-microscopy to capture three distinct functional states of hPNPase during RNA degradation. In the loading state, flexible loops facilitate the recruitment of the substrate RNA and guide it toward the active site. During the pre-catalytic state, terminal nucleotides reorient within the active site, positioning the RNA backbone for cleavage, which is stabilized by Mg2+. Finally, the catalytic state reveals a nucleophilic attack of phosphate on the RNA backbone, mediated by key active-site residues. These results offer a clear biochemical framework for hPNPase-mediated RNA turnover, clarifying its catalytic mechanism and highlighting how active-site integrity is crucial for efficient RNA degradation.
    DOI:  https://doi.org/10.1093/nar/gkaf1296
  7. Commun Biol. 2025 Dec 11. 8(1): 1759
    Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.
    Rubén Torregrosa-Muñumer, Jeremi Turkia, Rumeysa Ermiş, Jouni Kvist, Sandra Harjuhaahto, Jana Pennonen, Ville Hietakangas, Emil Ylikallio, Henna Tyynismaa.
      Hypermetabolism, a futile cycle of energy production and consumption, has been proposed as an adaptative response to deficiencies in mitochondrial oxidative phosphorylation. However, the cellular costs of hypermetabolism remain largely unknown. Here we studied the consequences of hypermetabolism in human motor neurons harboring a heteroplasmic mutation in MT-ATP6, which impairs ATP synthase assembly. Respirometry, metabolomics, and proteomics analyses of the motor neurons showed that elevated ATP production rates were accompanied with increased demand for acetyl-Coenzyme A (acetyl-CoA) and depleted pantothenate (vitamin B5), and the proteome was remodeled to support the metabolic adaptation. Mitochondrial membrane potential and coupling efficiency remained stable, and the therapeutic agent avanafil did not affect metabolite levels. However, a redistribution of acetyl-CoA usage resulted in metabolic trade-offs, including reduced histone acetylation and altered maintenance of the neurotransmitter acetylcholine, revealing potential vulnerabilities in motor neurons. These findings advance the understanding of cellular metabolic consequences imposed by hypermetabolic conditions.
    DOI:  https://doi.org/10.1038/s42003-025-09149-7
  8. Nat Commun. 2025 Dec 12. 16(1): 11104
    Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
    Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.
      Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.
    DOI:  https://doi.org/10.1038/s41467-025-66708-6
  9. FEBS J. 2025 Dec 07.
    The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
    Jiaxin Qian, Annika Nutz, Katja Hansen, Lea Bertgen, Mirita Franz-Wachtel, Boris Macek, Johannes M Herrmann, Doron Rapaport.
      The biogenesis of mitochondria relies on the import of newly synthesized precursor proteins from the cytosol. Tom70 is a mitochondrial surface receptor which recognizes precursors and serves as an interface between mitochondrial protein import and the cytosolic proteostasis network. Mitochondrial import defects trigger a complex stress response, in which compromised protein synthesis rates are a characteristic element. The molecular interplay that connects mitochondrial (dys)function to cytosolic translation rates in yeast cells is however poorly understood. Here, we show that the deletion of the two Tom70 paralogs of yeast (TOM70 and TOM71) leads to defects in mitochondrial biogenesis and slow cell growth. Surprisingly, upon heat stress, the deletion of ZUO1, a chaperone of the ribosome-associated complex (RAC), largely prevented the slow growth and the reduced translation rates in the tom70Δ/tom71Δ double deletion mutant. In contrast, the mitochondrial defects were not cured but even enhanced by ZUO1 deletion. Our study shows that Zuo1 is a critical component in the signaling pathway that mutes protein synthesis upon mitochondrial dysfunction. We propose a novel paradigm according to which RAC serves as a stress-controlled regulatory element of the cytosolic translation machinery.
    Keywords:  Tom70; mitochondria; protein import; proteostasis; ribosome‐associated complex
    DOI:  https://doi.org/10.1111/febs.70356
  10. Int J Mol Sci. 2025 Nov 24. pii: 11349. [Epub ahead of print]26(23):
    An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
    Roman Abrosimov, Ankush Borlepawar, Parvana Hajieva, Bernd Moosmann.
      Inhibition of respiratory chain complex I (NADH dehydrogenase) is a widely encountered biochemical consequence of drug intoxication and a primary consequence of mtDNA mutations and other mitochondrial defects. In an organ-selective form, it is also deployed as antidiabetic pharmacological treatment. Complex I inhibition evokes a pronounced metabolic reprogramming of uncertain purposefulness, as in several cases, anabolism appears to be fostered in a state of bioenergetic shortage. A hallmark of complex I inhibition is the enhanced biosynthesis of serine, usually accompanied by an induction of folate-converting enzymes. Here, we have revisited the differential transcriptional induction of these metabolic pathways in three published models of selective complex I inhibition: MPP-treated neuronal cells, methionine-restricted rats, and patient fibroblasts harboring an NDUFS2 mutation. We find that in a coupled fashion, serinogenesis and circular folate cycling provide an unrecognized alternative pathway of complete glucose oxidation that is mostly dependent on NADP instead of the canonic NAD cofactor (NADP:NAD ≈ 2:1) and thus evades the shortage of oxidized NAD produced by complex I inhibition. In contrast, serine utilization for anabolic purposes and C1-folate provision for S-adenosyl-methionine production and transsulfuration cannot explain the observed transcriptional patterns, while C1-folate provision for purine biosynthesis did occur in some models, albeit not universally. We conclude that catabolic glucose oxidation to CO2, linked with NADPH production for indirect downstream respiration through fatty acid cycling, is the general purpose of the remarkably strong induction of serinogenesis after complex I inhibition.
    Keywords:  NADPH-FADH2 axis; Parkinson’s disease; fatty acid cycling; futile cycle; glycolytic inhibition; metabolic reprogramming; metformin; mitochondrial disease; oxidative stress
    DOI:  https://doi.org/10.3390/ijms262311349
  11. Structure. 2025 Dec 11. pii: S0969-2126(25)00446-0. [Epub ahead of print]
    An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import.
    Maxwell J Bachochin, Kelly L McGuire, Brian D Cook, Qiaozhen Ye, Steven Silletti, Kevin D Corbett, Elizabeth A Komives, Mark A Herzik.
      Tom70 mediates mitochondrial protein import by coordinating transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 (HsTom70c) is entirely α-helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding and a C-terminal preprotein-binding domain. However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 Å crystal structure of unliganded HsTom70c, revealing two distinct conformations-open and closed-within the asymmetric unit. These states are stabilized by interdomain crystal contacts and supported in solution by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and network analyses reveal a continuum of motion linking the NTD and CTD via key residues in helices α7, α8, and α25. Engagement of the CTD by viral protein Orf9b disrupts this network, stabilizing a partially closed intermediate and dampening distal NTD dynamics.
    Keywords:  HDX-MS; Orf9b; Tom70; X-ray crystallography; allostery; mitochondrial protein import; molecular dynamics; protein dynamics
    DOI:  https://doi.org/10.1016/j.str.2025.11.011
  12. Brain Commun. 2025 ;7(6): fcaf446
    Serum neuronal, glial and mitochondrial markers in autosomal dominant optic atrophy and Leber hereditary optic neuropathy.
    Alessandra Rufa, Domenico Plantone, Alessia Bargagli, Delia Righi, Tommaso Bacci, Valeria Serchi, Guido Primiano, Gian Nicola Gallus, Diego Lopergolo, Elena Pretegiani, Francesca Rosini, Sara Locci, Gian Marco Tosi, Nicola De Stefano.
      Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (ADOA) are the two most prevailing primary mitochondrial optic neuropathies. Both diseases preferentially affect the smallest retinal ganglion cells (GCs) of the papillomacular bundle, causing central visual loss in young patients. Although ADOA and LHON show striking similarities, including the convergence of underlying pathologic mitochondrial mechanisms, they differ clinically. The major distinction lies in the timing and progression of axonal damage during neurodegeneration. The exact reasons for these differences remain unclear, but they may, in part, be due to distinct patterns of mitochondrial dysfunction. To identify differences that could point to distinct degenerative processes, we investigated clinical features, optical coherence tomography (OCT) findings, laboratory biomarkers [serum neurofilaments light chain (sNfL), serum glial fibrillary acidic protein (sGFAP) and serum growth differentiation factor-15 (sGDF15)] in a cohort of patients with these two heritable optic neuropathies in the chronic phase. Our OCT analysis reveals a more profound GC layer and papillomacular bundle loss in LHON, whereas ADOA shows a sparser damage of the retinal nerve fibre layer, including fibres originating from the nasal retina. We also observed increased plasma levels of sNfL and GFAP in both groups, supporting the presence of ongoing neurodegeneration in both optic neuropathies. Finally, our findings suggest the retinal astrocytes may play a contributive role in the neurodegenerative process at the level of the optic nerve head, particularly in ADOA.
    Keywords:  ADOA; Glia; LHON; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.1093/braincomms/fcaf446
  13. Nat Commun. 2025 Dec 12. 16(1): 11088
    Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
    Dilizhatai Saimi, Luc Reymond, Tursunjan Aziz, Xuan Shen, Ziying Luo, Shuaibo Pi, Yitong Liu, Song Fu, Shuangjin Ding, Anming Meng, Liangyi Chen, Hui Jiang, Zhixing Chen.
      Mitochondria are central to cellular metabolism. Various fluorescence tools have been developed for imaging the mitochondrial environment. Yet, new reporters and imaging methods for directly reading the mitochondrial status are needed for high spatial-temporal resolution imaging. Here, we introduce PK Mito Deep Red (PKMDR), a low-phototoxicity mitochondrial probe for time-lapse imaging, whose fluorescence lifetime serves as a sensitive indicator of mitochondrial membrane potential (Δψm). The positively charged PKMDR accumulates within mitochondria under a higher Δψm, leading to concentration-induced quenching and a measurable decrease in fluorescence lifetime. Since mitochondrial respiration primarily regulates Δψm, PKMDR's fluorescence lifetime effectively reports on the status of oxidative phosphorylation. Using PKMDR with fluorescence lifetime imaging microscopy (FLIM), we visualize heterogeneous Δψm across individual cells, organoids, and tissues over time. This method reliably reveals the heterogeneity between metabolically active peripheral mitochondria and relatively inactive perinuclear mitochondria in various cell types. Overall, PKMDR-FLIM is a robust tool for directly visualizing Δψm with high spatiotemporal resolution.
    DOI:  https://doi.org/10.1038/s41467-025-66042-x
  14. J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02861-3. [Epub ahead of print] 111009
    Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
    Megha Rajendran, William M Rosencrans, Nina A Bautista, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Jennifer D Petersen, Julie Hwang, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC1, VDAC2, and VDAC3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated for by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.
    Keywords:  CRISPR/Cas9 gene knockout; metabolic regulation; mitochondrial respiratory chain complex; proteomics; voltage-dependent anion channel
    DOI:  https://doi.org/10.1016/j.jbc.2025.111009
  15. Biol Chem. 2025 Dec 10.
    Emerging dimensions of mitochondrial specialization.
    Tslil Ast.
      The diverse, and sometimes opposing, roles of mitochondria require sophisticated organizational and regulatory strategies. This review examines emerging evidence that mitochondria can solve this challenge through functional specialization - adopting distinct bioenergetic and metabolic programs based on location, contacts, and cellular conditions. We discuss both established principles and recent technological breakthroughs that reveal this hidden complexity. Ongoing advances promise to move the field from describing mitochondrial diversity to uncovering its regulatory mechanisms and therapeutic potential.
    Keywords:  heterogeneity; metabolic specialization; mitochondria
    DOI:  https://doi.org/10.1515/hsz-2025-0210
  16. J Hum Genet. 2025 Dec 08.
    Respiratory complex I deficiency caused by a novel multi-exonic PUS1 deletion.
    Jun-Hui Yuan, Yujiro Higuchi, Masahiro Ando, Akihiro Hashiguchi, Yuji Okamoto, Yu Hiramatsu, Akiko Yoshimura, Kento Kodama, Yusuke Sakiyama, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima.
      Myopathy, lactic acidosis, and sideroblastic anemia type 1 (MLASA1) is an extremely rare mitochondrial disorder caused by biallelic pathogenic variants in PUS1, which encodes a mitochondrial tRNA pseudouridine synthase essential for mitochondrial protein synthesis. We describe two affected siblings presenting with progressive myopathy, lactic acidosis, sideroblastic anemia, short stature, developmental delay, and mild cognitive impairment. Depth-based copy number variation analysis of whole-exome sequencing data revealed a novel homozygous multi-exonic deletion in PUS1. The deletion breakpoints were defined by Sanger sequencing as a 9964 bp deletion spanning part of intron 3 through exons 4-6 and extending into the 3' untranslated region, resulting in complete loss of the C-terminal coding region. Skeletal muscle histology demonstrated ragged red fibers, whereas immunohistochemistry showed a selective and near-complete loss of NDUFB8, indicating impaired assembly of respiratory chain complex I. A systematic review of previously reported MLASA1 cases revealed marked clinical heterogeneity, including frequent developmental delay, dysmorphic features, and multi-organ involvement. These findings expand the genotypic and phenotypic landscape of MLASA1 and highlight the diagnostic value of copy number variation analysis in unresolved mitochondrial disorders. The impairment of complex I underscores the particular vulnerability of translation-dependent respiratory chain components in PUS1-related diseases.
    DOI:  https://doi.org/10.1038/s10038-025-01437-8
  17. Protein Cell. 2025 Dec 08. pii: pwaf109. [Epub ahead of print]
    Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.
    Yanan Lv, Xuejing Zhao, Di Li, Zhaoqi Hao, Yue Zhao, Yuhang Zhou, Yujing Zhang, Han Chen, Zhongbing Lu, Dong Li, Yuting Guo.
      Mitochondrial calcium fluxes serve as pivotal regulators of optimal organellar function and cellular viability, yet the spatiotemporal regulation of nanodomain Ca2+ transients at mitochondria-ER contact sites (MERCS) and their integration into adaptive mitochondrial stress signaling remain unresolved. In this study, we employed custom-built high temporal-spatial resolution GI/3D-SIM imaging techniques to achieve nanoscale resolution of calcium transients. We identify that MERCS-localized calcium oscillations gate retrograde stress signaling. Mechanistically, we demonstrate that augmented mitochondria-associated ER membrane (MAMs) connectivity unexpectedly attenuated global mitochondrial Ca2+ efflux, which triggering ATF5 shuttling-mediated transcriptional licensing and calcium-sensitive epigenetic reprogramming that synergistically activating stress-resilience programs. Quantitative protein expression and transcriptome analyses confirm that CsA-mediated calcium retention mimics MAMs induction preserves mitochondrial integrity and protecting cells from apoptosis in Aβ1-42-challenged neurons through synchronized UPRmt activation. Our findings reveal a novel mechanism by which MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations, offering therapeutic potential for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Mito-ER interaction; calcium transients; mitochondrial stress response; super-resolution microscopy
    DOI:  https://doi.org/10.1093/procel/pwaf109
  18. J Microsc. 2025 Dec 12.
    Integrated approaches for multiscale mitochondrial structure and function analysis.
    Adiba Patel, Prasanna Venkhatesh, Suraj Thapliyal, Margaret Mungai, Leo Jake Kazma, Muhammad Aftab, Antentor Hinton, Prasanna Katti.
      Mitochondria are double-membrane organelles whose architecture enables ATP (Adenosine Triphosphate) production, redox signalling, calcium homeostasis, and apoptosis. Visualisation of mitochondria requires imaging technologies across spatial and temporal scales. Conventional fluorescence microscopy techniques, such as wide-field, confocal, spinning-disk, and light-sheet microscopy, enable the real-time observation of mitochondrial networks and dynamics in live cells. Super-resolution methods, including structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), photoactivated localisation microscopy (PALM), stochastic optical reconstruction microscopy (STORM), and expansion microscopy, provide access to fine sub-mitochondrial structures, such as cristae, overcoming the diffraction limit. Additionally, proximity-based approaches such as FRET (Förster Resonance Energy Transfer), split-fluorescent proteins, and proximity ligation assays allow researchers to probe sub-compartmental interactions and organelle contact sites with nanometre-level sensitivity. Electron microscopy (EM) complements optical techniques by offering near-molecular resolution of mitochondrial ultrastructure, including membranes, cristae, and inter-organelle interfaces. In this review, we comprehensively examined the principles, capabilities, and limitations of these diverse imaging modalities, with a focus on recent advances. We highlight the development of novel fluorescent probes, integrated correlative techniques, and computational analysis pipelines to expand the utility of mitochondrial imaging. By placing these innovations in historical and theoretical contexts, we aim to clarify how each method works and why it is suited to biological questions. Finally, we explore how mitochondrial imaging has revolutionised our understanding of physiology and pathology.
    Keywords:  cristae; electron microscopy; membrane contact site; mitochondria; organelle dynamics; super‐resolution microscopy
    DOI:  https://doi.org/10.1111/jmi.70050
  19. Transl Neurodegener. 2025 Dec 08. 14(1): 64
    LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.
    Mei Ding, Fen Wang, Lan-Lan Jiang, Chao Ma, Yu-Wan Qi, Jun-Yi Liu, Juan Li, Mei-Xia Wang, Hong Jin, Jin-Ru Zhang, Cheng-Jie Mao, Xiao-Kang Li, Chun-Feng Liu, Xiao-Yu Cheng.
       BACKGROUND: Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.
    METHODS: DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.
    RESULTS: Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival.
    CONCLUSIONS: The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.
    Keywords:   LRRK2 G2019S mutation; Astrocyte; Dopaminergic neuron; Induced pluripotent stem cell; Membrane fusion-related protein STX17; Mitochondrial transfer; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-025-00525-1
  20. Cureus. 2025 Nov;17(11): e96098
    Fatal Presentation of Leigh Syndrome in a Neonate: Comprehensive Neuroimaging Findings With MT-ND5 Mutation.
    Shrinivas Radder, Nivedita Radder.
      Leigh syndrome represents a severe mitochondrial disorder characterized by progressive neurodegeneration, typically manifesting in infancy with devastating outcomes. We present a 30-day-old male infant who presented with acute neurological deterioration, including seizures, dystonia, and respiratory failure. Laboratory evaluation revealed elevated levels of lactate and pyruvate. Brain magnetic resonance imaging (MRI) demonstrated characteristic bilateral symmetric T2 hyperintensity with restricted diffusion involving the basal ganglia, thalami, brainstem structures, and multiple other regions. Single-voxel spectroscopy confirmed an elevated lactate peak in the basal ganglia. Genetic testing identified a 95% heteroplasmic pathogenic variant in MT-ND5, confirming mitochondrial DNA-associated Leigh syndrome. Despite intensive supportive care including mechanical ventilation and anticonvulsant therapy, the patient's condition progressively deteriorated, resulting in death 16 days after admission. This case highlights the fulminant presentation of neonatal Leigh syndrome and emphasizes the critical role of neuroimaging in establishing this diagnosis, particularly when combined with biochemical and genetic findings.
    Keywords:  leigh syndrome; mitochondrial disorder; mr spectroscopy; mt-nd5 mutation; neonatal encephalopathy; neuroimaging
    DOI:  https://doi.org/10.7759/cureus.96098
  21. Front Cell Dev Biol. 2025 ;13 1679675
    Mitochondrial structure and function in OCRL depleted cells.
    Ron George Philip, Priyanka Bhatia, Yojet Sharma, Padinjat Raghu.
      Lowe syndrome (LS) is an X-linked, recessive disease with a characteristic clinical triad of eye, brain, and kidney defects. LS results from mutations in the OCRL gene that encodes for inositol polyphosphate 5-phosphatase enzyme. The OCRL protein has been localized to multiple subcellular organelles including the plasma membrane and endo-lysosomal system, but the relevance of these to disease phenotypes is unclear. Previous studies have reported severe hypotonia at birth in LS patients along with structural changes in the mitochondria in muscle biopsies. These mitochondrial changes have been proposed to be secondary to renal tubular acidosis seen in LS patients. In this study, we find that neural stem cells and neurons differentiated from OCRL-depleted induced pluripotent stem cells (iPSCs) show mild defects in mitochondrial structure and function, whereas such defects are not seen in the iPSCs themselves. These mitochondrial phenotypes in neural stem cells and neurons were associated with modest changes in the mitochondrial transcriptome. Overall, our results indicate that loss of OCRL leads to mild cell autonomous defects in mitochondrial structure and function that is cell type-dependent.
    Keywords:  Lowe syndrome; glia; iPSC; metabolism; mitochondria; neural stem cells; neurons
    DOI:  https://doi.org/10.3389/fcell.2025.1679675
  22. Adv Biol (Weinh). 2025 Dec 12. e00472
    HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.
    Noemi Anna Pesce, Giulia Seminara, Giuseppe Giarrusso, Marianna Flora Tomasello.
      HK1 and HK2 are increasingly recognized not only as glycolytic enzymes but also as key modulators of mitochondrial function and cell fate through dynamic interactions with VDAC. This review explores how HK-VDAC complexes support metabolic flexibility, regulate apoptosis, and coordinate glycolytic and mitochondrial activity across diverse physiological and pathological conditions. We incorporate recent reinterpretations of the Warburg effect, emphasizing how spatial and functional reorganization of HK supports proliferative metabolism beyond classical models of mitochondrial dysfunction. Importantly, the HK-VDAC interaction is dynamically regulated by post-translational modifications and signaling pathways that control its stability and mitochondrial anchoring. Disruption of these regulatory mechanisms can impair the balance between glycolytic and mitochondrial metabolism, contributing to disease progression. Emerging evidence links altered HK-VDAC interactions to the metabolic and apoptotic imbalances observed in cancer, neurodegeneration, and aging. By integrating insights from structural biology, bioenergetics, and disease models, we highlight mitochondrial HK anchoring as a central hub for metabolic adaptation and stress response.
    Keywords:  HK‐VDAC; Warburg effect; aging; apoptosis; cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/adbi.202500472
  23. J Mol Neurosci. 2025 Dec 13. 75(4): 162
    Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.
    Ga Hyun Park, Hye In Park, Donghyuk Shin, Kwang Chul Chung.
      While Parkinson's disease (PD) is predominantly sporadic, various mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been linked to the autosomal recessive form of PD. PINK1, a serine/threonine protein kinase, holds a pivotal role in mitophagy - a process that selectively eliminates damaged mitochondria, overseeing mitochondrial quality control and ultimately safeguarding against neuronal cell loss in PD. Understanding the regulation of PINK1 stability is essential in comprehending PD pathology, given its involvement in a pro-survival pathway. Although some components of the ubiquitin-proteasome system (UPS) are recognized for mediating the proteolysis of PINK1, the specific enzyme(s) responsible for positively influencing PINK1 stability have remained elusive. In this study, we demonstrated that ubiquitin-specific protease 20 (USP20) functions as a novel deubiquitinating enzyme targeting PINK1. We found that USP20 positively regulates PINK1 levels by hydrolyzing Lys 48-linked polyubiquitin chains, promoting mitophagy under the treatment of mitochondrial depolarizing agent carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Furthermore, CCCP treatment accelerates the deubiquitinating activity of USP20, facilitating the degradation of impaired mitochondria and enhancing mitochondrial quality control via PINK1 accumulation. Taken together, these findings unveil a novel enzyme, USP20, positively impacting PINK1 level and promoting CCCP-induced mitophagy. In addition, this study establishes a comprehensive map depicting how PINK1 can be regulated both positively and negatively through the coordinated action of multiple members in the UPS.
    Keywords:  CCCP; Deubiquitinating enzyme; Mitophagy; PINK1; Parkinson’s disease; USP20; Ubiquitination
    DOI:  https://doi.org/10.1007/s12031-025-02457-x
  24. Nat Biotechnol. 2025 Dec;43(12): 1893
    FDA pitches new pathway for rare genetic diseases.
      
    DOI:  https://doi.org/10.1038/s41587-025-02967-4
  25. Nat Metab. 2025 Dec 10.
    Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
    Alice Pavlowsky, Bryon Silva, Ruchira Basu, Amandine Correia Delecourt, David Geny, Lydia Danglot, Pierre-Yves Plaçais, Thomas Preat.
      Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands1-3. In contrast, neurons, which are major energy consumers, are considered to rely essentially on glucose and its derivatives to support their metabolism. Here, using Drosophila melanogaster, we show that memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom body (MB), a major integrative centre in insect brains. We identify cortex glia as the provider of lipids to sustain the usage of FAs for this type of memory. Furthermore, we demonstrate that massed training is associated with mitochondria network remodelling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioural level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, revealing, on the contrary, that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation.
    DOI:  https://doi.org/10.1038/s42255-025-01416-5
  26. Biol Open. 2025 Dec 10. pii: bio.062106. [Epub ahead of print]
    Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.
    Hilario Ruelas-Ramírez, Ariann E Mendoza-Martínez, P Abril Medina-Flores, Soledad Funes.
      Mitophagy is essential for mitochondrial quality control, selectively removing damaged or superfluous mitochondria to maintain cellular health and metabolic homeostasis. While positive regulators of mitophagy are relatively well characterized, the mechanisms governing its downregulation remain less understood. In this study, we investigate the role of Saccharomyces cerevisiae Slm35-a protein previously involved in oxidative stress response-in the regulation of mitophagy. We discovered that Slm35 is a soluble mitochondrial matrix protein and functions as a novel negative regulator of mitophagy and the mitochondrial retrograde (RTG) signaling pathway. Our results show that Slm35 modulates mitophagy through the RTG pathway, independently of Atg32 proteolytic processing by Yme1 or mitochondrial membrane potential (MMP) dissipation. Notably, Slm35 is crucial for the dynamic regulation of the RTG pathway in mitophagy-inducing conditions. These findings highlight the importance of Slm35 in fine-tuning mitochondrial quality control in response to metabolic cues and suggest a critical role for dynamic RTG pathway regulation in mitophagy control.
    Keywords:  Atg32; Mitochondria; Mitochondrial retrograde signaling; Mitophagy; Yeast
    DOI:  https://doi.org/10.1242/bio.062106
  27. Geroscience. 2025 Dec 12.
    Elevated mtDNA copy number in older adults is linked to methylation of mitochondrial and nuclear regulatory regions.
    Hongbo Chi, Hongying Shu, Yingmei Yang, Yuji Ikeno, Jiong Wu, Zhihong Wang, Habil Zare, Mikhail Alexeyev, Yidong Bai.
      Growing evidence shows that epigenetic modification and mitochondrial dysfunction are hallmarks of aging and are associated with the development of a wide range of age-related diseases. Mitochondrial biogenesis, which is marked by mitochondrial DNA copy number (mtDNAcn), is one of the major regulations of mitochondrial function by a set of transacting elements, including mitochondrial DNA polymerase gamma (POLG), working on the mtDNA control region. In this study, we investigated the mtDNAcn and the methylation status at both mtDNA control and POLGA promoter regions in human blood cells from individuals with a wide range of ages. A total of 119 blood samples were collected, including 24 umbilical cord blood samples from newborns and 95 peripheral blood samples from individuals aged 18 to 96 years. We observed an increase in mtDNAcn, as well as a rise in the methylation levels of the mtDNA control region during aging, particularly in subjects aged ≥ 45. In addition, a positive correlation was also found between the methylation levels of the 4th CpG site in the POLGA promoter region and mtDNAcn during aging. These results suggest epigenetic regulation at mitochondrial and nuclear genes for mitochondrial biogenesis during aging in human blood cells.
    Keywords:  Aging; DNA methylation; DNA polymerase gamma A (POLGA); Mitochondrial DNA D-loop region; Mitochondrial DNA copy number; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1007/s11357-025-02037-2
  28. Trends Biochem Sci. 2025 Dec 05. pii: S0968-0004(25)00266-X. [Epub ahead of print]
    Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
    Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji.
      The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.
    Keywords:  alternating access transport mechanism; membrane protein structure; mitochondrion; solute carrier family SLC54; structure-based drug design; sugar and energy metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2025.11.002
  29. bioRxiv. 2025 Nov 27. pii: 2025.11.24.689866. [Epub ahead of print]
    AKAP1 regulates mitochondrial and synaptic homeostasis to enable neuroprotection and repair in retinal ganglion cell degeneration.
    Tonking Bastola, Keun-Young Kim, Ziyao Shen, Guy A Perkins, Muna Poudel, Veronica Gomez, Yoonjin Lim, Hyejeong Choi, Jae Yon Won, Soo-Ho Choi, Mark H Ellisman, Robert N Weinreb, Won-Kyu Ju.
      Glaucoma is a leading cause of irreversible blindness, characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. Mitochondrial dysfunction plays a central role in this neurodegeneration, yet effective targeted therapies remain limited. Here, we identify the mitochondrial scaffold A-kinase anchoring protein 1 (AKAP1) as a critical regulator of RGC resilience and axon regeneration. AKAP1 expression is diminished in human glaucomatous retinas and experimental glaucoma models, correlating with elevated intraocular pressure, disrupted mitochondrial dynamics, oxidative stress, and synaptic instability. Restoration of AKAP1 via adeno-associated virus serotype 2-mediated gene therapy preserves RGC survival, promotes mitochondrial fusion and cristae integrity, enhances ATP production, and mitigates oxidative and apoptotic stress in mouse models of glaucoma and optic nerve injury. Transcriptomic profiling of AKAP1 knockout retinas reveals widespread dysregulation of mitochondrial and synaptic gene networks. Mechanistically, AKAP1 stabilizes synapses by promoting mitochondrial biogenesis, modulating calcium/calmodulin-dependent kinase II and synapsin phosphorylation, maintaining synaptophysin expression, and suppressing complement component C1q expression, thereby preventing early synaptic loss in glaucomatous neurodegeneration. Moreover, restoring AKAP1 expression facilitates axonal regeneration, preserves the central visual pathway, and maintains visual function. Collectively, these findings establish AKAP1 as a master regulator of mitochondrial and synaptic homeostasis and axonal regeneration and a promising therapeutic target for vision preservation in glaucomatous neurodegeneration.
    One Sentence Summary: AKAP1 protects retinal ganglion cells and preserves vision by restoring mitochondrial and synaptic health in experimental glaucoma models.
    DOI:  https://doi.org/10.1101/2025.11.24.689866
  30. Oncogenesis. 2025 Dec 08.
    Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
    Melina C Mancini, Cameron P McCall, Robert C Noland, Wagner S Dantas, Timothy D Heden.
      Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.
    DOI:  https://doi.org/10.1038/s41389-025-00593-y
  31. FASEB J. 2025 Dec 31. 39(24): e71340
    Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes.
    Cem Özel, Katrin M Reitmeier, Emilia Kieckhöfer, Khawla Abualia, Duc Nguyen-Minh, Mahsa Matin, Henning Hagmann, Richard J M Coward, Sebastian Brähler, Philipp Antczak, Bernhard Schermer, Thomas Benzing, Patrick Giavalisco, Paul T Brinkkoetter.
      Mitochondrial dysfunction is central to the pathogenesis of podocytopathies, yet the determinants of metabolic resilience versus failure remain elusive. We investigated how distinct disruptions of mitochondrial architecture, specifically hyperfusion via OMA1 deletion versus compromised inner mitochondrial membrane (IMM) integrity via PHB2 knockdown, influence the metabolic fate and insulin responsiveness of podocytes. To this end, we analyzed conditionally immortalized mouse podocytes with genetic OMA1 deletion or inducible PHB2 knockdown and employed an integrated approach combining bioenergetic studies, quantitative proteomics, phosphoproteomics, metabolomics, and stable isotope tracing studies with 13C6-glucose and 13C5-glutamine. We characterized metabolic remodeling at baseline and after insulin treatment and uncovered profoundly divergent metabolic states. OMA1 deficiency conferred robust metabolic resilience, characterized by a compensatory glycolytic shift and remodeling of TCA cycle flux through glutamine-driven anaplerosis while maintaining oxidative phosphorylation. OMA1-deficient podocytes sustained bioenergetic homeostasis upon insulin challenge by flexibly rerouting carbon flux, including the GABA shunt. In contrast, PHB2 deficiency led to metabolic failure, impaired respiration, and anaplerotic insufficiency. While maintaining basal ATP levels at baseline, PHB2-deficient podocytes exhibited energetic collapse upon insulin treatment, revealing profound metabolic inflexibility. Taken together, the structural integrity of the inner mitochondrial membrane, rather than mitochondrial morphology per se, is a driving determinant of metabolic competence and resilience in podocytes.
    Keywords:  OMA1; PHB2; anaplerosis; glycolysis; insulin signaling; metabolism; mitochondria; podocytes
    DOI:  https://doi.org/10.1096/fj.202502934R
  32. Nature. 2025 Dec 10.
    Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
    Joshua D Meisel, Pallavi R Joshi, Amy N Spelbring, Hong Wang, Sandra M Wellner, Presli P Wiesenthal, Maria Miranda, Jason G McCoy, David P Barondeau, Gary Ruvkun, Vamsi K Mootha.
      Frataxin is a key component of an ancient, mitochondrial iron-sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1-5). Loss of frataxin levels underlies Friedreich's ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in 'permissive' low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2-NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron-sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron-sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich's ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich's ataxia.
    DOI:  https://doi.org/10.1038/s41586-025-09821-2
  33. Mol Neurobiol. 2025 Dec 10. 63(1): 279
    Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y Cells.
    Aline Broeglin, Aurélien Riou, Andreas Papassotiropoulos, Anne Eckert, Amandine Grimm.
      Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of tau protein in neurons, leading to cognitive impairment. A common feature of these disorders is mitochondrial dysfunction, which leads to bioenergetic deficits and contributes to neuronal cell death. As neurons have high energy demands, impaired mitochondrial function directly affects their viability and function. Thus, mitochondria represent an attractive target for neuroprotective strategies in tauopathies. Mitochondrial transplantation (MT) is an emerging therapeutic approach to restoring cellular bioenergetics. Although MT has shown promise in various models of brain diseases, its efficacy has not been evaluated in the context of tau-induced mitochondrial dysfunction. This study examines the impact of MT on healthy cells and in a cellular model of tauopathy. Mitochondria were freshly isolated from astrocytic cells and transplanted into healthy SH-SY5Y neuroblastoma cells and SH-SY5Y cells overexpressing the P301L tau mutation, for 24 and 48 h. Our results demonstrate that MT enhances cell viability, ATP production, mitochondrial membrane potential, and respiration in both healthy and tau-mutant SH-SY5Y cells. In addition, MT reduced mitochondrial superoxide anion levels and promoted neurite outgrowth in both cell lines. Key bioenergetic outcomes were recapitulated in neurons derived from induced pluripotent stem cells (iPSCs) carrying the P301L tau mutation. These findings suggest that MT might be a promising therapeutic strategy to counteract mitochondrial deficits in tauopathies. Importantly, this approach positions mitochondria not as a target but as the therapeutic agent itself. Further studies are warranted to advance MT toward in vivo applications in tau-related neurodegenerative disorders.
    Keywords:  Bioenergetic; Mitochondria; Neurites; P301Ltau mutation; Tauopathies; Transplantation
    DOI:  https://doi.org/10.1007/s12035-025-05604-y
  34. Clin Case Rep. 2025 Dec;13(12): e71622
    Mitochondrial HMG-CoA Synthase Deficiency Presenting as Pediatric Metabolic Stroke: A Case Report of a Novel Homozygous HMGCS2 (p.Ile56Asn) Variant.
    Yasmeen Alshami, Osama Hroub, Mohammad Hroub, Saja Abouodeh, Zahra Makhamre, Ahmad G Hammouri, Ibrahim Alzatari, Osama Atawneh.
      Mitochondrial HMG-CoA synthase deficiency should be suspected in infants with hypoketotic hypoglycemia, metabolic acidosis, and basal ganglia lesions. A 2-year-old boy with a novel HMGCS2 variant presented with refractory seizures and encephalopathy, highlighting the need for rapid metabolic and genetic evaluation for timely management.
    Keywords:  HMG‐CoA synthase deficiency; dystonia; metabolic disorders; mitochondrial disease; pediatric neurology
    DOI:  https://doi.org/10.1002/ccr3.71622
  35. Nature. 2025 Dec 10.
    A direct role for a mitochondrial targeting sequence in signalling stress.
    Zixuan Yuan, Megan Balzarini, Marina Volpe, Madeleine Goldstein, Tony Shengzhe Peng, Elizabeth Hui, Nancy Neng Fang, Waleed S Albihlal, Melika Hajimohammadi, Kevin Wei, Calvin K Yip, Folkert J van Werven, Thibault Mayor, Hilla Weidberg.
      Mitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.
    DOI:  https://doi.org/10.1038/s41586-025-09834-x
  36. Cell Commun Signal. 2025 Dec 09.
    Transcellular mitochondrial transfer from hypermetabolic astrocytes to neurons during cocaine and HIV-1 exposure.
    Santhanam Shanmughapriya, Taha Mohseni Ahooyi, Bahareh Torkzaban, Venkata Naga Srikanth Garikipati, Raj Kishore, Kamel Khallili, Dianne Langford, Kalimuthusamy Natarajaseenivasan.
      
    Keywords:  Astrocytes; Cocaine; HIV-1; Mitochondria; Mitorelease; Neurotrophic; Tat
    DOI:  https://doi.org/10.1186/s12964-025-02589-y
  37. ACS Biomater Sci Eng. 2025 Dec 10.
    Advances in Stimuli-Responsive Peptide-Polymer Carriers for Mitochondrial Therapeutics.
    Puja Das Karmakar, Masaki Odahara, Keiji Numata.
      Mitochondria are essential organelles that govern energy metabolism, redox balance, and cell survival; their dysfunction is implicated in a wide range of pathologies, including neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and cancer. Despite their significance as therapeutic targets, the unique structural and electrochemical properties of mitochondria, particularly the impermeable inner mitochondrial membrane and high membrane potential pose major challenges for the targeted delivery of therapeutic agents. Recent advances in biomaterials have spotlighted peptide-polymer conjugates as versatile platforms, capable of navigating intracellular barriers and achieving precise mitochondrial localization. These hybrid systems combine the physicochemical tunability of polymers with the biofunctionality of peptides, enhancing cellular uptake, endosomal escape, and suborganelle trafficking. The incorporation of stimuli-responsive elements further enables spatiotemporal control of cargo release in response to intracellular cues such as pH shifts, thermal fluctuations, redox gradients, or enzymatic activity. Such systems are especially promising for mitochondrial gene and protein delivery, offering improved selectivity, reduced systemic toxicity, and the potential to restore mitochondrial function under pathological conditions. This review showcases advanced strategies in stimuli-responsive peptide-polymer systems for mitochondria-targeted delivery, highlighting how their smart, responsive functions enable precise, controllable therapeutic interventions and drive the development of next-generation, transformative biomaterials in precision nanomedicine.
    Keywords:  gene therapy; mitochondria-targeted delivery; peptide–polymer conjugates; smart drug delivery systems; stimuli-responsive materials
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c01513
  38. Res Sq. 2025 Dec 03. pii: rs.3.rs-8177400. [Epub ahead of print]
    The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons.
    Yuanxin Chen, Lianteng Zhi, Shiquan Cui, Huaixin Wang, Chenbo Zeng, Hui Zhang.
      Background Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of Parkinson's disease (PD), particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons. Methods We employed a BAC transgenic mouse model overexpressing human LRRK2-R1441G and crossed it with TH-mito-roGFP mice to enable mitochondria-targeted redox imaging specifically in DA neurons. Acute midbrain slices from 3-, 6-, and 10-month-old mice were imaged using two-photon microscopy to assess mitochondrial oxidative stress. In parallel, mitochondrial respiratory function, membrane potential flickering events, and expression of uncoupling proteins (UCP4/UCP5) were analyzed. Spatial transcriptomic profiling was performed using the GeoMx® Digital Spatial Profiler to uncover associated molecular alterations. Results We observed a progressive increase in mitochondrial oxidative stress in SNc DA neurons of LRRK2 BAC-hR1441G mice at 3, 6, and 10 months of age. This was accompanied by reduced respiratory complex activity, attenuated mitochondrial membrane potential flickering, and diminished expression of UCP4 and UCP5. Spatial transcriptomic analysis revealed dysregulation of genes linked to mitochondrial uncoupling, calcium signaling, and redox regulation in LRRK2-R1441G SNc tissue. Conclusions These findings reveal an age-dependent progression of mitochondrial dysfunction in LRRK2-R1441G SNc DA neurons. Dysregulation of calcium channels and uncoupling proteins emerges as a key mechanism contributing to bioenergetic failure, suggesting potential therapeutic targets to mitigate PD progression.
    DOI:  https://doi.org/10.21203/rs.3.rs-8177400/v1
  39. BMC Pediatr. 2025 Dec 12. 25(1): 984
    Functional identification of two variants in unrelated Chinese patients with DNM1L-related mitochondrial disorders.
    Zhenkun Zhang, Zhehui Chen, Xiaofan Bie, Zhenhua Xie, Xian Li, Jing Liu, Mengjun Xiao, Qiang Zhang, Yaodong Zhang, Yanling Yang, Dongxiao Li.
       BACKGROUND: The DRP1 protein, a member of the dynamin superfamily of GTPases, is encoded by the dynamin-1-like (DNM1L) gene and plays a critical role in mitochondrial fission. There was significant clinical heterogeneity in DNM1L-related disorders.
    METHODS: Whole exome sequencing (WES) was used to identify potential genetic causes of the phenotype in probands. Bioinformatics analysis was performed to analyze the pathogenicity of the identified variants, and 3D protein modeling was constructed to predict their effects on protein structure. Preliminary studies of the functional effects of the variant sites on the encoded proteins were performed by in vitro experiments.
    RESULTS: Two de novo variants, c.1049G>C (p.Gly350Ala) and c.2161C>T (p.Gln721*), were detected in affected individuals. One patient presented with severe epileptic encephalopathy while the other exhibited a distinctive clinical phenotype of hemiparesis. In silico analysis, conservative analysis, and 3D homology modelling indicated that the p.Gly350Ala and the p.Gln721* variants are deleterious. Furthermore, the results of the artificial transfection experiments demonstrated that the p.Gly350Ala variant resulted in a reduction in DNM1L expression at both the transcriptional and protein levels (p < 0.05). In contrast, the p.Gln721* variant exhibited no significant alteration in protein levels (p = 0.08), although it did result in a reduction in mRNA levels.
    CONCLUSIONS: The present findings suggest that these variants may contribute to DRP1 deficiency, potentially triggering a range of DNM1L-related disease phenotypes. This study serves to expand the spectrum of variants associated with DNM1L-related disorders.
    Keywords:   DNM1L gene; Children; DRP1; Phenotypic spectrum; Variant; Whole exome sequencing
    DOI:  https://doi.org/10.1186/s12887-025-06299-9
  40. Epigenetics. 2025 Dec;20(1): 2598087
    Changes in nuclear and mitochondrial DNA methylation in cow blood associated with age and disease.
    Lotfi Bouzeraa, Camila Bruna de Lima, Helene Martin, Jessica C S Marques, Ronaldo Cerri, Mohamed Oudihat, Marc-Andre Sirard.
      DNA methylation is among the most promising biomarkers for age prediction, enabling the development of epigenetic clocks that correlate methylation profiles with chronological age. In this study, we investigated the relationship between ageing and disease susceptibility, focusing on both nuclear and mitochondrial DNA methylation in dairy cows. Genome-wide DNA methylation profiling was performed using enzymatic methyl-seq, covering 53 million CpG sites. The dataset included 96 cows with different phenotypes, sampled cross-sectionally and ranging from 2 to 9 years of age. We applied elastic net regression to identify the most predictive CpG sites for age estimation, achieving a mean absolute error of 111 days with a strong correlation to chronological age r = 0.97. Beyond chronological age prediction, we assessed the impact of disease status on epigenetic ageing. Our results revealed accelerated epigenetic ageing in cows susceptible to diseases, suggesting a link between health-related stress and disrupted DNA methylation dynamics. We further identified age-associated promoter methylation changes, particularly in MAB21L1, which may play a role in molecular ageing mechanisms. Additionally, we observed a decline in mitochondrial DNA methylation with age, notably in genes encoding Cytochrome c oxidase (COX), indicating a possible connection between mitochondrial dysfunction and epigenetic regulation. An inverse correlation between D-loop methylation and mtDNA copy number was also observed. This study demonstrates the potential of epigenetic models for biological age prediction in livestock, while recognizing that their accuracy may vary among species with different lifespans.
    Keywords:  DNA methylation; aging; epigenetic clock; mitochondria; nuclear genome
    DOI:  https://doi.org/10.1080/15592294.2025.2598087
  41. bioRxiv. 2025 Dec 01. pii: 2025.11.27.690007. [Epub ahead of print]
    Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis.
    Di Ran, Yongguo Zhang, Yueqing An, Ying Hu, Yinglin Xia, Jun Sun.
       Background and aims: Transfer RNA (tRNA) modifications determine translation fidelity and efficiency. It occurs through the action of specific enzymes that modify the nucleotides within the tRNA molecule. Our previous study demonstrated tRNA modopathies and altered queuine-related metabolites in inflammatory bowel diseases. Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) and QTRT 2 co-localize in mitochondria and form a heterodimeric TGT participating in tRNA Queuosine (tRNA-Q) modification. Human body acquires Queuine/Vitamin Q from intestinal microbiota or from diet. However, the roles of tRNA-Q modifications in the maintenance of intestinal mitochondrial homeostasis and microbiome are still unclear.
    Methods: We used publicly available human IBD datasets, QTRT1 knockout (KO) mice, QTRT1 intestinal epithelial conditional KO (QTRT1 ΔIEC ) mice, cultured cell lines with QTRT1-specific siRNA, and organoids from patients with IBD to investigate the mechanism of tRNA-Q modifications in intestinal mitochondrial homeostasis and therapeutic potential in anti-inflammation.
    Results: In single cell RNA sequencing datasets of human IBD, we identified significant reduced intestinal epithelial QTRT1 expression in the patients with Crohn's Disease. Using publicly available datasets, we identified significantly changes of Vitamin Q-associated bacteria in human IBD, compared to the healthy control. Qtrt1 -/- mice had significant reduction of Q-associated bacteria, e.g., Bacteroides . Alcian Blue and Mucin-2 staining revealed mucosal barrier damage and disrupted homeostasis, with reduced colonic cell proliferation. Intestinal tight junction integrity was impaired in QTRT1-KO mice, as evidenced by reduced ZO-1 and increased Claudin-10 expression. QTRT1 ΔIEC mice also showed dysbiosis and disrupted TJs. ATP synthesis was significantly decreased in the colon of QTRT1-KO mice, accompanied by severe mitochondrial dysfunction: reduced mitochondrial quality, Cytochrome-C release, and mitochondrial DNA (mtDNA) leakage. Mitochondrial dysfunction contributed to colonic cell death, as shown by elevated expressions of Cleaved Caspase-3 and Cleaved Caspase-1, increased BAX/Bcl-2 ratio, and positive TUNEL signals. Elevated CDC42, CD14, and CD4 levels in QTRT1-KO colon suggested mucosal immune activation and tissue repair responses. QTRT1-deficient CaCO2-BBE cells showed mitochondrial dysfunction. Cytochrome-C and mito-DNA release leading to cell death characterized by elevated expressions of Cleaved Caspase-3 and Caspase-1, increased BAX/Bcl-2 ratio, and higher apoptosis rate. Organoids isolated from patients with IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1.
    Conclusions: These findings underscore the critical role of QTRT1/Q-tRNA modification in maintaining intestinal and microbial homeostasis. Mechanistically, QTRT1 loss impacts mitochondrial integrity and mucosal homeostasis. Our study highlights the novel roles of tRNA-Q modification in maintaining mucosal barriers and innate immunity in intestinal health.
    What is already known about this subject?: Eukaryotes acquire queuine (q), also known as Vitamin Q, as a micronutrient factor from intestinal microbiota or from diet.Vitamin Q is needed for queuosine (Q) modification of tRNAs for the protein translation rate and fidelity.Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) is reduced in human IBD.However, health consequences of disturbed availability of queuine and altered Q-tRNA modification in digestive diseases remain to be investigated.
    What are the new findings?: QTRT1 deficiency leads to altered microbiome and reduced Vitamin Q-associated bacteria in human IBD and a QTRT1 KO animal model.QTRT1 protects the host against losing intestinal integrity during inflammation.QTRT1 localizes in mitochondria and plays novel functions by maintaining intestinal mitochondrial function. QTRT1 loss impacts tRNA modification in the intestine, linking to mitochondrial integrity and mucosal homeostasis.Human IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1.
    How might it impact on clinical practice in the foreseeable future?: Targeting tRNA-Q modification in enhancing mitochondrial function will be a novel method to maintain intestinal health.
    DOI:  https://doi.org/10.1101/2025.11.27.690007
  42. Nat Methods. 2025 Dec 12.
    Bio-friendly and high-precision super-resolution imaging through self-supervised reconstruction structured illumination microscopy.
    Jiahao Liu, Xue Dong, Huaide Lu, Tao Liu, Wei Liu, Xinyao Hu, Quan Meng, Amin Jiang, Tao Jiang, Xiaohan Geng, Haosen Liu, Jun Cheng, Edmund Y Lam, Yan-Jun Liu, Shan Tan, Dong Li.
      Deep-learning-based structured illumination microscopy (SIM) has demonstrated substantial potential in long-term super-resolution imaging of biostructures, enabling the study of subcellular dynamics and interactions in live cells. However, the acquisition of ground-truth (GT) data for training poses inherent challenges, limiting its universal applicability. Current approaches without using GT training data compromise reconstruction fidelity and resolution, and the lack of physical priors in end-to-end networks further limits these qualities. Here we developed self-supervised reconstruction (SSR)-SIM by combining statistical analysis of reconstruction artifacts with structured light modulation priors to eliminate the need for GT and improve reconstruction precision. We validated SSR-SIM on common biological datasets and demonstrated that SSR-SIM enabled long-term recording of dynamic events, including cytoskeletal remodeling in cell adhesion, mitochondrial cristae remodeling, interactions between viral glycoprotein and endoplasmic reticulum, endocytic recycling of transferrin receptors, vaccinia-virus-induced actin comet remodeling, and mitochondrial intercellular transfer through tunneling nanotubes.
    DOI:  https://doi.org/10.1038/s41592-025-02966-y
  43. Adv Sci (Weinh). 2025 Dec 08. e17721
    Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.
    Zhuoyuan Zhang, Tsering Yangzom, Ning Lu, Shenglong Deng, Xianglu Xiao, Guang Yang, Kristina Xiao Liang.
      Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA) copy number and the expression of mitochondrial replisome proteins (POLG, POLG2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin-induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox-related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for POLG-related disorders.
    Keywords:  POLG‐related disorders; cortical organoids; iPSCs; mitochondrial dysfunction; neurogenesis impairment
    DOI:  https://doi.org/10.1002/advs.202417721
  44. Saudi J Ophthalmol. 2025 Oct-Dec;39(4):39(4): 416-418
    Clinical insights into mitochondrial retinopathy: A case report on m.3243A>G mutation and macular dystrophy.
    Nourelhouda Boussaid Othmani, Sebastian Mathew.
      Mitochondrial disorders, particularly those associated with the m.3243A>G mutation in the MT-TL1 gene, can manifest with diverse systemic and ocular features, including mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness. Retinal involvement often presents as macular pattern dystrophy. A 65-year-old female with a known history of mitochondrial disease (m.3243A>G mutation) presented for evaluation of retinal findings. She had asymptomatic diabetes and deafness, with visual acuity measured at 0.12 bilaterally. Clinical examination revealed clear corneas, nonsignificant cataracts, and fundoscopic findings of patchy retinal and parafoveal atrophy with preserved foveal regions. Optical coherence tomography indicated a preserved fovea, but thinning of perifoveal layers. The findings suggest retinal dystrophy indicative of mitochondrial retinopathy, characterized by macular pattern dystrophy associated with the m.3243A>G mutation. Given the potential for varied clinical presentations linked to this mutation, multidisciplinary evaluations are essential to assess systemic involvement and facilitate appropriate management. This case underscores the importance of recognizing retinal manifestations in patients with mitochondrial disorders, particularly in those with the m.3243A>G mutation, and highlights the need for comprehensive monitoring and care.
    Keywords:  Deafness; diabetes; genetics; mitochondrial diseases; retinopathy
    DOI:  https://doi.org/10.4103/sjopt.sjopt_314_24
  45. Int J Mol Sci. 2025 Nov 30. pii: 11615. [Epub ahead of print]26(23):
    Cell-Free DNA and Mitochondria in Parkinson's Disease.
    Małgorzata Wojtkowska, Franciszek Ambrosius.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the gradual and irreversible loss of neurons, especially within the substantia nigra region of the midbrain. Early and accurate diagnosis remains a significant challenge in both research and clinical practice. This difficulty is further compounded by the substantial clinical and molecular heterogeneity of PD, emphasizing the urgent need for reliable biomarkers to enhance diagnostic precision and guide therapeutic strategies. One promising candidate biomarker is cell-free DNA (cfDNA), comprising short DNA fragments composed of mitochondrial (cf-mtDNA) and nucleus-derived (cf-ntDNA) DNA. cfDNA is released into body fluids through physiological or pathological processes such as apoptosis, necrosis, NETosis, or active secretion. The presence of cfDNA in human biological fluids has been utilized for years in oncology and prenatal medicine and, more recently, it has gained attention as a non-invasive diagnostic tool in the context of neurodegenerative diseases such as PD. This review article aims to provide a comprehensive overview of the current knowledge on the origin of cfDNA, highlighting the roles of the mitochondria and cf-mtDNA in PD, mitochondria quality control, and neuroinflammation in cfDNA biogenesis. The review collates available research on cfDNA types in human serum, plasma, and CSF, sequence analysis, and its potential application as a biomarker in the diagnosis and monitoring of PD, contributing to the ongoing search for non-invasive biomarkers of neurodegenerative diseases.
    Keywords:  Parkinson’s disease; cell-free DNA (cfDNA); cell-free mitochondrial DNA (cf-mtDNA); cell-free nuclear DNA (cf-ntDNA); cerebrospinal fluid; mitochondria; mitophagy; neuroinflammation; plasma; serum
    DOI:  https://doi.org/10.3390/ijms262311615
  46. Mol Ther Nucleic Acids. 2025 Dec 09. 36(4): 102769
    Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.
    Lauren C Testa, Dora Obiri-Yeboah, Hooda Said, Ping Qu, Michael A Levine, Mohamad-Gabriel Alameh, Kiran Musunuru, Qiaoli Li, Xiao Wang.
      Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder characterized by ectopic calcification of elastic fibers throughout the skin, retina, and arteries. It is caused by pathogenic variants in ABCC6, which encodes a transmembrane transporter that primarily localizes to hepatocytes. Loss of ABCC6 function in hepatocytes leads to systemic deficiency of inorganic pyrophosphate (PPi), a potent inhibitor of calcification; such depletion of PPi from the circulation is responsible for multisystemic ectopic calcification seen in PXE. Therefore, liver-targeted variant correction by genome editing and subsequent restoration of systemic PPi may offer a one-and-done therapeutic approach for PXE. The ABCC6 c.3490C>T (p.R1164X) variant is one of the most common variants found in PXE patients. Here, we show that liver-directed correction of the R1164X variant by adenine base editing restores plasma PPi and prevents ectopic skin calcification in mice fed a standard diet or an "acceleration diet" that exacerbates ectopic calcification. These results provide fundamental insight into the molecular etiology of PXE and provide a proof-of-principle that genetic correction of ABCC6 defects through adenine base editing may represent a novel, permanent therapy for the treatment of PXE.
    Keywords:  ABCC6; CRISPR; MT: RNA/DNA Editing; base editing; ectopic calcification; gene editing; genome editing; pseudoxanthoma elasticum; pyrophosphate; rare disease
    DOI:  https://doi.org/10.1016/j.omtn.2025.102769
  47. Int J Mol Sci. 2025 Nov 25. pii: 11395. [Epub ahead of print]26(23):
    Chemically Anchored Diamond with H3 Centers for Ratiometric Measurement of Isolated Mitochondria Temperature.
    Alexey M Romshin, Alexey G Kruglov, Anna B Nikiforova, Alexander A Zhivopistsev, Rustem H Bagramov, Vitaly I Korepanov, Dmitrii G Pasternak, Yuri M Shlyapnikov, Timur M Valitov, Vladimir P Filonenko, Igor I Vlasov.
      Precise measurement of mitochondrial temperature at different metabolic states remains one of the key challenges in cellular biophysics due to the lack of thermometers that combine nanoscale sensitivity with stable thermal contact with the organelle. Here, we present a hybrid sensing platform based on chemically functionalized diamond microparticles containing H3 luminescent centers, covalently bound to the outer membrane of isolated rat liver mitochondria. Surface activation via oxidation and EDC/HOBt chemistry provides a robust and reproducible thermal link between the thermometric probe and the organelle, minimizing heat dissipation through the surrounding medium. The local temperature is monitored ratiometrically from the emission ratio of H3 centers at 515-525 nm and 585-610 nm, showing a linear dependence on temperature with a relative sensitivity of 1.15%⋅°C-1 in aqueous environments. Upon the uncoupling of oxidative phosphorylation and the inhibition of electron transport, the diamond thermometers reproducibly recorded the local thermal changes in the range of 0.5-10 °C, depending on the degree of coverage by anchored mitochondria. The observed response reflects efficient local heat confinement within the diamond-mitochondrion assembly, suggesting that structural organization and thermal insulation at the subcellular level are critical modulators of mitochondrial thermogenesis.
    Keywords:  cell thermodynamics; color centers; diamond thermometer; mitochondria
    DOI:  https://doi.org/10.3390/ijms262311395
  48. Free Radic Biol Med. 2025 Dec 05. pii: S0891-5849(25)01406-6. [Epub ahead of print]244 84-106
    Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial transfer via NLRP3 inflammasome activation.
    Zixian Zhou, Pengcheng Zhang, Yanlin Jiang, Yingchun Xu, Fangzhou Liu, Xinyu Chen, Deng Chen, Wenfu Tang, Rujia Liao, Ling Liu.
      Epileptic seizures disrupt brain homeostasis not only by directly challenging neuronal excitability but also by impairing the intricate astrocyte-neuron cross-talk essential for metabolic support. Herein, we identify a novel pathogenic axis and a compensatory rescue mechanism that are critically interlinked. Following seizures, astrocytes initiate a protective response by forming tunneling nanotubes (TNTs) to deliver functional mitochondria to stressed neurons, thereby restoring neuronal bioenergetics. Paradoxically, this endogenous rescue pathway is suppressed by a seizure-induced, astrocyte-specific signaling cascade: the upregulation of Lipocalin-2 (LCN2) activates the NLRP3 inflammasome, triggering Gasdermin D-mediated pyroptosis and concurrently impairing TNT function. Crucially, genetic or pharmacological disruption of the LCN2/NLRP3 axis yielded dual therapeutic benefits-it robustly suppressed astrocytic pyroptosis and, unexpectedly, potentiated TNT-mediated mitochondrial transfer, leading to significant improvements in neuronal mitochondrial function and overall neurological outcomes. Our findings redefine the role of reactive astrocytes in epilepsy, revealing a single pathway that simultaneously controls an inflammatory death process and an intercellular organelle rescue system. Targeting this axis presents a promising therapeutic strategy to concurrently mitigate neuroinflammation and boost intrinsic neuroprotective mechanisms for improving post-seizure recovery.
    Keywords:  Astrocyte; Epilepsy; Lipocalin-2; Mitochondrial; NOD-Like receptor protein 3; Pyroptosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.061
  49. Environ Sci Technol. 2025 Dec 11.
    Mitochondrial Metabolomics Reveals the Mechanism of SCCP Induced Energy Metabolism Inhibition.
    Chenhao Huang, Shuangshuang Chen, Lin Cheng, Chengcheng Shi, Rong Cao, Li Wang, Yuan Gao, Ying Yu, Ningbo Geng, Jiping Chen.
      Short-chain chlorinated paraffins (SCCPs) disturb cellular energy metabolism in vitro, but their subcellular toxicity mechanisms are incompletely understood. This study employed mitochondrial metabolomics integrated with phenotypic assays to investigate the subcellular mechanisms of SCCP-induced energy metabolism inhibition. Exposure to SCCPs (0-100 μg/L) caused profound downregulation of ATP. Seahorse respirometry analyses revealed the dose-dependent inhibition of oxidative phosphorylation and compensatory upregulation of glycolysis. Mitochondrial ultrastructural damage (swelling and cristae loss) and dissipation of mitochondrial membrane potential confirmed mitochondria as the primary targets of SCCPs. Mitochondrial metabolomics demonstrated that the suppression of the TCA cycle (depleted citrate, oxaloacetate) and OXPHOS (reduced NAD+, ATP/ADP; inhibited Complex V activity) is responsible for the downregulation of ATP. The conversion from phosphatidylcholines to lysophosphatidylcholines further verified mitochondrial membrane damage. Perturbations in nucleotide metabolism reflected impaired synthesis pathways for DNA/RNA. Critically, medium-chain chlorinated paraffins (MCCPs), proposed as SCCP substitutes, induced qualitatively similar mitochondrial damage (respiration inhibition, cristae disruption, and ΔΨm loss), challenging the presumed safety of MCCPs as alternatives. This study revealed the key mechanisms of SCCP induced energy metabolism inhibition at the subcellular level, underscoring the need for careful reconsideration of MCCP usage.
    Keywords:  ATP Inhibition; SCCPs; Seahorse respirometry; mitochondrial dysfunction; mitochondrial metabolomics; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.1021/acs.est.5c12098
  50. Nat Commun. 2025 Dec 12. 16(1): 11103
    Dynamic changes in mitochondria support phenotypic flexibility of microglia.
    Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.
      Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.
    DOI:  https://doi.org/10.1038/s41467-025-66709-5
  51. Cell Death Dis. 2025 Dec 10.
    A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease.
    Davide Doni, Deborah Grifagni, Federica Cavion, Bianca Buchignani, Roberta Battini, Elisa Baschiera, Maria Andrea Desbats, Rosa Pasquariello, Giuseppina Covello, Eva De Pascale, Alice Boarolo, Ilaria Cestonaro, Denis Badocco, Paolo Pastore, Geppo Sartori, Oliver Stehling, Roland Lill, Filippo M Santorelli, Leonardo Salviati, Simone Ciofi-Baffoni, Paola Costantini.
      Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is a rare autosomal recessive neuromuscular disorder characterized by childhood onset of progressive muscle weakness and exercise intolerance. It is caused by mutations in the FDX2 gene, encoding the mitochondrial protein ferredoxin 2 (FDX2), a central component of the cellular FeS protein biogenesis. To date there are gaps in our understanding of how FDX2 mutations impact mitochondrial pathophysiology in MEOAL patients. In this work we report a multidisciplinary study of a pediatric patient with a diagnosis of neuromuscular disorder, with multiorgan involvement, associated with a novel homozygous mutation in FDX2, i.e., c.200+4 A > G. We found that: (i) the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids; (ii) patient's cells have low levels of FDX2; (iii) the mutant FDX2 likely retains its functional integrity, as can be inferred by the absence of significant structural or backbone dynamic differences relative to the wild type protein; (iv) cultured patient's cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation; (v) the levels of the mitochondrial SOD2 are significantly diminished in patient's cells and may contribute to weak ROS production. Collectively, the results show that the FDX2 mutation leads to a severe decrease of FDX2 protein, resulting in a primary mild cellular FeS protein assembly defect and in the secondary consequences mentioned above, that together may explain the pathogenesis of this MEOAL case.
    DOI:  https://doi.org/10.1038/s41419-025-08323-3
  52. Nature. 2025 Dec;648(8094): 522
    'Giant step forward' for Huntington's - the scientist behind the first gene therapy.
    Elie Dolgin.
      
    Keywords:  Brain; Gene therapy; Medical research; Neurodegeneration; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-025-03842-7
  53. Int J Biol Macromol. 2025 Dec 09. pii: S0141-8130(25)10149-9. [Epub ahead of print] 149592
    The curious life of human mitochondrial SOD2.
    Medhanjali Dasgupta, Miles L Graham, Gloria E O Borgstahl.
      Human manganese superoxide dismutase (MnSOD2) is a critical mitochondrial antioxidant that catalyzes the conversion of highly reactive superoxide radicals into molecular oxygen and hydrogen peroxide. The peroxide molecules are subsequently neutralized by other antioxidant systems, positioning MnSOD2 as the primary defense against mitochondrial oxidative stress and diseases associated with disrupted in vivo redox balance. MnSOD2 has been studied since its discovery in the early 1960s, particularly in the context of cellular pathology and as a therapeutic target. Recent studies combining neutron protein crystallography (NPC), X-ray absorption spectroscopy (XAS), and quantum mechanical (QM) computations have uncovered previously uncharacterized protonation states and atypically short and strong hydrogen bonds within the active site of MnSOD2. Together, these drive the enzyme's exceptionally rapid turnover. This focused review summarizes emerging insights to generate an updated landscape of MnSOD2's structure-function relationship and to highlight remaining challenges. The primary bottleneck to a complete understanding of the structural mechanism of MnSOD2 catalysis is the lack of a superoxide-bound MnSOD2 structure that resolves all proton positions, defines the redox state of the catalytic metal, the metal ligands, and the position of superoxide. Additionally, another largely unexplored area is how Fe substitution converts MnSOD2 into a peroxidase, and how this metal promiscuity affects mitochondrial redox homeostasis. This review synthesizes current evidence and states an informed hypothesis for the catalytic mechanism of Fe-substituted SOD2 (FeSOD2). Clarifying these gaps will advance our understanding of the structural basis of SOD2 catalysis and how it shapes mitochondrial redox biology in health and disease.
    Keywords:  Iron superoxide dismutase (FeSOD2); Manganese superoxide dismutase (MnSOD2); Metalloenzyme; Mitochondrial antioxidants; Oxidative stress; Proton- coupled Electron transfer (PCET); Redox balance
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149592
  54. Toxicol Lett. 2025 Dec 09. pii: S0378-4274(25)02750-X. [Epub ahead of print] 111804
    Rotenone-Induced Cellular Dysfunction in Human Blood Platelets: Unraveling Calcium Dysregulation, Mitochondrial Impairment, Oxidative Stress, and Apoptosis.
    Samir Kumar Beura, Nisha Yadav, Abhishek Kumar Maurya, Nikki Kumari, Sunil Kumar Singh.
      Rotenone, a naturally occurring pesticide and a well-established mitochondrial complex I inhibitor, disrupts electron transport chain activity, resulting in impaired energy metabolism, oxidative stress, and apoptosis. Our recent findings revealed that rotenone suppresses agonist-induced platelet functional activity; however, the molecular mechanisms underlying this effect remain largely unclear. In this study, we demonstrate that rotenone exposure induces pronounced cytotoxic effects in human platelets, evident from decreased cell viability and phosphatidylserine externalization, a hallmark of apoptosis-like processes. At the mitochondrial level, rotenone markedly compromises organelle integrity by inducing mitochondrial membrane potential depolarization, excessive reactive oxygen species generation, and calcium dysregulation. These mitochondrial perturbations act as key upstream signals that trigger caspase activation and drive apoptosis-like cascades in platelets. Collectively, our findings identify mitochondrial dysfunction, oxidative stress, and calcium imbalance as central mediators of rotenone-induced, caspase-dependent platelet apoptosis. This study demonstrates that rotenone induces cytotoxicity and organelle dysfunction in human blood platelets, thereby providing mechanistic insight into altered platelet functions.
    Keywords:  Apoptosis; Calcium; Caspase; Mitochondria; Oxidative stress; Platelet; Rotenone
    DOI:  https://doi.org/10.1016/j.toxlet.2025.111804
  55. Theranostics. 2026 ;16(3): 1410-1431
    PINK1/Parkin promotes liver regeneration via Sigma-1 ubiquitination to inhibit ER-Mitochondrial calcium transfer.
    Jian Xu, Yuechen Wang, Weizhe Zhong, Haoran Hu, Ye Zhang, Yiyun Gao, Ping Wang, Zhuqing Rao, Haoming Zhou, Xuehao Wang.
      Rationale: Liver regeneration is regulated by both metabolic processes and immune responses. Nonetheless, there is limited comprehension of the mechanisms involved. PINK1/Parkin-mediated mitophagy has been well documented, the role and underlying alternative mechanism of PINK1/Parkin in regulating mitochondrial metabolism during liver regeneration remains unclear. Methods: Liver tissues from mice undergoing hepatectomy were utilized to evaluate the expression levels of PINK1/Parkin. Hepatocyte-specific PINK1 knockout and transgenic mouse models were generated to investigate the impact of PINK1 on regeneration. Mass spectrometry, co-immunoprecipitation, and ubiquitination assays were performed to explore the underlying molecular mechanisms. Results: We observed PINK1/Parkin expression was markedly upregulated in hepatic tissue following liver resection. PINK1 depletion in hepatocytes caused impaired liver regeneration. Moreover, mitochondrial calcium overload was found be responsible for restricted TCA by inhibiting succinate dehydrogenase activity in PINK1 deficient hepatocytes. Interestingly, PINK1 deficiency leads to succinate accumulation and release from hepatocytes, which impairs liver regeneration by restricting macrophage pro-repair phenotypes. This effect was further confirmed by enhanced regeneration in myeloid SUCNR1 knockout mice. Mechanistically, Sigma-1 is a molecular chaperone of the endoplasmic reticulum calcium channel IP3R, which helps maintain its normal functional conformation. Parkin was able to bind Sigma-1 through its UBL domain, facilitating its k48-linked ubiquitination, which promotes Sigma-1 degradation and subsequently suppressing calcium transfer from the ER to mitochondria at the mitochondrial-associated ER membrane. Conclusions: Collectively, PINK1/Parkin signaling regulates hepatocellular mitochondrial ATP and succinate production by modulating ER-mitochondria calcium transfer to promote liver regeneration, revealing a promising therapeutic target for liver regeneration.
    Keywords:  MAM calcium channel; PINK1/Parkin; liver regeneration; sigma-1; succinate
    DOI:  https://doi.org/10.7150/thno.115726
  56. Mol Autism. 2025 Dec 12.
    Atypical GNAO1 variants in severe childhood speech disorders: clinical, genetic, and molecular insights.
    Yonika A Larasati, Moritz Thiel, Ainara Salazar-Villacorta, Alexey Koval, Manju A Kurian, Anne Koy, Angela T Morgan, Vladimir L Katanaev, Gonzalo P Solis.
       BACKGROUND: The etiology of severe childhood speech disorders, including childhood apraxia of speech (CAS), is currently understood as genetically heterogeneous, with over 40 distinct monogenic conditions reported to date. Among them, the p.Thr327Arg variant in GNAO1, encoding the major neuronal G protein Gαo, was identified in one patient diagnosed with CAS and intellectual disability (ID). This presentation is exceptionally rare, as GNAO1 mutations are commonly associated with epilepsy, hyperkinetic movement disorders, and global developmental delay, often accompanied by ID.
    METHODS: Here, we describe the clinical course of two patients with de novo heterozygous GNAO1 variants-p.Leu39_Gly40insVal and p.Thr327Lys-who exhibit severe speech disorder and ID as prominent symptoms. We also analyzed the biochemical and cellular properties of the mutant Gαo proteins alongside the previously reported p.Thr327Arg variant.
    RESULTS: Molecular investigation of these three atypical Gαo mutants revealed aberrant GTP binding and hydrolysis, impaired association with RGS19, and a strong neomorphic gain of Ric8A interaction. Yet, all variants show normal plasma membrane localization despite poor Gβγ association, with p.Leu39_Gly40insVal exhibiting weak coupling to G protein-coupled receptors and p.Thr327Arg/Lys displaying near-normal coupling. Importantly, all three Gαo variants respond to Zn2+, supporting the potential therapeutic use of zinc supplementation for the patients.
    LIMITATIONS: These rare findings are based on a limited number of cases and require confirmation in additional patients to establish firmer genotype-phenotype correlations for GNAO1-related severe speech disorders.
    CONCLUSIONS: Our results broaden the clinical and mechanistic spectrum of GNAO1-related disorders, showing that severe speech disorders and ID can occur as defining features even in the absence of seizures or movement disorders. These findings highlight the importance of including GNAO1 in genetic testing for children with severe speech disorders.
    Keywords:  Childhood apraxia of speech (CAS); G protein-coupled receptors (GPCRs); GNAO1; Gαo; Severe speech disorders
    DOI:  https://doi.org/10.1186/s13229-025-00696-8
  57. J Cereb Blood Flow Metab. 2025 Dec 07. 271678X251400466
    Editorial to the special issue on extracellular vesicles and mitochondria in CNS function and disease.
    Kazuhide Hayakawa, Dirk M Hermann.
      Extracellular vesicles (EVs) have emerged as critical mediators of cell-to-cell communication. More recently, a subset of these vesicles has been found to contain mitochondria (EV-Mito). These mitochondria-bearing EVs may act as non-cell-autonomous signaling entities and serve as potential biomarkers for injury and recovery in central nervous system (CNS) pathophysiology. Mitochondria play a vital role in regulating cellular respiration, metabolism, and overall tissue function. In the context of CNS injury or disease, mitochondrial dysfunction can disrupt metabolic homeostasis, leading to cell death and inflammation. Consequently, restoring mitochondrial function represents a key therapeutic target with strong translational potential. This special issue of JCBFM presents a multidisciplinary collection of high-impact reviews and original research articles. These contributions cover a broad spectrum-from basic studies on EV-mediated mechanisms in CNS disorders and the molecular pathways underlying intercellular mitochondrial transfer, to therapeutic applications of EVs and mitochondrial transplantation in cellular and animal models. The issue also highlights the latest clinical trial developments assessing the feasibility of EV and mitochondrial transplantation in cerebral ischemia. Collectively, these articles offer valuable insights into emerging research directions and underscore the many unresolved questions that remain-particularly regarding the quantitative thresholds required for treatment efficacy and the molecular mechanisms driving beneficial tissue remodeling.
    Keywords:  CNS disorders; Extracellular mitochondria; Extracellular vesicles; Therapy
    DOI:  https://doi.org/10.1177/0271678X251400466
  58. Front Aging Neurosci. 2025 ;17 1678460
    Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.
    Chang Liu, Wei He, JianHua Zhang.
      Parkinson's disease (PD) is a common neurodegenerative disorder with a rising incidence in aging populations, substantially diminishing patients' quality of life. Mitochondria are central to neuronal energy metabolism, and mitophagy plays a pivotal role in maintaining mitochondrial quality by removing damaged organelles. In PD, impaired mitophagy leads to the accumulation of dysfunctional mitochondria, exacerbating oxidative stress and bioenergetic deficits and thereby accelerating disease progression. In recent years, exercise has emerged as a safe and cost-effective intervention that alleviates PD symptoms. Exercise can activate mitophagy through key signaling pathways-including AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) and PTEN-induced kinase 1 (PINK1)/Parkin-thereby enhancing mitochondrial function and antioxidant capacity. This review synthesizes current evidence on how exercise modulates mitophagy to confer neuroprotection in PD, providing conceptual and practical insights for non-pharmacological management strategies in neurodegenerative disease.
    Keywords:  AMPK signaling; PINK1/Parkin pathway; Parkinson’s disease; exercise intervention; mitophagy
    DOI:  https://doi.org/10.3389/fnagi.2025.1678460
  59. Nature. 2025 Dec 09.
    What will be the first AI-designed drug? These disease-fighting antibodies are top contenders.
    Ewen Callaway.
      
    Keywords:  Machine learning; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-025-03965-x
  60. BMC Cardiovasc Disord. 2025 Dec 09.
    Integrated bioinformatic and in vivo analysis confirms the cardioprotective role of OPA1.
    Claire Fong-McMaster, Serena M Pulente, Luke S Kennedy, Tyler K T Smith, Stephanie Myers, Michel N Kanaan, Charbel Y Karam, Matthew Cope, Michelle M Levesque, Ella McIlroy, Ilka Lorenzen-Schmidt, Craig J Goergen, Morgan D Fullerton, Miroslava Cuperlovic-Culf, Erin E Mulvihill, Mary-Ellen Harper.
       BACKGROUND: OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia/reperfusion injury. We sought to further assess OPA1 in cardiac pathologies, hypothesizing that OPA1 will function in a protective manner in chronic heart failure.
    METHODS: Integrated analyses of publicly available histological and transcriptomic data were used to identify functional associations between OPA1 and other genes of interest. To experimentally assess these associations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to a modified transverse aortic constriction surgery and underwent 2-dimensional and 4-dimensional echocardiography along with molecular analyses including high-resolution respirometry, enzymatic activities, flow cytometry and transcript level analyses.
    RESULTS: Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were associated with fatty acid, branch chain amino acid and cardiac contractile gene signatures. These functional associations were further supported by in vivo findings showing that OPA1-OE mice displayed improved 2D ejection fraction, end systolic volume, end diastolic volume and 4D cardiac functional parameters including global peak circumferential and surface area strain compared to WT mice. As well, OPA1-OE mice displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers and no induction of fibrotic transcript markers.
    CONCLUSION: These results further demonstrate the important role of OPA1 in supporting optimal cardiac function and highlight potentially protective contractile and metabolic signaling pathways.
    Keywords:  4-dimensional echocardiography; Heart failure; Mitochondria; Mitochondrial fusion; Optic atrophy protein-1
    DOI:  https://doi.org/10.1186/s12872-025-05413-0
  61. Micron. 2025 Dec 08. pii: S0968-4328(25)00199-4. [Epub ahead of print]202 103981
    Morphometric analysis of axonal ultrastructure: Coordinated scaling of organelles and myelin.
    Vitalijs Borisovs, Mario Bossi, Guido Cavaletti.
      The endoplasmic reticulum (ER) is a crucial neuronal organelle involved in protein synthesis, calcium homeostasis, and metabolic support, essential for neuronal function and plasticity. Understanding its three-dimensional (3D) architecture is key to elucidating functional organization. Using SBF-SEM and AI-assisted segmentation, we established a quantitative framework to characterize ER and mitochondrial scaling within 35 peripheral nervous system (PNS) myelinated axons. Analysis of individual organelle morphometrics revealed a strong power-law relationship between surface area and volume for both mitochondria (R2 = 0.949) and ER (R2 = 0.949). The resulting exponents were super-isometric (kMito = 0.85, kER = 0.73), suggesting structural plasticity that prioritizes membrane surface expansion. A key finding was the distinction between size and number regulation: mitochondrial and ER volumes were negligibly correlated (r ≈ 0.03), implying independent size regulation. However, organelle abundance (counts) showed a strong positive correlation (r = 0.79), maintaining an extremely low Bonferroni-adjusted Q value (8.1 ×10-9), suggesting coordinated control of organelle number in response to axonal size. Axonal populations were heterogeneous, with larger axons consistently containing more ER elements (r = 0.59) and mitochondria (r = 0.69). Furthermore, a low correlation of axon length with organelle content supports the idea that regulation is primarily a local phenomenon tied to cross-sectional size. These findings provide a quantitative basis for understanding how ER and mitochondria structurally adapt to axonal size, laying the groundwork for future research into how these scaling relationships influence neuronal metabolic health and contribute to neurological disease.
    Keywords:  3D Reconstruction; Electron microscopy; Endoplasmic reticulum; Morphology; Neuron; Ultrastructure
    DOI:  https://doi.org/10.1016/j.micron.2025.103981
  62. Nat Cardiovasc Res. 2025 Dec 11.
    Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
    Abigail V Giles, Raul Covian, Hiran A Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P Murphy, Robert S Balaban.
      The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia-reperfusion injury, an unknown limiting the understanding of ischemia-reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1038/s44161-025-00752-9
  63. Int J Mol Sci. 2025 Nov 21. pii: 11257. [Epub ahead of print]26(23):
    Urinary Multi-Omics Profiling Reveals Systemic Molecular Alterations in Progressive External Ophthalmoplegia.
    Michela Cicchinelli, Guido Primiano, Francesca Canu, Jacopo Gervasoni, Aniello Primiano, Lavinia Santucci, Anna Percio, Viviana Greco, Chiara Leoni, Andrea Sabino, Michelangelo Ardito, Giuseppe Zampino, Serenella Servidei, Andrea Urbani, Federica Iavarone.
      Advances in next-generation sequencing have significantly improved the molecular diagnosis of mitochondrial diseases (MDs), a group of heterogeneous neurogenetic disorders. However, progress in understanding their pathogenic mechanisms and translating this knowledge into effective therapies remains limited. Elucidating the molecular determinants of phenotypic variability in primary MDs is essential to uncover disease mechanisms and identify novel therapeutic targets. We investigated a cohort of eight adult patients with genetically confirmed Progressive External Ophthalmoplegia (PEO)-an extremely rare mitochondrial disorder-and compared them with eight age- and sex-matched healthy controls. A comprehensive multi-omics approach combining LC-MS/MS-based proteomics, UPLC-MS/MS-based metabolomics, ATR-FTIR spectroscopy, and chemometric multivariate analysis was employed to identify molecular alterations associated with mitochondrial dysfunction. Distinct proteomic and metabolic patterns related to energy metabolism were observed in PEO patients, correlating with their genetic background. Metabolomic analysis showed altered amino acid levels (seven statistically relevant) and disruptions in the metabolism of cysteine, methionine, and glutathione; proteomics finding (154 differentially expressed proteins) revealed dysregulation in extracellular matrix (ECM) organization and immune response pathways. This integrative analytical strategy offers new insights into the molecular complexity of PEO and mitochondrial disorders. The identification of disease-associated molecular signatures may enhance the understanding of pathogenic mechanisms and support the development of improved diagnostic and therapeutic approaches for MDs.
    Keywords:  ATR-FTIR; LC-MS/MS; Progressive External Ophthalmoplegia (PEO); extracellular matrix; immune response; metabolomics; mitochondrial diseases; mitochondrial dysfunction; molecular mechanisms; multi-omics; multi-omics integration; proteomics; urine biomarkers
    DOI:  https://doi.org/10.3390/ijms262311257
  64. Biochemistry (Mosc). 2025 Nov;90(11): 1678-1697
    Relationships of GDAP1 Mutations to Disease Phenotype and Mechanisms of Therapeutic Action of Oxidative Metabolism Activators in a Patient with Charcot-Marie-Tooth Neuropathy Type 2K.
    Nadejda R Borisova, Alina A Emelyanova, Olga N Solovjeva, Natalia V Balashova, Olga P Sidorova, Victoria I Bunik.
      The development of personalized medicine, including the treatment of hereditary diseases, requires translation of advances in biochemistry into medical practice. Our work is dedicated to solving this problem in a clinical case of hereditary Charcot-Marie-Tooth neuropathy type 2K (CMT2K), induced by the compound heterozygous mutations in the GDAP1 gene leading to the protein variants with the most common in Europe substitution L239F (inherited from the father) and previously uncharacterized substitution A175P (inherited from the mother). The ganglioside-induced differentiation-associated protein 1 (GDAP1) encoded by the GDAP1 gene is located in the outer mitochondrial membrane and belongs to the glutathione S-transferase superfamily. Our structure-function analysis of GDAP1 shows that dimerization of its monomers with either L239F or A175P substitutions, along with the half-of-the-sites reactivity of GDAP1 to hydrophobic ligands, may synergistically impair the binding due to the double amino acid substitution in one of the active sites. This mechanism explains the early disease onset and progress in the child, whose parents heterozygous by each of the mutations are asymptomatic. Published phenotypes of amino acid substitutions in the GDAP1 region comprising the binding site for hydrophobic compounds are analyzed, including phenotypes of the homozygous L239F substitution and its compound heterozygous combinations with other substitutions in this region. Based on the found association of these substitutions with the axonal form of Charcot-Marie-Tooth disease (CMT) and disturbances in the NAD+- and thiamine diphosphate (ThDP)-dependent mitochondrial metabolism, the therapeutic effect of nicotinamide riboside (NR) and thiamine (precursors of NAD+ and ThDP, respectively) in the patient is studied. Oral administration of thiamine and NR increases levels of ThDP and NAD+ in the patient's blood, improves the hand grip strength, and, after a long-term administration, normalizes the ThDP-dependent metabolism. After the therapy, the diseased-altered activities of transketolase (TKT) and its apo-form, as well as the relationship between the activity of the TKT holoenzyme and ThDP and NAD+ levels in the patient's blood, approach those of healthy women. Our results demonstrate the therapeutic potential of thiamine and NR in correcting metabolic dysregulation in CMT caused by mutations in GDAP1, suggesting the underlying molecular mechanisms. Genetic diagnostics and biochemical characterization of mechanisms involved in the pathogenicity of mutations in clinically asymptomatic patients or patients at the early CMT stages may increase the efficacy of therapy, as it is easier to protect from the accumulating metabolic damage than to reverse it.
    Keywords:  Charcot–Marie–Tooth neuropathy; GDAP1; compound heterozygous mutations; muscle strength; nicotinamide riboside; pyruvate dehydrogenase kinase; thiamine; transketolase; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1134/S0006297925601911
  65. Nature. 2025 Dec 10.
    Causal modelling of gene effects from regulators to programs to traits.
    Mineto Ota, Jeffrey P Spence, Tony Zeng, Emma Dann, Nikhil Milind, Alexander Marson, Jonathan K Pritchard.
      Genetic association studies provide a unique tool for identifying candidate causal links from genes to human traits and diseases. However, it is challenging to determine the biological mechanisms underlying most associations, and we lack genome-scale approaches for inferring causal mechanistic pathways from genes to cellular functions to traits. Here we propose approaches to bridge this gap by combining quantitative estimates of gene-trait relationships from loss-of-function burden tests1 with gene-regulatory connections inferred from Perturb-seq experiments2 in relevant cell types. By combining these two forms of data, we aim to build causal graphs in which the directional associations of genes with a trait can be explained by their regulatory effects on biological programs or direct effects on the trait3. As a proof of concept, we constructed a causal graph of the gene-regulatory hierarchy that jointly controls three partially co-regulated blood traits. We propose that perturbation studies in trait-relevant cell types, coupled with gene-level effect sizes for traits, can bridge the gap between genetic association and biological mechanism.
    DOI:  https://doi.org/10.1038/s41586-025-09866-3
  66. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2522444122
    A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
    Weilong Pan, Dejia Guo, Daiyuan Liu, Xiaodong Wang.
      SARM1 is a neuronal Nicotinamide adenine dinucleotide (NAD+) hydrolase that drives axonal degeneration and neuronal death by depleting NAD+, yet how NAD+ loss triggers axon loss and cell death has remained unclear. Here, we define a nonapoptotic death program downstream of endogenous SARM1 activation and NAD+ loss using a genetically tractable nonneuronal eHAP cell model. Upon NAD+ depletion, BAX is activated but caspase activation is suppressed due to APAF1 degradation via the E3 ligase HERC4, effectively uncoupling mitochondrial outer membrane permeabilization from apoptosome formation. Mechanistically, NAD+ depletion inhibits mTOR/AKT signaling, destabilizing MCL1 and relieving BAX from repression. We further identified Neurofibromatosis type II, NF2, as a regulator that promotes SARM1 transcription through the Hippo-YAP/TAZ pathway. The SARM1-dependent BAX activation and the role of NF2 in axon degradation were validated in neuronal models of axon degeneration. Together, these findings reveal how SARM1-driven metabolic collapse rewires cell death execution, positioning BAX, MCL1, APAF1, NF2, and HERC4 as core effectors in a nonapoptotic degenerative pathway linking metabolic stress to neurodegeneration.
    Keywords:  APAF1; Apoptosis; BAX; NAD+; SARM1
    DOI:  https://doi.org/10.1073/pnas.2522444122
  67. eNeuro. 2025 Dec 12. pii: ENEURO.0436-25.2025. [Epub ahead of print]
    Anxiety-associated behaviors following ablation of Miro1 from cortical excitatory neurons.
    Abigail K Myers, Madison Sakheim, Cole Rivell, Catherine Fengler, Lindsay K Festa, Kathy M Guerra, Layla Jarrahy, Rachel Shin, Megan Case, Caroline Chapman, Leah Basel, Slade Springer, Nicholas Kern, Jennifer Gidicsin, Ginam Cho, Sungjin Kim, Mourad Tighiouart, Jeffrey A Golden.
      Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction (Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria dynamically translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 (Miro1) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility and homeostasis (Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development and function (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and used mice of either sex for experiments. We found that mitochondrial mis-localization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting behavior and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to some anxiety-like behaviors.Significance Statement Neuropsychological disorders such as autism spectrum disorder, schizophrenia, and bipolar disorder have overlapping endophenotypes. While the mechanisms underlying these disorders are poorly understood, recent evidence implicates mitochondrial dysfunction and cellular mis-localization playing a role. Mitochondria support energy requirements and other physiological functions in cells. Previous research from our lab has shown distinct dynamic localization patterns within migrating excitatory and inhibitory neurons during development. To further examine the importance of mitochondrial localization, we ablated MIRO1, a protein important for coupling mitochondria to motor proteins, in excitatory neurons. The mis-localization of mitochondria in migrating excitatory neurons is associated with diminished motor skills and anxiety-like behavior in post-natal mice.
    DOI:  https://doi.org/10.1523/ENEURO.0436-25.2025
  68. Nat Genet. 2025 Dec;57(12): 3175-3184
    A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic interaction effects.
    Boyang Fu, Ali Pazokitoroudi, Zhuozheng Shi, Asha Kar, Albert Xue, Aakarsh Anand, Prateek Anand, Zhengtong Liu, Richard Border, Päivi Pajukanta, Noah Zaitlen, Sriram Sankararaman.
      The contribution of genetic interactions (epistasis) to human complex trait variation remains poorly understood due, in part, to the statistical and computational challenges involved in testing for interaction effects. Here we introduce FAME (FAst Marginal Epistasis test), a method that can test for marginal epistasis of a single-nucleotide polymorphism (SNP) on a quantitative trait (whether the effect of an SNP on the trait is modulated by genetic background). FAME is computationally efficient, enabling tests of marginal epistasis on biobank-scale data. Applying FAME to genome-wide association study (GWAS)-significant trait-SNP associations across 53 quantitative traits and ≈300 000 unrelated White British individuals in the UK Biobank (UKBB), we identified 16 significant marginal epistasis signals across 12 traits ( P<5×10-853 ). Leveraging the scalability of FAME, we further localized marginal epistasis signals across chromosomes and estimated the proportion of variance explained by marginal epistasis effects. Our study provides evidence for interactions between individual genetic variants and polygenic background influencing complex traits.
    DOI:  https://doi.org/10.1038/s41588-025-02411-y
  69. BMJ Case Rep. 2025 Dec 11. pii: e269373. [Epub ahead of print]18(12):
    Juvenile/adult-onset POLG-related disease unmasked by valproate-associated fulminant hepatic failure.
    Akshay Mathavan, Kanika Rathi, Lalitkumar J Mundhra, Akash Mathavan.
      DNA polymerase subunit gamma-1 (POLG)-related disease is a heterogeneous spectrum of mitochondrial disorders with neurologic and hepatic manifestations. We report a woman in her 20s who developed refractory seizures followed by fulminant hepatic failure after valproic acid exposure. Laboratory evaluation revealed low copper indices without evidence of Wilson disease, neuroimaging demonstrated evolving posterior-predominant abnormalities, and liver biopsy showed acute hepatitis with microvesicular change and 'two-toned' hepatocytes. Rapid whole-genome sequencing identified compound-heterozygous POLG variants c.1399G>A p.(Ala467Thr) and c.2243G>C p.(Trp748Ser), confirming a juvenile/adult-onset POLG-related disorder. This case highlights key diagnostic pitfalls, including potential misdirection of copper studies and risk of valproate hepatotoxicity in patients with unrecognised POLG variants. Supportive clues like occipital-predominant electroencephalogram/MRI changes, rapid neurologic-hepatic progression and hepatic microvesicular pathology can aid early suspicion but are not universally present. Prompt genetic testing and multidisciplinary follow-up are essential to guide management, avoid harmful therapies and anticipate the trajectory of this multisystem disease.
    Keywords:  Epilepsy and seizures; Genetics; Immunology; Liver disease
    DOI:  https://doi.org/10.1136/bcr-2025-269373
  70. Nat Commun. 2025 Dec 10. 16(1): 11010
    GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
    Gregory Austin, Affiong I Oqua, Liliane El Eid, Mingli Zhu, Yusman Manchanda, Priyanka Peres, Helena Coyle, Yelyzaveta Poliakova, Zhanna Balkhiyarova, Karim Bouzakri, Alex Montoya, Dominic J Withers, Michele Solimena, Ben Jones, Steven J Millership, Steffen Burgold, David C A Gaboriau, Endre Majorovits, Evelyn Garlick, Maria Augusta do R B F Lima, Inga Prokopenko, Jonathon Nixon-Abell, Andreas Müller, Alejandra Tomas.
      Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and β-cell functional adaptation, with important consequences for the regulation of β-cell insulin secretion and survival to stress.
    DOI:  https://doi.org/10.1038/s41467-025-66115-x
  71. Nature. 2025 Dec;648(8093): 262-264
    Is your brain tired? Researchers are discovering the roots of mental fatigue.
    Lynne Peeples.
      
    Keywords:  Brain; Diseases; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03974-w
  72. Front Mol Biosci. 2025 ;12 1695486
    Autophagy-NAD+ axis: emerging insights into neuronal homeostasis and neurodegenerative diseases.
    Gamze Kocak, Mylla M Dimas, Luiz F S E Silva, Danyelle Silva-Amaral, Congxin Sun, Sophie Cruddas, Timothy Barrett, Daniel Martins-de-Souza, Edecio Cunha-Neto, Patricia S Brocardo, Tetsushi Kataura, Viktor I Korolchuk, Sovan Sarkar.
      Autophagy is an evolutionarily conserved catabolic process that plays a central role in maintaining cellular homeostasis by degrading and recycling damaged or surplus proteins, organelles, and other cellular macromolecules and components. A growing body of evidence highlights a bidirectional relationship between autophagy and nicotinamide adenine dinucleotide (NAD+), a vital metabolic cofactor involved in numerous cellular processes, including energy metabolism, genomic maintenance, stress resistance, and cell survival. Autophagy supports NAD+ homeostasis by recycling metabolic precursors, while NAD+-dependent enzymes such as sirtuins and PARPs regulate autophagy initiation and lysosomal function. Disruption of this autophagy-NAD+ axis has emerged as a common feature in several neurodegenerative diseases, where impaired cellular clearance and metabolic dysfunction contribute to neuronal vulnerability. In this review, we summarize the advances of the molecular links between autophagy and NAD+ metabolism, with a particular focus on their roles in mitochondrial quality control, bioenergetic regulation, and cellular resilience. We also discuss the therapeutic potential of targeting the autophagy-NAD+ axis to promote neuroprotection in neurodegenerative disease.
    Keywords:  NAD+; NAD+ precursor; NAD+ supplementation; NAD+-dependent enzyme; autophagy; autophagy inducer; neuronal cell death; neuroprotection
    DOI:  https://doi.org/10.3389/fmolb.2025.1695486
  73. Cell Biosci. 2025 Dec 11.
    A crucial role of KLF2-regulated mitochondrial oxidative phosphorylation in maintaining the stemness of mesenchymal stem cells derived from bone marrow.
    Zhiyuan Gong, Yangxi Cheng, Rui Deng, Ying Zhou, Dan Yu, Cheng Chen, Yingjie Wang, Huiyong Zhu.
      Mesenchymal stem cells (MSCs) have many uses in tissue engineering and clinical applications. However, maintaining their stemness during in vitro expansion is challenging. We previously found that Krüppel-like factor 2 (KLF2) plays a crucial role in maintaining the stemness of MSCs. In this study, KLF2 was revealed to be closely linked to mitochondrial oxidative phosphorylation (OXPHOS), and impaired KLF2 expression in MSCs led to mitochondrial dysfunction that ultimately resulted in the loss of stemness. Moreover, decreased KLF2 expression was associated with reduced expression of the mitochondrial electron transport chain components, particularly the accessory subunit of complex I, NDUFC1. Further study demonstrated that KLF2 transcriptionally regulates NDUFC1 expression by binding to its promoter region. In addition, NDUFC1 knockdown largely phenocopied KLF2 knockdown in mitochondrial dysfunction and loss of stemness, and these phenotypes were partially rescued by NDUFC1 overexpression. Taken together, we reveal that KLF2 critically maintains MSCs stemness by transcriptionally promoting the expression of mitochondrial electron transport chain components such as NDUFC1, and KLF2/NDUFC1 axis-regulated mitochondrial oxidative phosphorylation may serve as a novel therapeutic target for improving MSCs stemness.
    Keywords:  KLF2; MSCs; NDUFC1; OXPHOS; Stemness
    DOI:  https://doi.org/10.1186/s13578-025-01501-y
  74. Nat Cell Biol. 2025 Dec 10.
    Assessing gene loss after gene editing.
    Sabrya Carim.
      
    DOI:  https://doi.org/10.1038/s41556-025-01845-0
  75. Cells. 2025 Nov 27. pii: 1877. [Epub ahead of print]14(23):
    Imbalance in MICOS Proteins in Rat Liver Mitochondria in an Induced Hyperthyroidism Model.
    Natalya Venediktova, Ilya Solomadin, Anna Nikiforova, Tatiana Bessonova.
      This study investigated rearrangements in the cristae structure and the possible relationship between these changes and the MICOS levels in the liver mitochondria of rats with experimentally induced hyperthyroidism. In hyperthyroid rats (HRs), the number, area, and perimeter of mitochondria were increased, and organelles of a worm-shaped, branched, highly elongated, or spherical shape appeared. A structural change in the mitochondria of HR liver was detected, consisting of a decrease in the number of cristae relative to the cross-section of the organelle. In some mitochondria, multilamellar bodies were detected. Hyperthyroidism caused an increase in the expression of genes and the level of proteins of the MIC60 subcomplex, with an unchanged level of the MIC10 subcomplex. Moreover, the levels of Sam50 and OPA1 in HRs were reduced. A functional assessment of HR mitochondria revealed changes in oxygen consumption, a decrease in membrane potential, and disruption of Ca2+ homeostasis. These data indicate that excess thyroid hormones cause partial changes in liver mitochondrial structure and an imbalance in the levels of Mic60 and Mic10 subcomplex proteins. The decreased levels of Sam50 and OPA1 proteins suggest their potential as targets for correcting mitochondrial dysfunction in metabolic disorders.
    Keywords:  MICOS; OPA1; calcium retention capacity; cardiolipin; cristae membranes; hyperthyroidism; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cells14231877
  76. Mol Med. 2025 Dec 08.
    Human pluripotent stem cell-derived retinal ganglion cells: advances in differentiation and translational applications.
    Jessica Yuen Wuen Ma, Maciej Daniszewski, Alice Pébay.
      Retinal ganglion cells (RGCs) are neurons that transmit visual information from the retina to the brain. Their degeneration, as seen in glaucoma and other optic neuropathies, leads to irreversible vision loss. As mature human RGCs are difficult to access, most of their studies rely on rodent models, which do not fully recapitulate human retinal biology. Human pluripotent stem cells (hPSCs) provide a promising source for generating RGCs in vitro, supporting disease modelling, drug screening, and future cell replacement therapies. This review outlines key markers that define RGC identity, maturation stages, and subtype diversity. We summarise recent advances in the differentiation of hPSCs towards RGCs, their functional characterisation, and their applications in disease modelling, drug screening, and transplantation.
    Keywords:  Human pluripotent stem cells; Retinal ganglion cells; Retinal organoids; Transplantation
    DOI:  https://doi.org/10.1186/s10020-025-01405-0
  77. Front Aging Neurosci. 2025 ;17 1676115
    Absence of the LRRK2 mutation in Emirati Parkinson's disease patients in contrast to other Arab populations.
    Vinod Metta, Anjana Soorajkumar, Tom Loney, Nasna Nassir, K Ray Chaudhuri, Mohammed Jashim Uddin, Hani T S Benamer.
       Background: The role of genetic factors in the pathogenesis of Parkinson's disease (PD) is characterized by heterogeneity in specific genetic variations and their prevalence across different populations and geographic locations.
    Objective: To investigate the frequency of the Leucine-rich repeat kinase 2 (LRRK2) mutation, a well-known genetic risk factor for PD, within Emirati patients.
    Methods: Emirati PD patients were recruited from the United Arab Emirates between September 2022 and May 2024. Blood samples were systematically screened for mutations across all 52 exons of the LRRK2 gene.
    Results: The LRRK2 mutation was not detected in any of the 50 Emirati PD patients (mean age 64.2 ± 14.1 years, of whom 56% are male) examined.
    Conclusion: The absence of the LRRK2 and specifically the G2019S mutation in Emirati PD patients corroborates findings from Saudi Arabia and indicates a distinct genetic pattern compared to other Arab regions like Egypt and Maghreb (North African) countries, where the G2019S mutation prevalence ranges from 10 to 40%. This underscores the need for further research to unveil alternative genetic determinants specific to the Emirati PD population.
    Keywords:  Emirati population; Parkinson’s disease (PD); epidemiology; genetic; leucine-rich repeat kinase 2 (LRRK2)
    DOI:  https://doi.org/10.3389/fnagi.2025.1676115
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