bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–12–07
72 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
  2. Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.
  3. Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
  4. Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
  5. Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
  6. Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
  7. Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association.
  8. Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
  9. Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
  10. Translational activators align mRNAs at the small mitoribosomal subunit for translation initiation.
  11. Human d-Glycerate Kinase, Encoded by GLYCTK and Deficient in d-Glyceric Aciduria, Is a Mitochondrial Enzyme.
  12. Mitochondrial DNA A3243G variant: Current perspectives and clinical implications.
  13. Cardiac magnetic resonance findings in mitochondrial disease: a guide for clinicians.
  14. Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.
  15. Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
  16. Slirp2 modulates oogenesis via regulating mitochondrial protein translation.
  17. Targeting multiple genetic defects of mitochondrial diseases with a single bacterial lipoate protein ligase.
  18. Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.
  19. Molecular mechanisms of mitochondrial function in neurodegenerative diseases.
  20. Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival.
  21. Neuromodulatory control of energy reserves in dopaminergic neurons.
  22. Ca²⁺ in the Mitochondrial Intermembrane Space: A New Compartment Fueling Arrhythmias.
  23. Advanced therapies for inherited optic neuropathies.
  24. Receptor-mediated mitophagy: a new target of neurodegenerative diseases.
  25. Mitochondrial Disease Diagnosed Following Preterm Birth at 29 Weeks of Gestation and Postpartum Heart Failure: A Case Report and Literature Review.
  26. Protective or Pathogenic? Kinase activity and the neurodevelopmental origins of G2019S LRRK2-Associated Parkinson's disease.
  27. Fontan Circulation Beyond Preload: Metabolic Pathways and Mitochondrial Stress.
  28. Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
  29. Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
  30. Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
  31. The curvature code: BCL-w dimers rewire BAX-BCL-2 control of mitochondrial fate and apoptosis.
  32. Assessment of Mitochondrial Fission/Fusion Dynamics in Kidney Proximal Tubular Cells.
  33. Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
  34. Hypoxic preconditioning increases mitochondrial respiration and H2O2 production.
  35. Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.
  36. Modeling Familial MASH by iPSC-Hepatocytes.
  37. Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
  38. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
  39. Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.
  40. Critical role of mitochondrial aconitase in skeletal muscle maturation.
  41. Mitochondria at the crossroads of aging and cardiovascular disease.
  42. Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
  43. A Reversible Mitochondrial ROS Probe for Monitoring Mitophagy Dynamics: Development and Application of MitoFlare.
  44. Phospholipase A and acyltransferases as novel regulator of organelle dynamics.
  45. Structural basis of sodium ion-dependent carnitine transport by OCTN2.
  46. MAVS oligomerization drives a faster and more efficient antiviral signaling activation at peroxisomes compared to mitochondria.
  47. Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders.
  48. Involvement of the PINK1/PARKIN pathway in enhancing mitochondrial function and mitophagy in reserpine-induced fibromyalgia mice through strength exercise and coenzyme Q10.
  49. Cholesterol induced-mitochondrial calcium dysregulation facilitates atherosclerosis by promoting lipid accumulation in vascular smooth muscle cells.
  50. Old dogs-new tricks: multifaceted functions of MAVS beyond antivirus activity in human health and diseases.
  51. Modulating RNA condensates to control cell fate.
  52. NADH-Reductive Stress Induced by Dihydrolipoamide Dehydrogenase Activation Contributes to Cuproptosis.
  53. ALDH2 protects against dopaminergic neuronal cell ferroptosis by enhancing the enzyme activity of PRDX6 in Parkinson's disease.
  54. The Rieske iron-sulfur protein is a primary target of molecular hydrogen.
  55. Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
  56. A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
  57. Approaches for identification of 5' UTR mutations impacting translation and protein production from neurodevelopmental disorder genes.
  58. Endoplasmic reticulum, mitochondria, and their crosstalk in retinal ganglion cell degeneration.
  59. REECAP: Contrastive learning of retinal aging reveals genetic loci linking morphology to eye disease.
  60. Protocol for systematic screening of histone H3/H4 mutants to identify histone residues critical for BCAA-dependent replicative lifespan.
  61. Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.
  62. Molecular mechanism of PINK1 regulation by the Hsp90 machinery.
  63. Medium-chain Acyl-CoA Dehydrogenase Deficiency Identified by MS/MS Newborn Screening Challenges.
  64. Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes.
  65. Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
  66. MaveMD: A functional data resource for genomic medicine.
  67. From shadows to clarity: A new paradigm for comprehensive variant detection in undiagnosed dystrophinopathy using combined long-read and RNA sequencing.
  68. Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
  69. Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
  70. An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somite organization.
  71. Tom70-mediated mitochondria-nuclear envelope contacts regulate nuclear pore complex inheritance during gametogenesis.
  72. Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
  1. J Clin Invest. 2025 Dec 01. pii: e187571. [Epub ahead of print]135(23):
    Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
    Laura Sánchez-Benito, Melania González-Torres, Irene Fernández-González, Laura Cutando, María Royo, Joan Compte, Miquel Vila, Sandra Jurado, Elisenda Sanz, Albert Quintana.
      Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.
    Keywords:  Epilepsy; Inflammation; Mitochondria; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/JCI187571
  2. Nat Commun. 2025 Dec 04. 16(1): 10891
    Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.
    Yi Wang, Min Zhao, Hai-Xin Xie, Hao-Yuan Yu, Jing-Song Yang, Lu-Xin Qie, Na-Hui Liu, Jia-Qi Chen, Zi-Juan Yi, Tian-Jiao Zhou, Lei Xing, Xian Wu Cheng, Hu-Lin Jiang.
      Mutations in mitochondrial DNA (mtDNA) lead to various mitochondrial diseases for which no cure is currently available. Despite the promising potential of mtDNA correction to treat these disorders, the double mitochondrial membranes have proven to be a tough barrier to overcome. Here, we develop fluorinated lipid nanoparticles with a mitochondrial targeting sequence (F-M-LNP) to overcome the mitochondrial barrier by virtue of their high affinity for mitochondrial membranes, thereby effectively introducing gene into mitochondria. Through the rational design of ionizable lipid structures, we synthesize 16 lipid nanoparticles (LNPs) with varying degrees of fluorination and investigate the key structural features required for efficient mitochondria-targeted gene delivery. As fluorinated ionizable lipid-mediated mitochondrial transport is independent of mitochondrial membrane potential (MMP), F-M-LNPs deliver gene to mitochondria under pathological conditions where MMP is impaired, resulting in a 3.8-fold increase in functional protein expression compared to non-fluorinated LNPs. In a male mouse model of genetically induced mitochondrial disease, F-M-LNP demonstrate functional complementation of mutant mtDNA, alleviating disease symptoms. Together, our results show that modifying vectors with fluorinated groups offers valuable tools for correcting mitochondrial genome defects.
    DOI:  https://doi.org/10.1038/s41467-025-65874-x
  3. Nat Commun. 2025 Dec 01.
    Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
    J Botella, E Perri, N J Caruana, S López-Calcerrada, M Brischigliaro, N A Jamnick, V Oorschot, N J Saner, J Díaz-Lara, D F Taylor, A Garnham, E Fernández-Vizarra, C Ugalde, G Ramm, D A Stroud, M Lazarou, D J Bishop.
      Exercise is a key lifestyle intervention for mitochondrial health, yet the molecular mechanisms by which different exercise prescriptions regulate mitochondrial remodeling remain unclear. We conducted an open-label counterbalanced randomized controlled trial (ACTRN12617001105336) and observed that sprint-interval exercise (SIE; n = 14), compared to moderate-intensity continuous exercise (MICE; n = 14), induces a mitochondrial stress signature and unfolded protein response (UPRmt). SIE triggers morphological and structural mitochondrial alterations along with activation of the integrated stress response (ISR) and mitochondrial quality control (MQC) pathways. Following eight weeks of training, moderate-intensity continuous training (MICT) increases mitochondrial content, complex I activity, and displays an enrichment of tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) proteins, while sprint-interval training (SIT) improves respiratory function and upregulates pathways involved in 1-carbon metabolism and protein quality control. We identify COX7A2L accumulating in III2 + IV1 supercomplexes only after SIT. These findings elucidate how exercise intensity shapes mitochondrial remodeling, informing tailored exercise prescriptions.
    DOI:  https://doi.org/10.1038/s41467-025-66625-8
  4. Nat Commun. 2025 Dec 03.
    Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
    Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.
      Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.
    DOI:  https://doi.org/10.1038/s41467-025-66656-1
  5. Nat Commun. 2025 Dec 01. 16(1): 10426
    Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
    Su Bin Lee, Bui Thanh Thu, Tae Wook Nam, Yaechan Song, Jae Hoon Lee, Yangsik Jeong, Han-Woong Lee.
      Brown adipocytes facilitate non-shivering thermogenesis, which is critical for maintaining energy balance and heat production in response to environmental stimuli. Here, we delineate the physiological and biochemical role of etoposide-induced 2.4 (Ei24) in adenosine triphosphate (ATP) production and thermogenesis in brown adipocytes. We generated Ei24 adipocyte-specific knockout (EiaKO) mice that exhibited brown adipose tissue hypertrophy, lipid accumulation, and various mitochondrial abnormalities. Despite mitochondrial defects, uncoupling protein 1 (UCP1) expression and activity remained unchanged. However, those impairments caused lethal hypothermia in mice subjected to cold challenge, underscoring the key role of Ei24 in mitochondrial functions. Mechanistically, Ei24 deficiency disrupted cristae structure, dissipated mitochondrial membrane potential, and reduced matrix pH, leading to severe ATP depletion. We further identify the C-terminal region of Ei24 as essential for supporting ATP synthase function. Those bioenergetic defects not only destabilized the mitochondrial environment necessary for efficient UCP1-mediated thermogenesis, but also impaired ATP-dependent futile cycles such as SERCA-mediated calcium cycling and creatine substrate cycling. Together, our findings indicate that Ei24 functions as a thermogenic regulator that ensures mitochondrial ATP synthesis and structural integrity, enabling both coupled and uncoupled respiration in brown adipose tissue.
    DOI:  https://doi.org/10.1038/s41467-025-66460-x
  6. bioRxiv. 2025 Nov 19. pii: 2025.11.19.688750. [Epub ahead of print]
    Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
    Young-Seung Lee, Hee Soo Kim, Phuc L Nguyen, Junhyeong Lee, Dong-Il Kim, Jeongmin Lee, Changjong Moon, Kyoung-Oh Cho, Byung-Eun Kim, Jiyun Ahn, Timothy F Osborne, Taner Duysak, Jeong-Sun Kim, Chang Hwa Jung, Tae-Il Jeon.
      Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.
    DOI:  https://doi.org/10.1101/2025.11.19.688750
  7. Circulation. 2025 Dec 02.
    Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association.
    American Heart Association Council on Genomic and Precision Medicine Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation Council on Cardiovascular and Stroke Nursing Council on Peripheral Vascular Disease
      Metabolic and genetic abnormalities have long been noted in cardiovascular diseases, but the contribution of mitochondrial genetic (mitochondrial DNA [mtDNA]) variation is understudied. Mitochondrial genetics is complex in that each mitochondrion contains multiple mtDNA copies that may carry different variants, which is called heteroplasmy. Heteroplasmic variation is dynamic, increases with advancing age, and may contribute to aging-related cardiovascular diseases. Pathogenic variants in mitochondrial genes of the mtDNA or nuclear genome cause mitochondrial diseases, often with cardiac involvement, particularly in patients with adult-onset disease. Population-level studies have identified mtDNA variants associated with cardiovascular risk factors and disease, but evaluation of mtDNA genetic variation is often limited to only a handful of variants and small sample sizes. Studies in animal models have linked several mtDNA variants to cardiac remodeling and dysfunction and suggest a role for mitochondrial-nuclear genetic interactions in disease penetrance. The objective of this scientific statement is to outline the current state of understanding of the role of mitochondrial genetics in cardiovascular pathobiology and highlight important gaps in knowledge. The intended audience of this scientific statement is meant to be broad, spanning clinical, translational, and basic researchers and health care professionals. Despite remaining limitations and barriers, recent advances in genomic sequencing, mtDNA gene editing modalities, and the directed differentiation of stem cells to cardiovascular cell types are creating new opportunities to advance understanding of mitochondrial genetics in cardiovascular pathophysiology.
    Keywords:  AHA Scientific Statements; DNA, mitochondrial; cardiovascular diseases; genes, mitochondrial; mitochondria
    DOI:  https://doi.org/10.1161/CIR.0000000000001393
  8. Nat Commun. 2025 Dec 01. 16(1): 10817
    Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
    Mrityunjoy Mondal, Enzo Scifo, Rossella Erminia Ciliberti, Lena Wischhof, Tannaz Norizadeh Abbariki, Joshua Jackson, Ioanna-Maria Menegatou, Viktoria Zeisler-Diehl, Jan Riemer, Benjamin Jussila, Christopher E Hopkins, Sylwia Kierszniowska, Lukas Schreiber, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
      Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1038/s41467-025-66900-8
  9. Mol Cell Biochem. 2025 Dec 01.
    Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
    Chuanlong Zhang, Xiaoxia Zheng, Lijuan Xiang, Zhanguo Su.
      The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.
    Keywords:  Aging muscle; Exercise; Mitochondrial diseases; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s11010-025-05441-6
  10. Nat Struct Mol Biol. 2025 Dec 03.
    Translational activators align mRNAs at the small mitoribosomal subunit for translation initiation.
    Joseph B Bridgers, Andreas Carlström, Dawafuti Sherpa, Mary T Couvillion, Urška Rovšnik, Jingjing Gao, Bowen Wan, Sichen Shao, Martin Ott, L Stirling Churchman.
      Mitochondrial gene expression is essential for oxidative phosphorylation. Mitochondrial-encoded mRNAs are translated by dedicated mitochondrial ribosomes (mitoribosomes), whose regulation remains elusive. In Saccharomyces cerevisiae, nuclear-encoded mitochondrial translational activators (TAs) facilitate transcript-specific translation by a yet unknown mechanism. Here, we investigated the function of TAs containing RNA-binding pentatricopeptide repeats using selective mitoribosome profiling and cryo-electron microscopy (cryo-EM) structural analysis. These analyses show that TAs exhibit strong selectivity for mitoribosomes initiating on their target transcripts. Moreover, TA-mitoribosome footprints indicate that TAs recruit mitoribosomes proximal to the start codon. Two cryo-EM structures of mRNA-TA complexes bound to mitoribosomes stalled in the post-initiation, pre-elongation state revealed the general mechanism of TA action. Specifically, the TAs bind to structural elements in the 5' untranslated region of the client mRNA and the mRNA channel exit to align the mRNA in the small subunit during initiation. Our findings provide a mechanistic basis for understanding how mitochondria achieve transcript-specific translation initiation without relying on general sequence elements to position mitoribosomes at start codons.
    DOI:  https://doi.org/10.1038/s41594-025-01726-y
  11. J Inherit Metab Dis. 2026 Jan;49(1): e70119
    Human d-Glycerate Kinase, Encoded by GLYCTK and Deficient in d-Glyceric Aciduria, Is a Mitochondrial Enzyme.
    Anne Korwitz-Reichelt, Daniel Schulke, Melanie Walter, Jörn Oliver Sass.
      d-glyceric aciduria is a very rare inborn error of serine and fructose metabolism which is caused by d-glycerate kinase (GLYCTK) deficiency. So far, 18 individuals with this tentative diagnosis have been reported. Patients present with a wide range of clinical phenotypes, but asymptomatic cases have also been described. Given the highly variable clinical outcomes it has been suggested that d-glycerate kinase deficiency may be a mere biochemical variant rather than a disease. Previously, it was proposed and widely distributed in public databases, that two GLYCTK isoforms, which result from alternative splicing, are ubiquitously expressed in human tissues. It was further stated that the two isoforms are differentially localized in the cytosol and in mitochondria. Here, we show that human GLYCTK exclusively localizes to mitochondria. We propose that mitochondrial GLYCTK represents the functional enzyme and that the second transcript variant is nonfunctional under physiological conditions.
    Keywords:  GLYCTK; cytosol; d‐glycerate kinase deficiency; d‐glyceric aciduria; fructose; inborn errors of metabolism; mitochondria
    DOI:  https://doi.org/10.1002/jimd.70119
  12. Intractable Rare Dis Res. 2025 Nov 30. 14(4): 249-257
    Mitochondrial DNA A3243G variant: Current perspectives and clinical implications.
    Kuan-Yu Chu.
      The mitochondrial DNA A3243G variant, located in the MT-TL1 gene encoding tRNALeu(UUR), represents one of the most clinically significant pathogenic mitochondrial mutations. This point mutation accounts for approximately 80% of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) syndrome cases and is the primary cause of Maternally Inherited Diabetes and Deafness (MIDD) syndrome. The clinical spectrum associated with this mutation ranges from asymptomatic carriers to severe multisystem disease with early mortality. The pathophysiology involves impaired mitochondrial protein synthesis leading to respiratory chain dysfunction, with phenotypic expression determined by heteroplasmy levels and tissue-specific energy demands. Understanding the complex inheritance patterns, genetic bottleneck effects during oogenesis, and heteroplasmy variations is crucial for comprehending the variable clinical presentations observed in affected families. Histological examination reveals characteristic features including ragged-red fibers, cytochrome c oxidase-deficient fibers, and abnormal mitochondrial proliferation. Current therapeutic approaches focus on metabolic support, antioxidant therapy, and management of specific complications, with L-arginine showing promise for stroke-like episodes. However, careful attention to drug safety profiles and potential mitochondrial toxicity is essential in treatment planning. Understanding the diverse clinical manifestations and implementing appropriate screening strategies are crucial for early diagnosis and optimal patient management. This review synthesizes current knowledge regarding the A3243G variant's pathophysiology, clinical features, diagnostic approaches, and therapeutic interventions.
    Keywords:  MELAS syndrome; heteroplasmy; lactic acidosis; mitochondrial DNA (mtDNA); point mutation; transfer RNA (tRNALeu(UUR))
    DOI:  https://doi.org/10.5582/irdr.2025.01051
  13. Eur Heart J Imaging Methods Pract. 2025 Oct;3(4): qyaf134
    Cardiac magnetic resonance findings in mitochondrial disease: a guide for clinicians.
    Rhys Gray, Vasiliki Kantartzı, Luis R Lopes, Konstantinos Savvatis, Mark Westwood.
      Mitochondrial myopathies are heritable conditions caused by genetic variations in mitochondrial DNA or nuclear DNA. These result in dysfunctional cellular oxidative phosphorylation and ATP production, affecting organs with high-energy requirements such as the heart, brain and skeletal muscle. Cardiac involvement is common affecting one third of patients and includes left ventricular hypertrophy, conduction disease, Wolff-Parkinson-White syndrome, and dilated cardiomyopathy. Due to the variability in the clinical presentation, a multiparametric approach incorporating clinical, biochemical, histological/histochemical and genetic criteria is required to make the diagnosis. Cardiologists should be aware of the clinical red flags and imaging findings and how to differentiate mitochondrial cardiomyopathy from other causes of left ventricular hypertrophy. Cardiovascular magnetic resonance imaging is a highly sensitive tool for depicting myocardial abnormalities to aid in both the diagnosis of patients presenting with left ventricular hypertrophy, and in the assessment of cardiac involvement in patients with a known diagnosis of mitochondrial myopathy, as this is an independent predictor of morbidity and early mortality. The most common CMRI findings include increased maximal LV wall thickness and mass and non-ischaemic subepicardial and midwall LGE, most commonly affecting the basal inferolateral or lateral wall. Future studies should consider integrating late gadolinium enhancement imaging into risk prediction models to enhance stratification of major adverse cardiac events such as heart failure and arrhythmia. As our understanding of mitochondrial disease evolves, integrating advanced imaging with molecular diagnostics will be essential for early detection of disease, improved risk prediction and outcomes.
    Keywords:  cardiac MRI; mitochondria myopathy; mitochondrial cardiomyopathy; mitochondrial disease
    DOI:  https://doi.org/10.1093/ehjimp/qyaf134
  14. PLoS Genet. 2025 Dec 03. 21(12): e1011562
    Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.
    Qin Xie, Haibo Wu, Jiaxin Qiu, Junbo Liu, Xueyi Jiang, Huihui Wu, Qifeng Lyu, Hui Long, Wenzhi Li, Shuo Zhang, Yuxiao Zhou, Yining Gao, Aaron J W Hsueh, Yanping Kuang, Lun Suo.
      Mutations in mitochondrial DNA (mtDNA) can lead to mitochondrial and cellular dysfunction. However, recent studies suggest that purifying selection acts against mutant mtDNAs during transgenerational transmission. We investigated the mtDNA dynamics during ovarian follicle development. Using base-editing, we generated mice harboring a 3177 G > A mutation corresponding to the human Leber hereditary optic neuropathy (LHON)-related mtDNA mutation and confirmed a transgenerational reduction of the mutant mtDNA. Utilizing a mouse follicle culture system in which pathogenic mtDNA mutations were introduced in vitro, followed by mtDNA sequencing and digital PCR, we found that the germline heteroplasmy shift during early folliculogenesis was driven by a decrease in mutant mtDNA along with compensatory replication of wild-type mtDNA. In contrast, synonymous mtDNA mutations did not affect mtDNA dynamics. These findings demonstrate that mice can eliminate certain pathogenic mtDNA mutations in the germline during early folliculogenesis, thus advancing our understanding of mtDNA purifying selection during oogenesis. Furthermore, our use of mtDNA editing in in vitro-cultured follicles provides a novel approach to create and monitor mitochondrial DNA mutations.
    DOI:  https://doi.org/10.1371/journal.pgen.1011562
  15. Acta Neuropathol Commun. 2025 Dec 03.
    Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
    Eva D Ruiz-Ortega, Anna Wilkaniec, Josué Juárez, Agata Adamczyk.
      Parkinson's disease (PD) is defined by the progressive loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-syn), yet the molecular determinants of selective neuronal vulnerability remain unresolved. Increasing evidence implicates mitochondria-and particularly their membranes-as critical platforms where α-syn is toxic. This review highlights how α-syn engages mitochondrial membranes through two interconnected processes: classical aggregation and liquid‒liquid phase separation. Both pathways disrupt membrane architecture, compromise respiratory chain function, and impair mitophagy. A pivotal mediator of these events is cardiolipin (CL), a mitochondria-specific phospholipid essential for cristae organization and quality control pathways. Despite extensive progress, the precise mechanistic contributions of CL to α-syn aggregation, phase transitions, and neuronal degeneration remain poorly defined. Clarifying this interplay is crucial, as CL not only binds α-syn with high affinity but also determines whether it remains in a functional state or progresses toward toxic assemblies. By integrating recent advances, we propose a unifying perspective on CL as a molecular switch at the crossroads of mitochondrial biology, protein aggregation, and phase behavior. Beyond mechanistic insight, this view underscores the potential of CL as a target for the development of mitochondria-directed therapies in PD.
    Keywords:  Alpha-synuclein; Cardiolipin; Liquid‒liquid phase separation; Mitochondrial dysfunction; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40478-025-02190-x
  16. J Mol Cell Biol. 2025 Dec 02. pii: mjaf047. [Epub ahead of print]
    Slirp2 modulates oogenesis via regulating mitochondrial protein translation.
    Jinguo Cao, Jiting Zhang, Zhaoqi Wu, Wei Luan, Yue Zhou, Huihui Huang, Lingling Li, Wen Hu.
      Mitochondria are essential organelles responsible for generating ATP through oxidative phosphorylation (OXPHOS). Despite having their own genome, mitochondria rely on a complex interplay with nuclear-encoded proteins to maintain their function, as mutations in these proteins can lead to mitochondrial dysfunction and associated diseases. Mutations in the SLIRP (stem-loop interacting RNA-binding protein) gene are known to cause severe human mitochondrial diseases, and loss of SLIRP function can impair mitochondrial mRNA stability and translation. However, in vivo roles of the SLIRP protein remain inadequately understood. Drosophila melanogaster serves as a powerful model for studying mitochondrial function, particularly in the context of reproductive system development and gametogenesis. In this study, we focus on the role of the fly Slirp2 in oogenesis. Loss of Slirp2 impairs mitochondrial protein synthesis, leading to reduced OXPHOS efficiency, diminished ATP production, and disrupted insulin/mTOR signaling. These defects ultimately promote reactive oxygen species-induced programmed cell death, resulting in infertility. Our findings provide novel insights into the mechanistic role of Slirp2 in mitochondrial function and reproductive biology in vivo. We demonstrate that Slirp2 exhibits species-specific regulation of mitochondrial translation, revealing its complex, context-dependent function. These results have broader implications for understanding mitochondrial diseases, suggesting that the effects of Slirp2 mutations may vary across different organisms and tissue types.
    Keywords:  SLIRP; Slirp2; mitochondrial diseases; oogenesis
    DOI:  https://doi.org/10.1093/jmcb/mjaf047
  17. Sci Adv. 2025 Dec 05. 11(49): eaea8481
    Targeting multiple genetic defects of mitochondrial diseases with a single bacterial lipoate protein ligase.
    Zhijuan Hu, Junru Yu, Ziwei Liu, Min Jiang, An-Ping Zeng.
      Metabolic disorders caused by defects in energy metabolism can lead to many life-threatening diseases; their therapy remains elusive in most cases. Conventional gene therapy relies on the "one gene for one genetic defect" strategy. Here, we demonstrate a more efficient strategy to target multiple genetic defects with a single gene intervention. Specifically, we used a bacterial lipoate protein ligase involved in protein lipoylation to rescue mitochondrial dysfunctions in human lipoylation pathway (LIPT2, LIAS, and LIPT1), lipoyl precursor supply (MECR), and sulfur insertion accessary partner (FDX1). The efficacy and safety of Escherichia coli-derived LplA or Bacillus subtilis-derived LplJ were validated in human cells and mouse models. LplA knock-in mice exhibited normal health with enhanced energy expenditure. Overexpressing LplA through a mating strategy rescued embryonic lethality in Lipt1-/- mutants, yielding viable offspring with normal body weight, energy expenditure, tissue morphology, and biochemical profile. Our work highlights how evolutionary differences in biosynthetic pathways between humans and bacteria can be leveraged for cross-species therapeutic innovations.
    DOI:  https://doi.org/10.1126/sciadv.aea8481
  18. Eur J Pharmacol. 2025 Dec 03. pii: S0014-2999(25)01187-2. [Epub ahead of print] 178433
    Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.
    Xihang Piao, Xiaolei Tang, Li Li, Ying Zhang, Haiyan Li.
      Stroke remains a leading cause of death and long-term disability worldwide. Although revascularization therapies have transformed acute care, effective neuroprotective strategies are still lacking. Intercellular mitochondrial transfer has recently gained attention as a promising endogenous repair mechanism. Through tunneling nanotubes, extracellular vesicles, or cell fusion, healthy mitochondria can be transferred from donor to recipient cells, helping restore bioenergetic homeostasis in injured neurons. This phenomenon, functionally comparable to organelle-level metabolic rescue, offers several advantages. It avoids the ethical concerns associated with genetic manipulation, leverages intrinsic intercellular communication for targeted delivery, and provides mitochondrial DNA complementation to correct metabolic defects. Here, we integrate current evidence on the cellular sources, transfer routes, and regulatory mechanisms underlying poststroke mitochondrial exchange; delineate the coordinated contributions of astrocytes, mesenchymal stem cells, microglia, and endothelial cells to this process; and critically evaluate its translational promise alongside the key barriers that must be addressed for successful clinical application.
    Keywords:  Mitochondrial transfer; multicellular cooperation; stroke; therapeutic strategies; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178433
  19. Mol Biol Rep. 2025 Dec 01. 53(1): 143
    Molecular mechanisms of mitochondrial function in neurodegenerative diseases.
    Heather M Wilkins, Simone Patergnani.
      Mitochondria regulate cellular homeostasis and function in both neurons and glial cells, but molecular mechanisms are not fully understood. Recent advances have expanded our understanding of how mitochondrial dynamics, quality control, bioenergetics, redox regulation, and proteostasis contribute to neurodegenerative processes. The collection "Neuroscience: Mitochondrial Function in Neurons and Glia" highlights the pivotal role of mitochondria in energy production, redox signaling, calcium buffering, and apoptosis. Articles within this collection discuss the effects of mitochondria in neurodegeneration. Together, these studies emphasize ongoing challenges in defining cell type specific mitochondrial responses and point to the need for improved strategies to target mitochondrial dysfunction in neurological disease.
    DOI:  https://doi.org/10.1007/s11033-025-11303-7
  20. PLoS Biol. 2025 Dec;23(12): e3003075
    Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival.
    Athena L Munden, Arjamand Mushtaq, Dominique S Lui, Katherine M Edwards, Daniel P Higgins, Kasturi Biswas, Rachel M Walker, Leah H Crowley, Matthew J Fanelli, Thien-Kim Ngyuen, Maria Ericsson, Adwait A Godbole, John A Haley, Caroline A Lewis, Jessica B Spinelli, Benjamin Harrison, Daniel Raftery, Danijel Djukovic, Daniel E L Promislow, Dana L Miller, Amy K Walker.
      S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.
    DOI:  https://doi.org/10.1371/journal.pbio.3003075
  21. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2523019122
    Neuromodulatory control of energy reserves in dopaminergic neurons.
    Camila Pulido, Matthew S Gentry, Timothy A Ryan.
      The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson's disease, a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics. In skeletal muscle, energy homeostasis under varying demands is achieved in part by its ability to rely on glycogen as a fuel store, whose conversion to ATP is under hormonal regulatory control. In neurons, however, the absence of easily observable glycogen granules has cast doubt on whether this fuel store is operational, even though brain neurons express the key regulatory enzymes associated with building or burning glycogen. We show here that in primary mid-brain dopaminergic neurons, glycogen availability is under the control of dopamine autoreceptors, such that dopamine itself provides a signal to store glycogen. We find that when glycogen stores are present, they provide remarkable resilience to dopamine nerve terminal function under extreme hypometabolic conditions, but loss of this dopamine-derived signal, or impairment of access to glycogen, makes them hypersensitive to fuel deprivation. These data show that neurons can use an extracellular cue to regulate local metabolism and suggest that loss of dopamine secretion might make dopamine neurons particularly subject to neurodegeneration driven by metabolic stress.
    Keywords:  ATP; dopamine; glycogen; synapse
    DOI:  https://doi.org/10.1073/pnas.2523019122
  22. Circ Res. 2025 Dec 05. 137(12): 1404-1406
    Ca²⁺ in the Mitochondrial Intermembrane Space: A New Compartment Fueling Arrhythmias.
    Luis A Gonano, Cecilia Mundiña-Weilenmann.
      
    Keywords:  Editorials; arrhythmias, cardiac; calcium; calcium signaling; mitochondria, heart; ryanodine receptor calcium release channel; sarcoplasmic reticulum
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327610
  23. Eye (Lond). 2025 Nov 29.
    Advanced therapies for inherited optic neuropathies.
    David Chuen Soong Wong, Rahul Makam, Patrick Yu-Wai-Man.
      Inherited optic neuropathies (IONs), such as Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), typically lead to irreversible severe vision loss due to mitochondrial dysfunction causing retinal ganglion cell degeneration. Although current treatment options are limited, substantial progress has been made recently in our understanding of the molecular genetic pathways that lead to retinal ganglion cell loss. Clinical trials for LHON have demonstrated the efficacy of idebenone, an oral neuroprotective agent, and gene replacement therapy using allotopic gene expression. Early phase clinical trials are underway for ADOA caused by variants in the nuclear gene OPA1 using innovative techniques to modulate gene expression in a variant-agnostic manner. In this review, we have critically appraised a range of therapeutic strategies, including gene editing and stem cell-based optic nerve regeneration, with a discussion of the barriers to translation. Future studies focussing on understanding genetic heterogeneity, disease variability and optimising patient selection for clinical trials are essential to improve patient management and fast track transformative therapies for IONs.
    DOI:  https://doi.org/10.1038/s41433-025-04109-1
  24. Front Neurol. 2025 ;16 1665315
    Receptor-mediated mitophagy: a new target of neurodegenerative diseases.
    Junlan Yang, Fuquan Yang, Guiyan Chen, Ming Liu, Shiqing Yuan, Tian-E Zhang.
      Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.
    Keywords:  PINK1/Parkin-independent mitophagy; autophagy receptors; mitochondria; mitochondrial dysfunction; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fneur.2025.1665315
  25. Clin Case Rep. 2025 Dec;13(12): e71532
    Mitochondrial Disease Diagnosed Following Preterm Birth at 29 Weeks of Gestation and Postpartum Heart Failure: A Case Report and Literature Review.
    Tomoyuki Watanabe, Gen Ishikawa, Tsutomu Tabata.
      In some cases, mitochondrial disease can remain undiagnosed until pregnancy reveals systemic symptoms. Clinicians should therefore consider this diagnosis in young patients presenting with diabetes, kidney disease, and hearing loss. Early diagnosis can improve maternal and fetal outcomes, particularly in high-risk pregnancies complicated by unexplained preterm birth or cardiomyopathy.
    Keywords:  diabetes mellitus; mitochondrial DNA; mitochondrial diseases; pregnancy; premature birth
    DOI:  https://doi.org/10.1002/ccr3.71532
  26. Parkinsonism Relat Disord. 2025 Nov 25. pii: S1353-8020(25)00882-X. [Epub ahead of print] 108133
    Protective or Pathogenic? Kinase activity and the neurodevelopmental origins of G2019S LRRK2-Associated Parkinson's disease.
    Emilia M Gatto, Alberto J Espay, Melisa Espindola, Gustavo Da Prat, Marcelo A Kauffman.
      Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common monogenic cause of Parkinson's disease (PD), with the p.Gly2019Ser (G2019S) variant being particularly prevalent. The LRRK2 gene encodes a large, multi-domain protein (LRRK2) belonging to the Roco family, possessing both kinase and GTPase activities. Because normal LRRK2 function is critical for neuronal development, synaptic plasticity, vesicle trafficking, mitochondrial homeostasis, and neuroinflammatory pathways, pathogenic LRRK2 variants likely impair these functions. This is supported by rodent models and induced pluripotent stem cell (iPSC) studies suggesting that G2019S LRRK2 variants accelerate neuronal differentiation and disrupt synaptic function early in development, while kinase overactivity (phosphorylation of various substrates) is critical during normal embryonic growth. Contrary to the dominant gain-of-toxic-function hypothesis, these observations support an alternative loss-of-function framework, whereby increased kinase activity may be a compensatory cellular strategy to counteract the loss or alteration of the homeostatic and neurodevelopmental functions associated with G2019S LRRK2. If validated by further studies, including ongoing LRRK2 kinase inhibitor trials, future LRRK2-PD therapeutic strategies may shift from broad kinase inhibition toward individualized modulation of specific LRRK2-mediated impairments, such as vesicle trafficking, mitochondrial integrity, or microglial dysfunction. Such an approach would recognize LRRK2-PD not as a single entity but as a biologically heterogeneous group of PD subtypes.
    Keywords:  G2019S LRRK2; Mitochondrial dysfunction; Neurodegeneration; Neurodevelopment; Neuroinflammation; Parkinson's disease; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.parkreldis.2025.108133
  27. Can J Cardiol. 2025 Dec 02. pii: S0828-282X(25)01556-9. [Epub ahead of print]
    Fontan Circulation Beyond Preload: Metabolic Pathways and Mitochondrial Stress.
    Ashish H Shah.
      
    Keywords:  Fontan circulation; mitochondrial dysfunction; multi-omics
    DOI:  https://doi.org/10.1016/j.cjca.2025.11.046
  28. Res Sq. 2025 Nov 17. pii: rs.3.rs-8077579. [Epub ahead of print]
    Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
    Adam Antebi, Wenming Huang, Jonathan Kölschbach, Anna Loehrke, Hormos Dafsari, Emily Baum, Chun Kew, Ivan Dikic.
      Spliceosomal dysfunction profoundly impacts cellular metabolism, yet mechanistic links between RNA splicing defects and metabolic rewiring remain limited. Here, we investigate Verheij syndrome (VRJS), a rare disease caused by mutations in the core splicing factor PUF60 . Using a Caenorhabditis elegans model, human cell lines, and patient-derived samples, we demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, culminating in impaired S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental and growth defects. Vitamin B12 (VB12) supplementation restores metabolic balance by reactivating SAM-dependent phospholipid remodelling and mTORC1 activity, effectively rescuing VRJS-like phenotypes. Similar metabolic responses arise from perturbations in other spliceosomal factors such as PRPF19/PRP-19, indicating a conserved mechanism across spliceosomopathies. Interestingly, we identify intron retention of the nhr-114/HNF4 transcription factor as a primary driver of growth defects, and restoring its splicing robustly suppresses these phenotypes. Our findings establish a mechanistic connection between RNA splicing and lipid metabolism, implicating VB12-dependent one-carbon metabolism as a metabolic modulator with broad implications for spliceosome-related diseases, and suggesting VB12 as a potential strategy to mitigate VRJS-related anomalies.
    DOI:  https://doi.org/10.21203/rs.3.rs-8077579/v1
  29. Nat Commun. 2025 Nov 29.
    Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
    Carla Pernaci, Avalon Johnson, Sydney Gillette, Anna S Warden, Chad McCormick, Sammy Weiser-Novak, Gabriela Ramirez, Emily H Broersma, Priyanka Mishra, Anusha Sivakumar, Stephanie Cherqui, Nicole G Coufal.
      Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.
    DOI:  https://doi.org/10.1038/s41467-025-66710-y
  30. Nat Commun. 2025 Dec 02.
    Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group
      We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.
    DOI:  https://doi.org/10.1038/s41467-025-65845-2
  31. Cell Cycle. 2025 Dec 01. 1-6
    The curvature code: BCL-w dimers rewire BAX-BCL-2 control of mitochondrial fate and apoptosis.
    Gaetano Santulli.
      
    DOI:  https://doi.org/10.1080/15384101.2025.2597275
  32. J Vis Exp. 2025 Nov 14.
    Assessment of Mitochondrial Fission/Fusion Dynamics in Kidney Proximal Tubular Cells.
    Vikky Awasthi, Sulaiman Qamar Sharief, Meriem Bkhache, Aasthika Das, Rihab Bouchareb.
      Mitochondria are best recognized for their role in ATP synthesis and serve as key regulators of cellular metabolism. Mitochondrial dynamics comprehend the intracellular and intercellular movement of mitochondria, as well as the processes of fission/fusion. These events are fundamental to maintaining mitochondrial function by maintaining cellular homeostasis, morphology, bioenergetics, quality control, and stress responses. On the other hand, dysregulation of mitochondrial dynamics impacts cellular morphology and function. Precise measurement of mitochondria fission/fusion events can be indicative of cellular health. Current methodologies to measure mitochondria dynamics employ advanced imaging like super-resolution microscopy, fluorescence techniques (Fluorescence Recovery After Photobleaching (FRAP)) for connectivity, and optogenetic tools for spatiotemporal control. Quantitative analysis utilizes computational tools to measure parameters like length, number, and branching, which indicate fission/fusion balance. However, these methods require skills and sophisticated instruments. In this article, we describe the use of confocal microscopy combined with free-to-use tools in ImageJ (Fiji) to study fission/fusion events using the photo-switching property of the dendra2 protein, tagged to mitochondrial cytochrome c.
    DOI:  https://doi.org/10.3791/69268
  33. Nat Commun. 2025 Dec 05.
    Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
    Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.
      The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-66901-7
  34. Front Mol Neurosci. 2025 ;18 1628567
    Hypoxic preconditioning increases mitochondrial respiration and H2O2 production.
    Lisa Bergmeister, Carolina Doerrier, Barbara Fogli, Tímea Komlódi, Amrei Fischer, Kerstin Springer, Christoph Schwarzer, Erich Gnaiger.
       Introduction: Hypoxia, an inadequate tissue oxygen supply, poses a threat to the brain, which relies heavily on oxygen for its energy requirements. However, mild oxygen deficiency triggers cellular stress, leading to a defensive state known as hypoxic preconditioning (HPC). Despite its potential as a treatment option for neurodegenerative diseases, research on preconditioning remains a challenge. Therefore, this study aimed to further explore biochemical changes induced by HPC, with a specific emphasis on mitochondria, the primary oxygen consumers.
    Methods: We assessed the neuroprotective impact of a HPC protocol used by examining the seizure thresholds of mice. Additionally, we analyzed mitochondrial respiration under varying oxygen levels, reactive oxygen species (ROS) production, and mitochondrial morphology following HPC treatment.
    Results: HPC treatment of mice raised their seizure threshold, indicating an enhanced resistance to epileptic seizures and highlighting the protective effects of the HPC protocol. HPC increased mitochondrial oxygen consumption and ROS production, primarily originating from Complex I. Importantly, ROS levels remaining within the physiological range potentially activate cell signaling pathways. Our findings underscored the importance of controlling oxygen at physiologically relevant intracellular tissue levels (intracellular tissue normoxia) during mitochondrial respiration measurements. Notably, HPC-treated mitochondria generally exhibited reduced oxygen consumption compared to controls under effectively hyperoxic air-saturated oxygen conditions. However, mitochondrial respiration was increased under intracellular tissue normoxia in comparison to the controls measured at air saturation. Moreover, following HPC treatment, we observed alterations in mRNA expression levels associated not just with mitochondrial dynamics but also with perinuclear mitochondrial accumulation and pro-survival signaling. Furthermore, an immediate increase in mitochondrial fusion was observed following hypoxia treatment.
    Keywords:  epilepsy; high-resolution respirometry; hypoxia; hypoxic preconditioning; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3389/fnmol.2025.1628567
  35. Sci Rep. 2025 Dec 02. 15(1): 43031
    Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.
    Jiaying Zhao, Bowen Xu, Tianhui Huang, Sewanou Hermann Honfo, Caroline Trumpff, Martin Picard, Alan A Cohen, Molei Liu.
      Mitochondrial disease (MitoD), a clinical condition caused by genetic mitochondrial defects, affects cellular energy transformation and alters multiple dimensions of health. Recently, we collected a longitudinal saliva proteomics data set consisting of six healthy controls and six MitoD subjects throughout the awakening response process. We undertook three independent unsupervised or inferential approaches to characterize proteome dynamics and assessed their ability to separate MitoD individuals from controls. First, we designed a permutation test to detect the global difference in the proteomic co-regulation structure between healthy and unhealthy subjects. Second, we performed non-linear embedding and cluster analysis on elasticity to capture a more complicated relationship between health and the proteome. Third, we developed a machine learning algorithm to extract low-dimensional representations of the proteome dynamic and use them to cluster subjects into healthy and unhealthy groups without any knowledge of their true status. All three methods showed clear differences between MitoD individuals and controls. Our results revealed a significant and consistent association between MitoD status and the saliva proteome at multiple levels during the awakening response, including its dynamic change, co-regulation structure, and elasticity. Pipelines such as those shown here are the first step toward establishing interpretable and accurate framework for detecting signals related to mitochondrial disease progression from proteome dynamics.
    DOI:  https://doi.org/10.1038/s41598-025-23879-y
  36. medRxiv. 2025 Nov 22. pii: 2025.11.18.25338158. [Epub ahead of print]
    Modeling Familial MASH by iPSC-Hepatocytes.
    Cristina Esteva-Font, Jacquelyn J Maher, Eric Rulifson, Mark Pabst, Nathan Bass, Holger Willenbring, Aras N Mattis.
      Increasing obesity has led to a vast rise in metabolic dysfunction-associated steatotic liver disease (MASLD) in the general population with a significant fraction progressing to metabolic dysfunction-associated steatohepatitis (MASH). Patients with MASH progressively develop inflammation and fibrosis that over time can develop into cirrhosis with an increased risk for hepatocellular carcinoma. Despite the study of human hepatoma lines and development of numerous mouse models to dissect this disease, none of these truly function as a preclinical platform for the human disease. To faithfully model this disease pathogenesis, we identified several families with a genetic predisposition for MASH identified via the clinic, reprogramed their skin fibroblasts into induced pluripotent stem cells (iPSCs) and differentiated these to hepatocytes (iHeps). Focusing on one family, and compared to control iHeps, this MASH family showed increased baseline steatosis. Whole exome sequencing revealed the presence of numerous single nucleotide polymorphisms (SNP) of unclear significance. Interestingly these patients were heterozygous for the transmembrane 6 superfamily member 2 (TM6SF2) E167K SNP. We further analyzed these iHeps for spontaneous steatosis, apoptosis, mitochondrial function, and ER stress. Our findings illustrate the complexity of human genetic MASH patients but also highlights the power of using iHeps to characterize complex human diseases.
    DOI:  https://doi.org/10.1101/2025.11.18.25338158
  37. Sci Rep. 2025 Dec 01. 15(1): 42939
    Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
    Maureen Yin, Eva M Palsson-McDermott, Órlaith C Henry, Ziqian Ge, Juliana E Toller-Kawahisa, Yukun Min, Anne F McGettrick, Adam L Gordon, Stella B Heffernan, Laura Marrone, Bryan P Marzullo, Katherine L Eales, Sally A Clayton, Daniel A Tennant, Richard K Porter, Luke A J O'Neill.
      Mitochondrial glutathione (mtGSH) supports iron-sulfur cluster (ISC) stability in the electron transport chain (ETC). Here we have investigated the role of the mtGSH transporter SLC25A40 in macrophage activation. SLC25A40 is present in both murine and human macrophages and its expression was increased by LPS treatment. Reducing SLC25A40 expression using siRNA destabilized ISC-rich ETC proteins and elevated mitochondrial and cellular reactive oxygen species (ROS). It also induced expression of the genes Gclc and Gclm, which are involved in GSH biosynthesis. SLC25A40 deficiency also diminished IL-1β and IL-10 production at the transcriptional level in response to LPS. As a result, the production of mature IL-1β was decreased following activation of NLRP3 by nigericin or ATP, with no effect on pyroptosis. Depleting mtGSH with mitochondrially-targeted CDNB phenocopied these defects, whereas supplementation with a cell-permeable GSH ester partially restored pro-IL-1β production. Together, these data identify SLC25A40 as a key regulator that sustains ETC integrity to promote cytokine production, revealing a previously unrecognized role for the SLC25A40-mtGSH axis in coupling mitochondrial redox control to macrophage activation.
    Keywords:  Cytokine; Electron transport chain (ETC); Glutathione (GSH); Macrophage immunometabolism; Mitochondria; SLC25A39/40
    DOI:  https://doi.org/10.1038/s41598-025-30333-6
  38. Cell Metab. 2025 Dec 03. pii: S1550-4131(25)00486-3. [Epub ahead of print]
    Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
    Yan Huang, Biao Hu, Ya Liu, Ling-Qi Xie, Yu Dai, Yu-Ze An, Xin-Yi Peng, Ya-Lun Cheng, Yi-Fan Guo, Wei-Hong Kuang, Yao Xiao, Xin Chen, Yong-Jun Zheng, Gen-Qing Xie, Jian-Ping Wang, Hui Peng, Xiang-Hang Luo.
      Excessive exercise impairs cognitive function, but the underlying mechanism remains unclear. Here, we show that excessive vigorous exercise-induced lactate accumulation stimulates muscles to secrete mitochondria-derived vesicles (MDVs), driving cognitive impairment. These MDVs (named otMDVs) are characterized by high mtDNA levels and the surface marker PAF. They tend to migrate into hippocampal neurons, substituting endogenous mitochondria and triggering a synaptic energy crisis. Mechanistically, otMDVs release mtDNA, which activates cGAS-STING-dependent inhibition of kinesin family member 5, preventing hippocampal mitochondria from transporting to synapses. Simultaneously, the otMDV marker PAF cooperates with syntaphilin to occupy mitochondrial anchoring sites, impairing synaptic energy supply. Blocking otMDVs migration into the hippocampus with a PAF-neutralizing antibody alleviates excessive vigorous exercise-induced synapse loss and cognitive dysfunction. Notably, human studies link high circulating otMDV levels to cognitive impairment. Together, our findings reveal that a unique muscle-derived MDV subpopulation, which displaces hippocampal mitochondria and disrupts their function, causes cognitive decline.
    Keywords:  MDVs; cognitive decline; excessive vigorous exercise
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.002
  39. bioRxiv. 2025 Nov 21. pii: 2025.11.20.689615. [Epub ahead of print]
    Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.
    Jose Cevallos, Elena Eubanks, Sunghoo Jung, Yiming Huang, Elyse Guadagno, Neeharika Rao Suvvari, Aryan Doshi, Nitya Ravinutala, Alejandro Mosera, Nagendran Ramalingam, Arati Tripathi, Tim Bartels, Ulf Dettmer, Eleanna Kara.
      Alpha-synuclein (αSyn) inclusions, termed Lewy bodies, are the characteristic neuropathological feature of Parkinson's disease. Growing evidence points towards a role of aberrant liquid-liquid phase separation in the dysregulation of αSyn and sequence of events that lead to the formation of Lewy bodies. However, the triggers leading to aberrant phase separation are unknown, as is the relevance of this phenomenon to the neurodegeneration process. In this study, we showed that αSyn spontaneously phase separates into condensates in the presence of lipid droplets. These lipid droplet-rich condensates represent a toxic species of αSyn that prevents the turnover of the entrapped lipid droplets; they are also toxic to neighbouring mitochondria which are depolarized and undergo increased mitophagy. These findings underscore the increasing importance of lipid droplets in the pathogenesis of neurodegenerative diseases, and Parkinson's disease in particular. The lipid droplets are significantly enriched within the neuromelanin in midbrain dopaminergic neurons in the substantia nigra and could therefore uniquely facilitate the early αSyn-associated neurodegeneration of this region in PD. Our findings reveal a novel pathway implicated in the dysregulation of αSyn that connects aberrant liquid-liquid phase separation, lipid droplets and mitochondrial toxicity.
    DOI:  https://doi.org/10.1101/2025.11.20.689615
  40. Sci Rep. 2025 Dec 02. 15(1): 42957
    Critical role of mitochondrial aconitase in skeletal muscle maturation.
    Tomoya Fukawa, Miho Takata, Kota Kishida, Kosuke Sugiura, Minori Suzuki, Haruka Tsuda, Iori Sakakibara, Takayuki Uchida, Md Mizanur Rahman, Anayt Ulla, Koichi Sairyo, Takahiko Sato, Madoka Ikemoto-Uezumi, Akiyoshi Uezumi, Takeshi Nikawa.
      Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.
    Keywords:  Aconitase 2-knockout mice; Apoptosis; Mitochondrial dysfunction; Sarcomere disruption; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-025-25560-w
  41. Life Sci. 2025 Nov 29. pii: S0024-3205(25)00763-5. [Epub ahead of print]385 124127
    Mitochondria at the crossroads of aging and cardiovascular disease.
    Olubodun Michael Lateef, Sodiq Fakorede, Chanel Harris, Adeola Mariam Lateef, Ayodeji Folorunsho Ajayi.
      Mitochondrial dysfunction plays a critical role in cardiovascular aging and is a key player in the development of cardiovascular diseases (CVDs) such as hypertension, arteriosclerosis, aneurysms, and heart failure. Aging disrupts mitochondrial function through impaired oxidative phosphorylation, excessive reactive oxygen species generation, mitochondrial DNA mutations, endoplasmic reticulum stress, mitochondrial enzyme dysregulation, and impaired calcium homeostasis. These alterations drive endothelial dysfunction, arterial stiffening, cardiac remodeling, and ultimately exacerbate age-related cardiovascular decline. Despite extensive research, the precise mechanisms by which mitochondrial aging impairs the function of endothelial cells, vascular smooth muscle cells, and cardiomyocytes remain poorly understood. Therefore, this review synthesizes current evidence on how aging-associated mitochondrial dysfunction contributes to endothelial dysfunction, arterial stiffening and remodeling, and cardiac dysfunction. It also outlines emerging pathophysiological mechanisms linking mitochondrial dysfunction to age-related CVDs, offering insights into potential therapeutic targets to promote cardiovascular health in aging populations. This review highlights key biomarkers of declining mitochondrial function to facilitate early diagnosis of CVD-related mitochondrial dysfunction. We show that aging disrupts key regulators of mitochondrial dynamics and quality control in the vasculature and heart across human studies and preclinical models of aging. Recent evidence indicates that impaired mitochondrial function in aging cardiomyocytes results in valvular degeneration, left ventricular hypertrophy, diastolic dysfunction, atrial fibrillation, and diminished exercise capacity. Therefore, understanding the pathophysiological mechanisms linking mitochondrial dysfunction to cardiovascular aging may guide the development of new therapeutic strategies for mitigating age-related cardiovascular decline in older adults.
    Keywords:  Arterial disease; Cardiomyopathy; Cardiovascular aging; Endothelial dysfunction; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.lfs.2025.124127
  42. Nat Metab. 2025 Dec 03.
    Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
    Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.
    DOI:  https://doi.org/10.1038/s42255-025-01412-9
  43. bioRxiv. 2025 Nov 18. pii: 2025.11.18.689025. [Epub ahead of print]
    A Reversible Mitochondrial ROS Probe for Monitoring Mitophagy Dynamics: Development and Application of MitoFlare.
    Shanshan Hou, Xin Yan, Xiaoxu Li, Jingyue Ju, Zhiying Shan, Lanrong Bi.
      Mitochondrial dysfunction and defective mitophagy are defining features of numerous neurodegenerative and metabolic disorders, yet existing tools provide limited ability to quantify mitophagy dynamics in real time within living, post-mitotic cells. Here we present MitoFlare, a mitochondria-targeted, reversible mtROS-responsive fluorogenic probe that enables continuous, non-genetic visualization of mitochondrial oxidative activation and turnover. MitoFlare incorporates dual TEMPO nitroxide quenchers into a long-wavelength rhodamine scaffold, producing >95% basal quenching and rapid, fully reversible fluorescence activation in response to mitochondrial superoxide, hydroxyl radicals, lipid-derived peroxyl species, and peroxynitrite. When combined with LysoTracker Green, MitoFlare forms a dual-probe imaging platform that resolves the entire mitophagy cascade with high spatial and temporal fidelity in intact PC12 neuronal cells. Using this platform, we established a quantitative framework comprising three mechanistically distinct metrics: (i) a proximity index that reports early mitochondrial engagement with lysosomes, (ii) Manders' M1 coefficient that captures mid-stage mitochondria-lysosome fusion and mitophagosome formation, and (iii) a quenching/swelling index that resolves terminal lysosomal degradation. Nutrient deprivation induced a complete, temporally ordered mitophagy program, including mtROS priming, Parkin-OPTN-associated fusion, and efficient acidification-dependent cargo degradation. In contrast, inhibition of v-ATPase with bafilomycin A1 arrested mitophagy at the fusion stage, resulting in persistent redox-active mitochondrial cargo that failed to undergo lysosomal digestion. Importantly, MitoFlare's reversible redox chemistry uniquely revealed accumulation of undegraded, oxidatively active mitochondrial remnants within non-acidified vesicles-pathological intermediates that are undetectable using irreversible ROS dyes or genetically encoded reporters. These findings demonstrate that mitophagy proceeds through discrete, redox-regulated and lysosome-dependent phases that can be quantitatively mapped in real time. By enabling synchronized measurement of oxidative activation, organelle trafficking, fusion, and degradation, the MitoFlare-LysoTracker system establishes a new benchmark for dynamic mitophagy analysis in physiologically relevant models. This platform provides a powerful foundation for mechanistic interrogation of mitochondrial quality control and for accelerating the discovery of therapeutic strategies aimed at restoring mitophagic fidelity in neurodegenerative, cardiovascular, and metabolic diseases.
    DOI:  https://doi.org/10.1101/2025.11.18.689025
  44. J Biochem. 2025 Dec 02. pii: mvaf076. [Epub ahead of print]
    Phospholipase A and acyltransferases as novel regulator of organelle dynamics.
    Naoki Matsumoto, Atsushi Yamashita.
      Phospholipase A (PLA) and acyltransferases coordinate glycerophospholipid remodeling to maintain membrane diversity and function. The phospholipase A and acyltransferase (PLAAT) family combines PLA1/PLA2 with N- and O-acyltransferase activities, generating N-acylethanolamines with diverse bioactivities and enabling acyl-CoA-independent remodeling. PLAAT3 has been identified as a causative gene for human lipodystrophy. In addition to adipocyte dysfunction, PLAAT3-deficient mice develop cataracts due to impaired organelle degradation in lens fiber cells. In non-mammalian vertebrates such as zebrafish, which lack PLAAT3, PLAAT1 is highly expressed in the lens, and its deficiency similarly causes cataract-like abnormalities by blocking organelle clearance. A recent study reported that PLAAT1 promotes cardiolipin production in cultured cells, indicating a role in mitochondrial membrane lipid metabolism; however, its direct involvement in mitochondrial dynamics remains unclear. To address this, Sikder et al. (J. Biochem. 175:101-113, 2023) established a doxycycline-inducible mouse PLAAT1 expression system in HEK293 cells. Catalytically active PLAAT1 rapidly induced mitochondrial fragmentation and peroxisome loss, independently of changes in Drp1, Mfn2, and Opa1 expression. These findings reveal a previously unrecognized role of PLAAT1 in regulating organelle dynamics and maintaining cellular homeostasis.
    Keywords:  PLAAT; mitochondrion; organelle; peroxisome; phospholipase A1
    DOI:  https://doi.org/10.1093/jb/mvaf076
  45. Nat Commun. 2025 Nov 29.
    Structural basis of sodium ion-dependent carnitine transport by OCTN2.
    James S Davies, Yi C Zeng, Chelsea Briot, Simon H J Brown, Renae M Ryan, Alastair G Stewart.
      Carnitine is essential for the import of long-chain fatty acids into mitochondria, where they are used for energy production. The carnitine transporter OCTN2 (novel organic cation transporter 2, SLC22A5) mediates carnitine uptake across the plasma membrane and as such facilitates fatty acid metabolism in most tissues. OCTN2 dysfunction causes systemic primary carnitine deficiency (SPCD), a potentially lethal disorder. Despite its importance in metabolism, the mechanism of high-affinity, sodium ion-dependent transport by OCTN2 is unclear. Here we report cryo-EM structures of human OCTN2 in three conformations: inward-facing ligand-free, occluded carnitine- and Na+-bound, and inward-facing ipratropium-bound. These structures define key interactions responsible for carnitine transport and identify an allosterically coupled Na+ binding site housed within an aqueous cavity, separate from the carnitine-binding site. Combined with electrophysiology data, we provide a framework for understanding variants associated with SPCD and insight into how OCTN2 functions as the primary human carnitine transporter.
    DOI:  https://doi.org/10.1038/s41467-025-66867-6
  46. FEBS J. 2025 Dec 05.
    MAVS oligomerization drives a faster and more efficient antiviral signaling activation at peroxisomes compared to mitochondria.
    Bruno Ramos, Jéssica Sarabando, Mariana Marques, Jonathan C Kagan, Daniela Ribeiro.
      Peroxisomes and mitochondria are important platforms for antiviral signal transduction, as detection of cytosolic viral RNA by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) induces the activation of the mitochondrial antiviral signaling adaptor (MAVS) at both organelles. To decisively elucidate the mechanistic differences and similarities in kinetics and end products between these two pathways, we developed a doxycycline-inducible system that allows for precise control of MAVS expression and activation at either peroxisomes or mitochondria, in a timely manner, and across various cell types. Our findings demonstrate that both peroxisomal and mitochondrial MAVS induce type I and III interferon-dependent antiviral signaling and that the peroxisomal signaling occurs significantly faster than its mitochondrial counterpart. Importantly, using not only the doxycycline-inducible system but also the conventional activation of the MAVS pathway through direct stimulation of RIG-I-like receptors, we demonstrate that the rapid and robust antiviral response resulting from peroxisomal MAVS activation is mechanistically due to the faster oligomerization of MAVS at the membranes of this organelle, when compared to mitochondria. These data emphasize the versatility and speed of the peroxisome-dependent antiviral response and may lead to the identification of specific targets to develop novel host-directed antiviral strategies.
    Keywords:  MAVS; MAVS oligomerization; antiviral signaling; mitochondria; peroxisomes
    DOI:  https://doi.org/10.1111/febs.70360
  47. J Inherit Metab Dis. 2026 Jan;49(1): e70120
    Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders.
    Jonathan Martens, Udo F H Engelke, Ron A Wevers, Dirk J Lefeber, Purva Kulkarni.
      Inherited metabolic disorders (IMDs) encompass a diverse and expanding group of rare diseases caused by genetic disruptions mainly in metabolic enzymes and transporters. Clinical diagnosis of IMDs presents significant challenges due to phenotypic heterogeneity, nonspecific symptoms, and the limited scope of current targeted biochemical assays typically available. Recent advances in mass spectrometry-based untargeted metabolomics offer promising solutions to several of these challenges by simultaneous detection and relative quantification of thousands of metabolites, not relying on any prior hypotheses. With the expansion of genetic diagnostics via whole-exome and whole-genome sequencing, metabolic insights are often crucial for understanding the pathogenicity of genetic variants of unknown significance, often enabling a clear diagnosis for patients. This review details current applications of untargeted metabolomics in IMDs, including biomarker discovery and elucidation of previously unknown pathophysiological mechanisms. Successful examples of biomarker identification in well-studied IMDs, such as pyridoxine-dependent epilepsy and phenylketonuria, are highlighted to provide novel disease insights. Additionally, we address technical and interpretation challenges inherent to this methodology, particularly concerning metabolite identification, high-dimensional data complexity, and limited patient numbers. Emerging analytical technologies and data analysis approaches are highlighted that are poised to mitigate these challenges in the upcoming years. Finally, we provide an outlook on future directions, emphasizing the complementary roles of targeted and untargeted metabolomics and the prospects for the identification of new therapeutic targets as well as therapy monitoring for the clinical management of IMDs.
    Keywords:  biomarkers; dark matter of the metabolome; de‐VUSing; diagnostics; inborn errors of metabolism; mass spectrometry; metabolic disease discovery; untargeted metabolomics
    DOI:  https://doi.org/10.1002/jimd.70120
  48. Eur J Appl Physiol. 2025 Dec 02.
    Involvement of the PINK1/PARKIN pathway in enhancing mitochondrial function and mitophagy in reserpine-induced fibromyalgia mice through strength exercise and coenzyme Q10.
    Hoda M Moghazy, A A Seham, Motamed Mahmoud, Sahar M Gebril, Dina M Monir.
       PURPOSE: To assess the impact of reserpine-induced fibromyalgia and evaluate the potential effects of resistance exercise or CoQ10 administration on muscle strength, structure, and expression of mitochondrial markers in adult mice. Central to this investigation is an exploration of the molecular mechanisms underlying mitophagy via the PINK1/Parkin pathway.
    METHODS: This study sought to elucidate the Impact of 4 weeks of either climbing exercise or coenzyme Q10 (CoQ10) supplementation (10 mg/kg, administered once daily) on skeletal muscle and mitochondrial functions within a reserpine-induced fibromyalgia (FM) mouse model. Evaluation encompassed the assessment of key mitochondrial markers, including PTEN-induced kinase 1 (PINK1), PARKIN, Mitofusion2, cytochrome c oxidase, citrate synthase, and fibronectin type III domain-containing protein 5 (FNDC5), alongside morphological examinations of the gastrocnemius muscle.
    RESULTS: Climbing exercise significantly improved fibromyalgia (FM)-like symptoms and enhanced the expression of mitochondrial marker genes in the gastrocnemius muscle. Histological and ultra-structural studies showed nearly normal muscle fiber structure, banding patterns, mitochondria shape and size, and a notable reduction in collagen fibrosis compared to FM. CoQ10 supplementation also improved mitochondrial gene expression but did not significantly affect FNDC gene expression. Ultrastructural analysis revealed mostly normal muscle fibers with regular banding, though some areas showed disturbances with multiple sub-sarcolemmal and interfibrillar mitochondria.
    CONCLUSION: This study underscores the efficacy of both resistance exercise and CoQ10 supplementation as viable strategies for improving FM-related symptoms and enhancing mitochondrial function in mice.
    Keywords:  Climbing exercise; Coenzyme Q10; Fibromyalgia; Mitochondria; Mitophagy; PARKIN; PINK1
    DOI:  https://doi.org/10.1007/s00421-025-05990-0
  49. Mol Biomed. 2025 Dec 02. 6(1): 129
    Cholesterol induced-mitochondrial calcium dysregulation facilitates atherosclerosis by promoting lipid accumulation in vascular smooth muscle cells.
    Zhiwang Zhang, Fan Yang, Wei Wang, Qi Cao, Long Zhang, Yu Zhang, Dong Ma, Xinhua Zhang, Jinkun Wen, Bin Zheng.
      Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis.
    Keywords:  Atherosclerosis; MCU inhibitor; MICU1; Mitochondrial calcium
    DOI:  https://doi.org/10.1186/s43556-025-00384-2
  50. Cell Biosci. 2025 Dec 04.
    Old dogs-new tricks: multifaceted functions of MAVS beyond antivirus activity in human health and diseases.
    Yating Lu, Yaxuan Qi, Qingqing Yinliang, Rui Zhu, Alexey Sarapultsev, Shanshan Luo, Jing Cui, Desheng Hu.
      Mitochondrial Antiviral Signaling Protein (MAVS), a key adaptor in the innate immune system, has traditionally been recognized for its role in defending against viral infections through activation of the interferon (IFN) and NF-κB signaling pathways. Recent studies, however, have expanded this view, revealing that MAVS also functions at the intersection of innate immunity, mitochondrial dynamics, and cellular metabolism. Located on the outer mitochondrial membrane, MAVS serves as a critical signaling hub, linking pathogen detection to inflammatory and stress responses. Beyond its canonical antiviral roles, MAVS is now implicated in diverse physiological and pathological processes, including regulation of apoptosis, NLRP3 inflammasome activation, metabolic reprogramming, and autophagy. Its dysregulation contributes to the onset and progression of a range of diseases, such as cancer, cardiovascular and autoimmune disorders, and neurological conditions. This review provides a comprehensive overview of MAVS activation, downstream signaling outputs, and regulatory mechanisms. We also discuss the emerging evidence on MAVS-related diseases and therapeutic strategies targeting MAVS, emphasizing its broader significance in human health beyond antiviral immunity.
    Keywords:  Human disease; Innate immunity; MAVS; Mitochondria; Therapeutics
    DOI:  https://doi.org/10.1186/s13578-025-01512-9
  51. Nat Biotechnol. 2025 Dec 02.
    Modulating RNA condensates to control cell fate.
    Kasey S Love, Kate E Galloway.
      
    DOI:  https://doi.org/10.1038/s41587-025-02936-x
  52. Adv Sci (Weinh). 2025 Dec 05. e20444
    NADH-Reductive Stress Induced by Dihydrolipoamide Dehydrogenase Activation Contributes to Cuproptosis.
    Si-Yi Zhang, Xing-Hua Ren, Cheng-Hong Zhang, Zhan-You Wang.
      Copper (Cu) is an essential trace element for cellular metabolism, while excessive Cu accumulation leads to neurotoxicity. Current therapeutic strategies for Cu overload remain inadequate in mitigating neurological symptoms. The recently discovered Cu-dependent mitochondrial cell death pathway, cuproptosis, offers novel insights into Cu-mediated neurotoxicity. In this study, the mechanistic link between mitochondrial respiration and cuproptosis is elucidated. The current study demonstrates that activated dihydrolipoamide dehydrogenase (DLD), induced by excess Cu under alkaline mitochondrial pH conditions, drives nicotinamide adenine dinucleotide (NADH) accumulation. Cu mediated mitochondrial permeability transition pore (mPTP) opening that facilitates NADH translocation to the cytosol, triggering NADH-reductive stress. This promotes aberrant purine biosynthesis, leading to severe adenosine triphosphate depletion and energy stress. Pharmacological interventions targeting DLD activity, cytosolic NADH, mPTP opening, purine biosynthesis, or energy stress effectively rescued Cu-induced cell death in SH-SY5Y neuroblastoma cells. Collectively, these findings reveal characteristics of NADH-reductive stress under excessive Cu exposure, establishing cuproptosis as a novel NADH-reductive stress-dependent cell death pathway. This mechanistic insight provides new therapeutic avenues for Cu-associated neurological pathologies and new aspects to explore Cu cellular physiology.
    Keywords:  NADH‐reductive stress; copper; cuproptosis; dihydrolipoamide dehydrogenase; mitochondrial permeability transition pore
    DOI:  https://doi.org/10.1002/advs.202520444
  53. NPJ Parkinsons Dis. 2025 Dec 02.
    ALDH2 protects against dopaminergic neuronal cell ferroptosis by enhancing the enzyme activity of PRDX6 in Parkinson's disease.
    Xuan Li, Si-Jia Peng, Yu Wang, Xin Chen, Ting-Ting Wu, Ya Feng, Xi-Xi Wang, Huiyong Yin, Yun-Cheng Wu.
      Emerging evidence suggests that ferroptosis is probably involved in the selective loss of dopaminergic neurons in Parkinson's disease (PD). Acetaldehyde dehydrogenase 2 (ALDH2) plays an important role in detoxifying lipid aldehydes derived from lipid peroxidation, a process that is closely linked to ferroptosis. In our study, ALDH2 knockout (KO) mice were more susceptible to the loss of tyrosine hydroxylase-positive neurons and behavioral changes in a PD mouse model. Similar observations were made in a knock-in (KI) mouse model with one of the most common single-nucleotide polymorphisms of ALDH2, rs671. Interestingly, ALDH2 KO or KI mice showed enhanced ferroptosis in the SN. Moreover, expression of ALDH2 modified the sensitivity of SH-SY5Y cells to ferroptosis inducers. Mechanistic studies have shown that ALDH2 regulates neuronal cell ferroptosis by interacting with the antioxidant enzyme peroxiredoxin 6 (PRDX6) to enhance its enzymatic activity, whereas the ALDH2 rs671 variant weakens its binding to PRDX6.
    DOI:  https://doi.org/10.1038/s41531-025-01155-0
  54. Redox Biol. 2025 Nov 27. pii: S2213-2317(25)00465-3. [Epub ahead of print]88 103952
    The Rieske iron-sulfur protein is a primary target of molecular hydrogen.
    Shuto Negishi, Mikako Ito, Tomoya Hasegawa, Hikaru Otake, Bisei Ohkawara, Akio Masuda, Hiroyuki Mino, Tyler W LeBaron, Kinji Ohno.
      The mechanisms underlying the biomedical effects of molecular hydrogen (H2) remain poorly understood and are often attributed to its selective reduction of hydroxyl radicals, based on the long-held notion that H2 is biologically inert. We demonstrate that H2 is biologically active, specifically targeting the Rieske iron-sulfur protein (RISP). We first observed that H2 induces the mitochondrial unfolded protein response (UPRmt) in cultured cells exposed to H2 and in mouse liver after H2 water administration. H2 suppressed electron transport chain complex III activity in mouse liver homogenates to 78.5 % within 2 min. Given the evolutionary link with hydrogenases, we examined RISP as a potential target of H2. We found that H2 promotes RISP degradation within 1 h in cultured cells by activating mitochondrial Lon peptidase 1 (LONP1). Loss of RISP and subsequent UPRmt induction may explain the pleiotropic and paradoxical effects of H2. These findings identify RISP as a primary target of H2, demonstrating that H2 is biologically active as a signaling molecule.
    Keywords:  Hydrogenase; Mitochondrial unfolded protein response; Molecular hydrogen; Rieske iron-sulfur protein
    DOI:  https://doi.org/10.1016/j.redox.2025.103952
  55. Nat Commun. 2025 Dec 04. 16(1): 10898
    Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
    Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.
      T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.
    DOI:  https://doi.org/10.1038/s41467-025-65910-w
  56. Cell. 2025 Dec 04. pii: S0092-8674(25)01310-8. [Epub ahead of print]
    A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
    Svenja M Lorenz, Adam Wahida, Mark J Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S Woo, Jana K Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla Ayala, Valeria Napolitano, Marta Kolonko-Adamska, Stefan Gaussmann, Juliane Merl-Pham, Stefanie Hauck, Anna Pertek, Tanja Orschmann, Emily van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, Joris M Frenz, Lohans Pedrera, Amalia Dolga, Markus Kraiger, Martin Hrabé de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela Vogt-Weisenhorn, Lillian Garrett, Sabine M Hölter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J Garcia-Saez, Anna Tietze, Sanath Kumar Ramesh, Scott Ayton, Michelle Vincendeau, Manuel A Friese, Kristen Wigby, Michael Sattler, Matthias Mann, Irina Ingold, Ashok Kumar Jayavelu, Grzegorz M Popowicz, Marcus Conrad.
      Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
    Keywords:  Alzheimer’s disease; GPX4; SSMD; Sedaghatian type; cell death; ferroptosis; neurodegeneration; neuroinflammation; spondylometaphyseal dysplasia
    DOI:  https://doi.org/10.1016/j.cell.2025.11.014
  57. Cell Rep Methods. 2025 Dec 03. pii: S2667-2375(25)00283-8. [Epub ahead of print] 101247
    Approaches for identification of 5' UTR mutations impacting translation and protein production from neurodevelopmental disorder genes.
    Stephen P Plassmeyer, Colin P Florian, Rebecca Chase, Michael J Kasper, Shayna Mueller, Yating Liu, Kelli McFarland White, Llaelyn Sierra-Cortez, Anthony D Fischer, Courtney F Jungers, Slavica Pavlovic Djuranovic, Sergej Djuranovic, Joseph D Dougherty.
      Coding mutations can cause neurodevelopmental disorders (NDDs), including autism. Yet, predicting which non-coding (e.g., 5' untranslated region [UTR]) mutations are functional is challenging. We tested assays of various throughput for the assessment of 997 mutations from NDD families. A massively parallel reporter assay (MPRA) using polysomes from cell lines identified >100 altering translation, with a subset subsequently altering endogenous protein production in patient lymphoblastoid cell lines. Next, since UTR function varies by cell type, we optimized Cre-dependent MPRAs, enabling assessment in neurons in vivo. We demonstrate that neurons have different principles of regulation by 5' UTRs and discover mutations altering translational activity. Finally, we tested whether polysome-MPRAs predict changes in canonical open reading frame (ORF) protein production. Only for mutations altering UTR structure was there a reasonable correlation. Overall, we benchmarked a variety of approaches for assessing impacts of 5' UTR mutation and identified functional 5' UTR mutations from known NDD genes, including LRRC4 and ZNF644.
    Keywords:  CP: molecular biology; CP: neuroscience; massively parallel reporter assay; neurodevelopment; untranslated region
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101247
  58. Biomed Pharmacother. 2025 Nov 29. pii: S0753-3322(25)01029-7. [Epub ahead of print]193 118835
    Endoplasmic reticulum, mitochondria, and their crosstalk in retinal ganglion cell degeneration.
    Baohua Li, Yipeng Shi, Mengyu Liu, Wengxuan Cao, Fuyuan Zhang, Zefeng Kang.
      Retinal ganglion cells (RGCs) serve as the terminal output neurons in the retina and are responsible for transmitting visual information from photoreceptors to higher-level centers in the brain. Because of their highly polarized structure, substantial energy demands, and complex protein synthesis activities, the function of RGCs is critically dependent on the homeostasis of intracellular organelles, particularly the endoplasmic reticulum (ER) and mitochondria. Recent studies have shown that these two organelles engage in close physical and functional crosstalk through specific microdomains known as "mitochondria-associated ER membranes" (MAMs), which are crucial for the survival and function of RGCs. This review delves into the critical roles of the ER and mitochondria in the mechanisms of RGC degeneration. Furthermore, the mechanisms by which mitochondrial-ER contact site (MERC)-mediated interorganelle communication exacerbates RGC degeneration by disrupting Ca2 + homeostasis and inducing ER stress and oxidative stress are elucidated. Drugs targeting mitochondria, ER, and MERCs to prevent and treat RGC degeneration are summarized to provide new perspectives and references for studying the pathological mechanisms of RGC degeneration and developing targeted therapeutic strategies.
    Keywords:  Endoplasmic reticulum; Mitochondria; Mitochondria-associated membrane; Retinal ganglion cell; Retinal neuron degeneration
    DOI:  https://doi.org/10.1016/j.biopha.2025.118835
  59. medRxiv. 2025 Nov 27. pii: 2025.11.19.25340555. [Epub ahead of print]
    REECAP: Contrastive learning of retinal aging reveals genetic loci linking morphology to eye disease.
    Liubov Shilova, Daniel Sens, Ayshan Aliyeva, Shubham Chaudhary, Qiaohan Xu, Emmanuelle Salin, Johannes Schiefelbein, Ben Asani, Oana Veronica Amarie, Elida Schneltzer, Ayellet V Segrè, Julia A Schnabel, Na Cai, Bjoern M Eskofier, Francesco Paolo Casale.
      Deep learning foundation models excel at disease prediction from medical images, yet their potential to bridge tissue morphology with the genetic architecture of disease remains underexplored. Here, we present REECAP (Representation learning for Eye Embedding Contrastive Age Phenotypes), a framework that fine-tunes the RETFound retinal foundation model using a contrastive objective guided by chronological age. Applied to 87,478 fundus images from 52,742 UK Biobank participants, REECAP aligns image representations along the aging axis, yielding multivariate ageing phenotypes for genome-wide association studies (GWAS). GWAS of REECAP embeddings identifies 178 loci, including 27 that colocalize with risk loci of age-related eye diseases, 14 of which remained undetected by conventional disease-label GWAS. By enabling conditional image synthesis, REECAP further links genetic variation to interpretable anatomical changes. Benchmarking against alternative embedding models, we show that REECAP enhances both locus discovery and disease relevance of genetic associations, suggesting that aging-informed tissue embeddings represent a powerful intermediate phenotype to discover and interpret disease loci.
    DOI:  https://doi.org/10.1101/2025.11.19.25340555
  60. STAR Protoc. 2025 Nov 28. pii: S2666-1667(25)00649-5. [Epub ahead of print]6(4): 104243
    Protocol for systematic screening of histone H3/H4 mutants to identify histone residues critical for BCAA-dependent replicative lifespan.
    Sejung Park, Yan Liu, Seong Hoon Ahn.
      Here, we present a protocol for high-throughput replicative lifespan (RLS) screening in Saccharomyces cerevisiae using micromanipulation-based aging assays with growth phenotyping. We describe steps for preparing yeast strains, isolating virgin cells, and monitoring divisions to calculate lifespan changes in histone H3/H4 mutants. We also describe sulfometuron methyl (SM) spotting assay to evaluate growth phenotypes linked to branched-chain amino acid (BCAA) metabolism, enabling identification of residues critical for lifespan regulation. For complete details on the use and execution of this protocol, please refer to Park et al.1.
    Keywords:  Cell Biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2025.104243
  61. Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00905-0. [Epub ahead of print]
    Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.
    Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R Foltz.
      Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.
    Keywords:  PRPS; PRPSAP; chromatin; chromatin assembly; histone chaperone; histone deposition; histone supply; metabolism; nucleotide metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.009
  62. Nat Commun. 2025 Dec 01. 16(1): 10801
    Molecular mechanism of PINK1 regulation by the Hsp90 machinery.
    Xuyang Tian, Jiayue Su, Ziyi Wang, Tao Liu, Huifang Xiong, Shan Sun, Kunrong Mei, Sen-Fang Sui.
      Hundreds of human kinases, including PINK1-a protein kinase associated with familial Parkinson's disease-are regulated by Hsp90 and its cochaperones. While previous studies have elucidated the mechanism of kinase loading into the Hsp90 machinery, the subsequent regulation of kinases by Hsp90 and its cochaperones remains poorly understood. In this study, using complexes obtained through PINK1 pulldown, we determine the cryo-EM structures of the human Hsp90-Cdc37-PINK1 complex at 2.84 Å, Hsp90-FKBP51-PINK1 at approximately 6 Å, and Hsp90- PINK1 at 2.98 Å. These structures, along with the bound nucleotide in the Hsp90 dimers of the three complexes, provide insights into the Hsp90 chaperone machinery for kinases and elucidate the molecular mechanisms governing cytosolic PINK1 regulation.
    DOI:  https://doi.org/10.1038/s41467-025-65859-w
  63. J Mother Child. 2025 Feb 01. 29(1): 227-233
    Medium-chain Acyl-CoA Dehydrogenase Deficiency Identified by MS/MS Newborn Screening Challenges.
    Ewa Głąb-Jabłońska, Joanna Taybert, Anna Wiśniewska, Mariola Sasin-Rokita, Mariusz Ołtarzewski, Magdalena Chełchowska.
       BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of metabolism resulting in the absence or reduced activity of the enzyme responsible for the β-oxidation of medium-chain fatty acids. MCAD deficiency can lead to metabolic decompensation, presenting as hypoketotic hypoglycaemia, hepatic encephalopathy (Reye-like syndrome), or death regardless of the patient's age.
    MATERIAL AND METHODS: Blood samples in the national newborn screening programme were collected using 903 filter paper (dry blood spot - DBS). Routine dried blood spots from newborn screening (NBS) were analysed by flow injection and derivatised tandem mass spectrometry method (MS/MS). Positive screening cases in the MCAD deficiency profile were verified through GC/MS urine organic acid profiling and enzymatic and/or molecular testing.
    RESULTS: A total of 3,806,166 newborns were screened between 2014-2024, resulting in the identification of 94 cases of MCAD deficiency. Analysis of the obtained results revealed a consistent pattern in the levels of octanoylcarnitine (C8), hexanoylcarnitine (C6), and decanoylcarnitine (C10) acylcarnitines, as well as the C8/C10 ratio across these cases. Only one case of confirmed MCAD deficiency with an atypical acylcarnitine profile was found.
    CONCLUSIONS: The use of tandem mass spectrometry has enabled the inclusion of MCAD deficiency in newborn screening programmes. This has facilitated early detection, diagnosis, and initiation of therapeutic interventions to prevent metabolic decompensation. We emphasize the need for repeated sampling and further testing if C8 is even slightly elevated.
    Keywords:  C8; DBS; MCAD deficiency; MS/MS; atypical acylcarnitine profile; newborn screening; tandem mass spectrometry
    DOI:  https://doi.org/10.34763/jmotherandchild.20252901.d-25-00025
  64. Stem Cell Reports. 2025 Dec 04. pii: S2213-6711(25)00327-3. [Epub ahead of print] 102723
    Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes.
    Hannah D Franklin, Hamish Crerar, Nishita Parnandi, Michael Lattke, Stanislaw Majewski, Benjamin E Clarke, Husayn Pallikonda, Michael Howell, Simon J Boulton, Rickie Patani.
      Astrocytes are essential regulators of neuronal health, and their dysfunction contributes to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Using human induced pluripotent stem cell (iPSC)-derived astrocytes carrying ALS-associated VCP mutations, we uncover cell-autonomous activation of the hypoxia response under basal conditions. VCP-mutant astrocytes exhibit increased nuclear hypoxia-inducible factor (HIF)-1ɑ, mitochondrial depolarization, and lipid droplet accumulation. Mimicking hypoxia in control astrocytes by HIF-1ɑ stabilization with dimethyloxalylglycine recapitulates these phenotypes. Transcriptomic and CUT&RUN profiling reveal direct HIF-1ɑ binding to canonical hypoxia-responsive genes in VCP-mutant astrocytes and a transcriptional signature of metabolic reprogramming and mitochondrial dysfunction under normoxia. Furthermore, conditioned medium from hypoxia-exposed astrocytes fails to rescue RNA-binding protein mislocalization in motor neurons, unlike medium from healthy counterparts. Together, these findings demonstrate that aberrant HIF-1ɑ activation drives astrocytic dysfunction and compromises neuronal support, identifying hypoxic stress as an early and functionally consequential event in VCP-mutant ALS, with therapeutic implications for targeting HIF-1ɑ signaling.
    Keywords:  HIF-1α; RNA-binding proteins; VCP mutation; amyotrophic lateral sclerosis; astrocytes; disease modelling; human iPSCs; hypoxia; neurodegeneration
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102723
  65. Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]
    Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
    Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.
      The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.
    Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor
    DOI:  https://doi.org/10.1016/j.cell.2025.11.002
  66. medRxiv. 2025 Nov 19. pii: 2025.11.15.25336228. [Epub ahead of print]
    MaveMD: A functional data resource for genomic medicine.
    Abbye E McEwen, Jeremy Stone, Malvika Tejura, Pankhuri Gupta, Benjamin J Capodanno, Estelle Y Da, Sally B Grindstaff, Nick Moore, David Reinhart, Ashley E Snyder, Andrew B Stergachis, Lea M Starita, Douglas M Fowler, Alan F Rubin.
      Variant interpretation remains one of the most significant challenges in clinical genetics. Variants of uncertain significance (VUS) undermine precision medicine implementation because they have an unknown relationship to disease and cannot be used for clinical decision-making. While evidence from multiplexed assays of variant effect (MAVEs) and other functional assays can help classify variants, major barriers prevent routine use in clinical variant classification, including fragmentation across multiple repositories, insufficient data standards, and the need to calibrate assays clinically. Here we address these challenges by presenting a new interface for the MaveDB database called MaveMD (MAVEs for MeDicine) that integrates with external resources such as ClinVar and the ClinGen Allele Registry, displays clinical evidence calibrations, provides intuitive visualizations, and exports structured evidence compatible with ACMG/AMP variant classification guidelines. MaveMD implements automatic mapping of MaveDB datasets to the human reference genome, dramatically simplifying the clinical translation of new MAVE data. We also defined a new metadata model after curating 438,318 variant effect measurements from 74 MAVE datasets spanning 32 disease-associated genes, and created an interface aimed at enabling effective clinical decision-making. Thus, MaveMD makes MAVE data accessible and easily usable for variant classification, and will scale seamlessly with future data generation efforts to empower the use of MAVE evidence in clinical practice.
    DOI:  https://doi.org/10.1101/2025.11.15.25336228
  67. Comput Struct Biotechnol J. 2025 ;27 5036-5044
    From shadows to clarity: A new paradigm for comprehensive variant detection in undiagnosed dystrophinopathy using combined long-read and RNA sequencing.
    Lei Zhao, Shirang Pan, Chaoping Hu, Yiyun Shi, Xihua Li.
      Approximately 2-5 % of dystrophinopathy cases remain undiagnosed at the molecular level following standard multiplex ligation-dependent probe amplification (MLPA) and exome sequencing (ES), precluding these patients from variant-specific genetic counseling and therapy eligibility assessment. We developed an integrated diagnostic pipeline combining targeted long-read sequencing (LRS) with muscle RNA-seq and applied it to 50 Chinese patients (46 males, 4 females) with biopsy-confirmed dystrophinopathy in whom MLPA and ES had yielded negative results. A molecular diagnosis was achieved for all 50 probands: 30 (60 %) harbored intronic single nucleotide variants (SNVs) leading to pseudoexon inclusion or exon skipping, while the remaining 20 (40 %) carried complex structural variants (SVs), including inversions (n = 13), translocations (n = 5), and insertions/deletions (n = 2). Of these, 23 (46 %) were novel variants not previously recorded in disease databases, and RNA-seq confirmed their aberrant splicing effects. A notable discovery was a 1.9 kb intronic inversion that uniquely activated cryptic splice sites on the antisense strand, representing a previously unreported pathogenic mechanism in dystrophinopathies. Cascade screening identified 45 carriers across 28 families, revealing a maternal carrier rate of 84.8 % (28/33). This integrated LRS and RNA-seq approach demonstrates significant value in resolving molecularly undiagnosed dystrophinopathy cases and enabling comprehensive genetic counseling. Furthermore, it establishes a robust diagnostic paradigm for molecularly unresolved neuromuscular disorders.
    Keywords:  Deep intronic variants; Duchenne muscular dystrophy; Dystrophinopathy; Long-read sequencing; Muscle biopsy; Pseudoexon; RNA-seq
    DOI:  https://doi.org/10.1016/j.csbj.2025.10.049
  68. Nat Commun. 2025 Dec 04. 16(1): 10909
    Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
    Cindy Dong, Alison Finigan, Nichola Figg, Benjamin Jenkins, Albert Koulman, Suvagata R Chowdhury, Anne-Marie Tricolici, Jordi Lambert, Sebnem Oc, Helle F Jørgensen, Julien Prudent, Michael P Murphy, Martin Bennett, Emma Yu.
      Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth's Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease.
    DOI:  https://doi.org/10.1038/s41467-025-65873-y
  69. Sci Adv. 2025 Dec 05. 11(49): eaea7451
    Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
    Longfei Gao, Desmond Dickson, Huijuan Feng, Chaolin Zhang, Lei Ding.
      Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here, we found that HSCs displayed a distinct messenger RNA alternative splicing pattern and preferentially expressed Rbfox2, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.
    DOI:  https://doi.org/10.1126/sciadv.aea7451
  70. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2511727122
    An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somite organization.
    Audrey G O'Neill, Morgan E McCartney, Gavin M Wheeler, Jeet H Patel, Gardenia Sanchez-Ramirez, Justin M Kollman, Andrea E Wills.
      IMP dehydrogenase (IMPDH) controls a key regulatory node in purine biosynthesis. Gain-of-function mutations in human IMPDH2 are associated with neurodevelopmental disorders and neuromuscular symptoms including dystonia, but the developmental mechanisms underlying these defects are unknown. We previously showed that these mutants are insensitive to GTP inhibition and hypothesized that their hyperactivity would affect nucleotide metabolism in vivo. Here, we characterize the metabolic and developmental consequences of the neurodevelopmental disorder-associated IMPDH2 mutant, S160del, in Xenopus tropicalis. We show that expressing S160del but not WT human IMPDH2 disrupts purine pools and somite organization in the developing tadpole. We also show that S160del disrupts in vivo IMPDH filament assembly, a well-described IMPDH regulatory mechanism. Cryo-EM structures show that S160del disrupts filament assembly by destabilizing the dimerization of regulatory Bateman domains. Dimerization of Bateman domains and subsequent filament formation can be restored with a high affinity ligand, but this does not restore sensitivity to GTP inhibition, suggesting S160del also disrupts allostery of IMPDH2 filaments. This work demonstrates that the structural effects of patient IMPDH2 variants can cause disruptions both to nucleotide levels and to the normal development of sensorimotor structures, helping us better understand the physiological basis of disease in these patients.
    Keywords:  allostery; cryo-EM; enzyme filaments; neuromuscular development; nucleotide biosynthesis
    DOI:  https://doi.org/10.1073/pnas.2511727122
  71. bioRxiv. 2025 Nov 21. pii: 2025.11.20.689567. [Epub ahead of print]
    Tom70-mediated mitochondria-nuclear envelope contacts regulate nuclear pore complex inheritance during gametogenesis.
    Cyrus T Ruediger, Benjamin S Styler, Eric M Sawyer, Silvan Spiri, Grant King, Madison E Walsh, Gloria A Brar, Danielle M Jorgens, Elçin Ünal.
      Gametogenesis rejuvenates the cellular lineage and excludes senescence-associated factors from gametes. In Saccharomyces cerevisiae , this involves sequestration of nuclear constituents into the Gametogenesis-Uninherited Nuclear Compartment (GUNC), which is excluded from gametes. Here we identify the conserved mitochondrial import receptor Tom70 as a key regulator of GUNC-mediated exclusion. Loss of TOM70 disrupts the sequestration of nuclear pore complexes, but not senescence-associated aggregates and nucleolar components, into the GUNC. Tom70's role appears independent of its canonical function in mitochondrial import and instead reflects a meiosis-specific requirement for mitochondria-nuclear envelope tethering. During meiosis II, Tom70 concentrates around the GUNC, where it recruits the nuclear envelope tethering protein Cnm1. Loss of CNM1 partially phenocopies tom70Δ , consistent with parallel tethering interactions. These findings uncover a previously unrecognized organelle contact-dependent pathway that remodels the nuclear envelope to support selective nuclear inheritance. More broadly, they highlight how organelle contacts integrate with nuclear quality control to safeguard gamete integrity.
    DOI:  https://doi.org/10.1101/2025.11.20.689567
  72. Mol Metab. 2025 Nov 29. pii: S2212-8778(25)00201-7. [Epub ahead of print] 102294
    Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
    Dipsikha Biswas, Ever Espino-Gonzalez, Danial Ahwazi, Jordana B Freemantle, Amy M Ehrlich, Charline Jomard, Jonas Brorson, Agnete N Schou, Jean Farup, Julien Gondin, Jesper Just, Marc Foretz, Jonas T Treebak, Marianne Agerholm, Kei Sakamoto.
       OBJECTIVE: Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.
    METHODS: Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1-/-/γ3-/-) and single knockout (imγ1-/- and imγ3-/-) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
    RESULTS: snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1-/-/γ3-/- muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3-/-, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1-/- mice.
    CONCLUSIONS: While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
    Keywords:  AICAR; AMP-activated protein kinase; MK-8722; Single nucleus RNA sequencing; glucose uptake
    DOI:  https://doi.org/10.1016/j.molmet.2025.102294
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