bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–01–04
forty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae.
  2. Mitochondrial tRNA-Derived Diseases.
  3. Hippocampal cell- and circuit-specific differences in mitochondrial form and function.
  4. Ferroptosis susceptibility in primary coenzyme Q10 deficiency: Cellular insights from patient fibroblasts and clinical course of six individuals.
  5. Self-renewal of neuronal mitochondria through asymmetric division.
  6. Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.
  7. Synuclein and Mitochondrial Dysfunction: Regulating the Protein Import Complex toward PD Treatment?
  8. Mitochondria and Lipids in Cellular Signaling of the Brain: from Physiology to Neurodegeneration.
  9. Propofol-Induced Mitochondrial Dysfunction Is Independent of Mitochondrial Permeability Transition.
  10. Extracellular mitochondria: a potential player involved in exercise health benefits.
  11. Real-Time Super-Resolution Tracking of mtDNA Remodeling and Inflammatory Release with a Selective Fluorescent Probe.
  12. Mitochondrial calcium shapes B cell signaling and mitochondrial function.
  13. Real-time measurement of the mitochondrial membrane potential in the intact mouse heart.
  14. Pterostilbene restores mitochondrial retrograde signaling to activate protective stress responses in Parkinson's disease.
  15. Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.
  16. ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
  17. Elevated cerebrospinal fluid 2-Hydroxybutyric acid in two siblings with aspartate-glutamate carrier 1 deficiency.
  18. Systems-Level Integration of Multi-Omics Identifies Genetic Modifiers of TANGO2 Deficiency Disorder.
  19. SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging.
  20. Tiny genome with big impact: mitochondrial DNA in cardiovascular health.
  21. Novel DNJ Derivative Ameliorates Cardiac Hypertrophy by Targeting OPA1 and Restoring Mitochondrial Health.
  22. Muscle-Targeted Nanocomposite Therapy Alleviates Age-Related Sarcopenia via Antioxidant and Metabolic Reprogramming.
  23. Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells.
  24. First Latin American Case of MLASA2 Caused by a Pathogenic Variant in the Anticodon-Binding Domain of YARS2.
  25. A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
  26. Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies.
  27. Mild and late onset forms of type I 3-methylglutaconic aciduria presenting as isolated cerebellar ataxia without leukodystrophy: case reports and phenotype expansion.
  28. ISG15 dysregulates endoplasmic reticulum-mitochondrial contacts and calcium homeostasis in Ataxia telangiectasia.
  29. Perturbation of NAD(P)H metabolism with the LbNOX xenotopic tool extends lifespan and mitigates age-related changes.
  30. Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments.
  31. Spinal Spheroids as Screening Platform for Peripheral Neuropathies.
  32. Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
  33. An integrated platform for concurrent structural and single-nucleotide variants improves copy-number detection and reveals pathogenic alleles in undiagnosed Mendelian families.
  34. Mitochondrial dysfunction in Wilson disease: a systematic review and meta-analysis across human and animal models.
  35. Not Aging but Calorie Restriction Strongly Affects Protein Oxidation in Heart and Brain Mitochondria.
  36. The metabolic-epigenetic interface: lysine succinylation orchestrates bidirectional crosstalk in neurodegenerative disorders.
  37. Protocol to assess retinal metabolic flux of mice via stable isotope-resolved metabolomics.
  38. Gatekeepers of the Germ Line: How Mitochondria Shape Reproductive Evolution in Metazoans.
  39. Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights.
  40. High-Photostability Perylene-Derived Probe Enables Accurate Dual-Modality Imaging of Mitochondrial Membrane Potential.
  1. Genetics. 2025 Dec 29. pii: iyaf279. [Epub ahead of print]
    Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae.
    Gargi Mishra, Xiaowen Wang, Eamon Fitzpatrick, Auyon Ghosh, Xin Jie Chen.
      Mitochondrial biogenesis requires the import of ∼1,000-1,500 nuclear-encoded proteins across the Translocase of Outer Membrane (TOM) and the Translocase of Inner Membrane (TIM) 22 or 23 complexes. Protein import defects cannot only impair mitochondrial respiration but also cause mitochondrial Precursor Overaccumulation Stress (mPOS) in the cytosol. Recent studies have shown that specific mutations in the nuclear-encoded Adenine Nucleotide Translocase 1 (ANT1) cause musculoskeletal and neurological diseases by clogging TOM and TIM22 and inducing mPOS. Here, we found that overexpression of MFB1, encoding the mitochondrial F-box protein 1, suppresses cell growth defect caused by a clogger allele of AAC2, the yeast homolog of human Ant1. Disruption of MFB1 synergizes with a clogger allele of aac2 to inhibit cell growth. This is accompanied by increased retention of mitochondrial proteins in the cytosol, suggesting exacerbated defect in mitochondrial protein import. Proximity-dependent biotin identification (BioID) suggested that Mfb1 interacts with several mitochondrial surface proteins including Tom22, a component of the TOM complex. Loss of MFB1 under clogging conditions activates genes encoding cytosolic chaperones including HSP31. Interestingly, disruption of HSP31 creates a synthetic lethality with protein import clogging under respiring conditions. We propose that Mfb1 functions to maintain mitochondrial protein import competency under clogging conditions, whereas Hsp31 plays an important role in protecting the cytosol against mPOS. Mutations in DJ-1, the human homolog of Hsp31, and mitochondria-associated F-box proteins (eg., Fbxo7) are known to cause early-onset Parkinson's disease. Our work may help to better understand how these mutations affect cellular proteostasis and cause neurodegeneration.
    Keywords:  DJ-1; F-box protein; Parkinson’s disease; Yeast; chaperone; clogging; mPOS; mitochondria; protein import
    DOI:  https://doi.org/10.1093/genetics/iyaf279
  2. Int J Mol Sci. 2025 Dec 13. pii: 12023. [Epub ahead of print]26(24):
    Mitochondrial tRNA-Derived Diseases.
    Antonia Petropoulou, Nikolaos Kypraios, Dimitra Rizopoulou, Adamantia Kouvela, Alexandros Maniatis, Katerina Anastasopoulou, Alexandra Anastogianni, Theodoros Korfiatis, Katerina Grafanaki, Vassiliki Stamatopoulou, Constantinos Stathopoulos.
      Mitochondrial tRNA genes are critical hotspots for pathogenic mutations and several mitochondrial diseases. They account for approximately 70-75% of disease-causing mtDNA variants despite comprising only 5-10% of the mitochondrial genome. These mutations interfere with mitochondrial translation and affect oxidative phosphorylation, resulting in remarkably heterogeneous multisystem disorders. Under this light, we systematically reviewed PubMed, Scopus, and MITOMAP databases through October 2025, indexing all clinically relevant pathogenic mt-tRNA mutations classified by affected organ systems and underlying molecular mechanisms. Approximately 500 distinct pathogenic variants were identified across all 22 mt-tRNA genes. Beyond typical syndromes like MELAS, MERRF, Leigh syndrome, and Kearns-Sayre syndrome that are linked to mt-tRNA mutations, they increasingly implicate cardiovascular diseases (cardiomyopathy, hypertension), neuromuscular disorders (myopathies, encephalopathies), sensory impairment (hearing loss, optic neuropathy), metabolic dysfunction (diabetes, polycystic ovary syndrome), renal disease, neuropsychiatric conditions, and cancer. Beyond sequence mutations, defects in post-transcriptional modification systems emerge as critical disease mechanisms affecting mt-tRNA function and stability. The mutations on tRNA genes described herein represent potential targets for emerging genome editing therapies, although several translational challenges remain. However, targeted correction of pathogenic mt-tRNA mutations holds transformative potential for precision intervention on mitochondrial diseases.
    Keywords:  human diseases; mitochondrial tRNA; mt-tRNA modifications; mtDNA mutations
    DOI:  https://doi.org/10.3390/ijms262412023
  3. bioRxiv. 2025 Dec 17. pii: 2025.12.16.694759. [Epub ahead of print]
    Hippocampal cell- and circuit-specific differences in mitochondrial form and function.
    Mayd Alsalman, Lucy Turner, Katy Pannoni, Renesa Tarannum, Rutvi Desai, Sharon A Swanger, Shannon Farris.
      Mitochondrial morphology varies by neuronal cell type and subcellular compartment; however, the functional significance of these differences is unclear. Hippocampal CA2 neurons are enriched for genes encoding mitochondrial proteins compared to CA1 neurons, suggesting a difference in metabolic demand across hippocampal circuits. However, whether CA2 neuron mitochondria are structurally or functionally distinct to support circuit-specific energy demands is unknown. Here we compared mitochondrial morphology, protein expression, and calcium levels across CA1 and CA2 circuits. We found mitochondria in CA2 dendrites were larger than mitochondria in CA1 dendrites. However, both subregions harbored larger mitochondria in the entorhinal cortex (EC)-contacting distal dendrites compared to CA3-contacting proximal dendrites. Together, these data demonstrate both cell type- and input-specific regulation of mitochondrial morphology that likely influences the function of these distinct circuits. To determine whether differences in mitochondrial fission or fusion account for cell and/or layer specific differences in morphology, we immunostained for OPA1 and MFF, which showed a general enrichment in distal dendrites relative to proximal dendrites, and an unexpected increase in CA1 distal dendrites compared to CA2 distal dendrites. To show whether these morphological differences result in functionally distinct mitochondria, we measured mitochondrial calcium levels in live slices. We found a striking enrichment of mitochondrial calcium levels in CA2 distal dendrites relative to proximal dendrites, and this layer-specific effect was significantly different from that in CA1 dendrites at baseline and after activity. Collectively, these findings reveal discrete morphological and functional differences in mitochondria across hippocampal subregions and dendritic layers, which likely confer unique circuit properties and/or vulnerabilities to disease.
    DOI:  https://doi.org/10.64898/2025.12.16.694759
  4. Brain Dev. 2025 Dec 29. pii: S0387-7604(25)00179-2. [Epub ahead of print]48(1): 104497
    Ferroptosis susceptibility in primary coenzyme Q10 deficiency: Cellular insights from patient fibroblasts and clinical course of six individuals.
    Chika Watanabe, Akihiko Miyauchi, Shiho Aoki, Miyuki Watanabe, Eriko F Jimbo, Yuudai Miyama, Hirotsugu Kitayama, Yuichi Uno, Kenji Watanabe, Yuka Hattori, Yuka Yotsumoto, Takanori Onuki, Yohei Sugiyama, Keiko Ichimoto, Yukiko Yatsuka, Yasushi Okazaki, Toshiyuki Imasawa, Kei Murayama, Akira Ohtake, Takanori Yamagata, Hitoshi Osaka.
       BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiency is a group of mitochondrial disorders caused by pathogenic variants of genes involved in CoQ10 biosynthesis. Although some patients respond to oral CoQ10 supplementation, the pathophysiology remains poorly understood. Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, is suppressed by reduced CoQ10via ferroptosis suppressor protein 1 (FSP1). However, its involvement in primary CoQ10 deficiency has not yet been studied using patient-derived cells.
    CASES AND RESULTS: We reported six patients from three families and investigated ferroptosis susceptibility in fibroblasts from three representative patients: one with COQ2 variants and two with COQ4 variants. Fibroblasts with COQ2 variants showed increased vulnerability to ferroptosis inducers, plasma membrane lipid peroxidation. In contrast, fibroblasts with COQ4 variants exhibited only mild changes. Notably, susceptibility to ferroptosis remained unchanged after increasing intracellular CoQ10 levels. Despite this persistent ferroptosis sensitivity in vitro, the COQ2 patient exhibited significant clinical improvement following CoQ10 supplementation. These findings suggest that ferroptosis may contribute to cellular vulnerability in primary CoQ10 deficiency but may not be the primary driver of renal and neurological symptoms.
    CONCLUSIONS: Our results highlight a complex interplay between CoQ10 biosynthesis, ferroptosis defense, and therapeutic response, warranting further investigation of subcellular CoQ10 distribution and ferroptosis-related mechanisms.
    Keywords:  Coenzyme Q(10); Ferroptosis; Ferroptosis suppressor protein 1 (FSP1); Mitochondrial disease; Primary coenzyme Q(10) deficiency
    DOI:  https://doi.org/10.1016/j.braindev.2025.104497
  5. bioRxiv. 2025 Dec 18. pii: 2025.12.17.694973. [Epub ahead of print]
    Self-renewal of neuronal mitochondria through asymmetric division.
    Tejashree Pradip Waingankar, Camryn Zurita, Angelica E Lang, Cliff Vuong, Ahmad Shami, Diana Bautista, Catherine Drerup, Samantha C Lewis.
      Mitochondrial ATP production is essential for life. Mitochondrial function depends on the spatio-temporal coordination of nuclear and mitochondrial genome expression, yet how this coordination occurs in highly polarized cells such as neurons remains poorly understood. Using high-resolution imaging in mouse peripheral sensory neurons and zebrafish larvae, we identified a sub-population of mitochondria enriched in mtDNA that are positioned at the collateral branch points of long sensory neurites, both in vitro and in vivo . While the mitochondria in neurites are generally depleted of mtDNA, those at axon branch points preferentially engage in mtDNA replication and transcription, accumulate nuclear-encoded mitochondrial mRNA, and are spatially linked to nascent cytosolic peptide synthesis. The mtDNA-positive mitochondrial pool exhibits asymmetric genome partitioning at division, shedding highly motile daughters that lack mtDNA. Asymmetric division rejuvenates the membrane potential of the mtDNA-rich, biogenesis-dedicated mitochondria. We also found that, in peripheral sensory neurons, axonal mitochondria rarely fuse or share matrix contents, explaining how differentiated daughters maintain their distinct composition and fate after fission. Thus, division-coupled mitochondrial self-renewal is yoked to neurite topology in sensory neurons, patterning mitochondrial diversity and homeostasis from micron to meter scales.
    DOI:  https://doi.org/10.64898/2025.12.17.694973
  6. Int J Mol Sci. 2025 Dec 08. pii: 11852. [Epub ahead of print]26(24):
    Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.
    Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Vito Pesce, Anna Picca.
      Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.
    Keywords:  axonal transport; cell architecture; cell quality; cytoskeleton; mitochondrial dynamics; mitochondrial quality; mitophagy; neurofilaments; neuron; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms262411852
  7. ACS Chem Neurosci. 2025 Dec 27.
    Synuclein and Mitochondrial Dysfunction: Regulating the Protein Import Complex toward PD Treatment?
    Udit Kumar Dash, Radhakrishnan Mahalakshmi.
      Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by severe motor symptoms. While the degeneration of dopaminergic neurons in the substantia nigra plays a central role, other neurotransmitter systems also contribute to PD symptoms. α-Synuclein (αSyn), normally expressed in neurons to support synaptic function and neurotransmitter release, becomes pathologically accumulated in PD, despite not being upregulated under physiological conditions. Intracellular aggregation of αSyn into Lewy bodies is a hallmark of synucleinopathies. A vital facet of both the onset and progression of PD involves mitochondrial dysfunction, which links αSyn misimport into mitochondria with neuronal death. The interaction of αSyn with mitochondrial membranes has been identified, yet the complex stepwise biological mechanisms of αSyn misimport into the mitochondrial compartments, followed by its aggregation, culminating in mitochondria-mediated apoptosis, remain unknown. The Translocase of the Outer Mitochondrial Membrane (TOM) complex, vital for unidirectional import of >1300 mitochondrial proteins from the cytosol, can additionally misimport αSyn into mitochondria. This TOM-αSyn interplay can alter calcium homeostasis, reduce ATP biogenesis, elevate reactive oxygen species generation, and compromise mitochondrial dynamics, resulting in mitochondrial dysfunction and triggering cell death in dopaminergic neurons. Detailed analyses of TOM complex function, interactome, and TOM-αSyn association could lead to treatment approaches that restore mitochondrial homeostasis by mitigating the effects of αSyn pathology in neurodegenerative conditions. This review details the most recent findings on independent regulators of αSyn and the TOM complex and discusses TOM-αSyn interaction mechanisms and their outcomes on mitochondrial dynamics toward promoting development of therapeutics for neurodegeneration.
    Keywords:  Parkinson’s diseases; TOM complex; aggregation blockers; mitochondrial misimport; neurotoxic plaque; synuclein
    DOI:  https://doi.org/10.1021/acschemneuro.5c00323
  8. Mol Cell Biol. 2026 Jan 02. 1-19
    Mitochondria and Lipids in Cellular Signaling of the Brain: from Physiology to Neurodegeneration.
    Plamena R Angelova, Lauren Millichap, Andrey Y Abramov.
      The brain is one of the most lipid-rich organs, reflecting the critical role of lipid metabolism in neuronal and glial cell function. While mitochondria are central to energy metabolism, calcium signaling, and cell death, they do not utilize lipid oxidation for energy but rely on lipids for membrane integrity and intracellular communication. Here we review the interactions between lipids and mitochondria in intracellular signaling within brain cells, examining their roles in normal physiology and the mechanisms underlying major neurodegenerative diseases. Alterations in lipid homeostasis and mitochondrial metabolism are implicated in neurodegeneration, highlighting the importance of lipid-mediated mitochondrial signaling pathways. Understanding these interactions provides insights into cellular dysfunction in neurodegenerative disorders and may inform future therapeutic strategies targeting lipid and mitochondrial pathways.
    Keywords:  Lipid signaling; calcium signaling; lipid peroxidation; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.1080/10985549.2025.2607428
  9. Biomedicines. 2025 Dec 18. pii: 3125. [Epub ahead of print]13(12):
    Propofol-Induced Mitochondrial Dysfunction Is Independent of Mitochondrial Permeability Transition.
    Aya Kawachi, Shoichiro Shibata, Eskil Elmér, Hiroyuki Uchino.
      Background/Objectives: In recent years, it has been suggested that sedatives may cause brain damage. One possible mechanism is interference with oxidative phosphorylation of brain mitochondria, but much remains unknown. In this study, we focused on dexmedetomidine, midazolam, and propofol, essential sedatives in anesthesia and intensive care, and aimed to understand the effects of these drugs on mouse brain mitochondria. Methods: We measured changes in mitochondrial respiratory capacity and swelling rate upon exposure to these sedatives in a wide concentration range. For the sedative that demonstrated impaired mitochondrial function we explored the possible involvement of mitochondrial permeability transition pore opening using brain mitochondria from cyclophilin D knockout (CypD KO) mice and detected cytochrome c (cyt c) release by Western blot. Results: Of the three sedatives, only high concentrations of propofol exhibited reduced respiratory capacity and mitochondrial swelling, toxicity which was not prevented by CypD KO. Furthermore, propofol did not induce cyt c release. Conclusions: These results suggest that propofol-induced brain mitochondrial dysfunction is a mechanism independent of mPTP opening.
    Keywords:  cyclophilin D; mitochondrial dysfunction; mitochondrial permeability transition pore; mitochondrial respiratory capacity; mitochondrial swelling; propofol
    DOI:  https://doi.org/10.3390/biomedicines13123125
  10. Biochimie. 2025 Dec 26. pii: S0300-9084(25)00316-5. [Epub ahead of print]242 97-107
    Extracellular mitochondria: a potential player involved in exercise health benefits.
    Mafalda Barbosa Pedrosa, Lúcio Lara Santos, Rita Ferreira, José Magalhães.
      Exercise is widely recognized as an effective nonpharmacological therapy for noncommunicable diseases, with its health benefits mediated in part by exerkines. Recently, extracellular mitochondria (ex-Mito) have been suggested as a player in mediating intercellular communication. While it is known that the health benefits of exercise involve the remodeling of mitochondria in multiple organs, the impact of exercise on circulating ex-Mito is poorly understood. Most existing studies have focused on cell-free circulating mitochondrial DNA, skeletal muscle-derived extracellular vesicles, or platelet-derived mitochondria, without focusing on other types of ex-Mito. The cellular origin of exercise-induced circulating ex-Mito and the role of each form (vesicle-enclosed, free, or as mitochondrial components) in mediating exercise's therapeutic effects are yet to be elucidated. This review aims to delve into the role of ex-Mito as potential players in exercise-related health benefits, paving the way for future research aimed at uncovering the molecular culprits of this nonpharmacological therapy, including mitochondrial transfer and transplantation.
    Keywords:  Exercise training; Mitochondrial remodeling; Mitochondrial transfer; Mitochondrial transplantation; Nonpharmacological therapy
    DOI:  https://doi.org/10.1016/j.biochi.2025.12.011
  11. Angew Chem Int Ed Engl. 2025 Dec 30. e20934
    Real-Time Super-Resolution Tracking of mtDNA Remodeling and Inflammatory Release with a Selective Fluorescent Probe.
    Shixian Cao, Caixia Sun, Xin-Yue Zhang, Changyu Yoon, Zhiqiang Liu, Jiyoung Yoo, Yujin Kim, Xiaoqiang Yu, Yunjie Xu, Jong Seung Kim, Kang-Nan Wang.
      Mitochondrial DNA (mtDNA) is vital for mitochondrial function and cellular homeostasis, with its spatiotemporal dynamics are tightly linked to development, metabolism, and disease progression. However, super-resolution tracking of mtDNA in live cells remains limited by lack of selective, photostable small-molecule probes. Here, we present mtNARed, a rationally engineered, wash-free fluorescent probe featuring a large Stokes-shift, and high photostability that enables super-resolution tracking of mtDNA dynamics in live cells using stimulated emission depletion (STED) microscopy, with complementary readouts by fluorescence-lifetime imaging microscopy (FLIM). mtNARed precisely localizes to mitochondrial nucleoids and supports long-term imaging while minimizing interference from nuclear DNA. This capability generalizes across diverse mammalian cell types, including highly polarized sperm cells. Importantly, under mitochondrial stress or inflammatory stimulation, mtNARed reports in situ and at super-resolution of the progressive release of mtDNA, correlating with mitochondrial depolarization, membrane disintegration, and immune activation. This work provides a robust and versatile platform for advanced mtDNA imaging, opening opportunities to dissect mitochondrial genome dynamics, maintenance, and signaling across physiological and pathological states.
    Keywords:  STED super resolution imaging; mtDNA dynamics tracking; mtDNA remodeling & inflammatory release; mtDNA selective targeting probe
    DOI:  https://doi.org/10.1002/anie.202520934
  12. Front Immunol. 2025 ;16 1710128
    Mitochondrial calcium shapes B cell signaling and mitochondrial function.
    Hakan Taskiran, Elena Czeslik, Leonhard Stark, Kathrin Kläsener, Theresa Elisa Schnalzger, Jürgen Ruland, Michael Reth, Julia Jellusova.
       Introduction: Calcium (Ca2+) signaling plays a pivotal role in determining B cell fate, shaping processes such as activation, differentiation, anergy or apoptosis. Upon B cell antigen receptor activation, Ca2+ is rapidly mobilized from the endoplasmic reticulum and supplemented by Ca2+ influx from the extracellular space, ultimately driving activation of various signaling pathways required for appropriate B cell responses. Although mitochondria also harbor significant levels of Ca2+, how mitochondrial Ca2+ dynamics are regulated in B cells in response to activation or other cues remains unknown, as do the functional consequences of altered mitochondrial Ca2+ levels.
    Methods: Chemical dyes as well as a genetically encoded Ca2+ sensor with a mitochondrial targeting sequence were used to study mitochondrial Ca2+ dynamics in response to various stimuli. Proximity ligation assays were performed to assess interaction between mitochondria and the endoplasmic reticulum. Primary mouse B cells and the Burkitt lymphoma cell line Ramos were used to study functional consequences of the loss of the Mitochondrial Calcium Uniporter.
    Results: Here, we show that mitochondrial Ca2+ levels dynamically respond to cell activation, stress and metabolic cues and that mitochondrial Ca2+ uptake is largely dependent on the Mitochondrial Calcium Uniporter. Reduced mitochondrial Ca2+ uptake has a negative impact on mitochondrial activity and also affects cell signaling. These findings demonstrate that changes in mitochondrial Ca2+ contribute to shaping functional B cell responses.
    Discussion: The spatial and temporal dynamics of Ca2+ accumulation within distinct subcellular compartments, particularly the cytosol, endoplasmic reticulum and mitochondria, are essential for translating extracellular and intracellular signals into specific cellular outcomes. Our study provides new insights into the regulation of Ca2+ homeostasis in B cells.
    Keywords:  B lymphocyte; calcium; metabolism; mitochondria; signaling
    DOI:  https://doi.org/10.3389/fimmu.2025.1710128
  13. Nat Cardiovasc Res. 2026 Jan 02.
    Real-time measurement of the mitochondrial membrane potential in the intact mouse heart.
      
    DOI:  https://doi.org/10.1038/s44161-025-00767-2
  14. Front Aging Neurosci. 2025 ;17 1692777
    Pterostilbene restores mitochondrial retrograde signaling to activate protective stress responses in Parkinson's disease.
    Fanshuai Zeng, Wei Li, Liyue Yang, Lu Yao, Xinna Wang.
      Parkinson's disease (PD) is the selective demise of dopaminergic neurons in the substantia nigra. Conventional neuroprotective strategies based on exogenous antioxidants have shown minimal clinical efficacy. Emerging evidence suggests that neuronal loss in PD may stem not only from direct mitochondrial damage but, more critically, from the failure of an intrinsic "early-warning system"-the mitochondrial retrograde signaling (MRS) pathway-impairing the nucleus's ability to launch timely protective responses. This review repositions pterostilbene, a bioavailable dietary polyphenol, from a simple antioxidant to a "signal fidelity enhancer" that supports mitochondria-to-nucleus communication. By stabilizing mitochondrial function and modulating stress-sensing pathways, pterostilbene may restore MRS integrity and promote activation of endogenous defense mechanisms such as the mitochondrial unfolded protein response (UPRmt). The article advocates a paradigm shift in nutritional neuroprotection: from passive supplementation toward reinforcing the neuron's intrinsic capacity for self-maintenance and resilience.
    Keywords:  Parkinson’s disease; cellular resilience; dopaminergic neurons; mitochondrial retrograde signaling; neuroprotection; polyphenols; pterostilbene
    DOI:  https://doi.org/10.3389/fnagi.2025.1692777
  15. Cell Death Dis. 2025 Dec 27.
    Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.
    Alessandra Scagliola, Annarita Miluzio, Martina Pauselli, Marcello Ceci, Stefano Biffo, Sara Ricciardi.
      Vanishing White Matter Disease (VWMD) is a devastating, currently incurable neurodevelopmental disorder primarily affecting white matter. The prevailing view attributes VWMD to the activation of the canonical integrated stress response (c-ISR). However, recent studies have identified a novel, distinct pathway called the split ISR (s-ISR), though its activation has so far only been documented in mouse stem cells harboring a single eIF2B mutation, leaving uncertainty about whether it occurs in human cells, whether other mutations can trigger it, and what role it plays in the disease. Here, we used prime editing (PE) to engineer multiple eIF2B pathogenic mutations into HEK293T and induced pluripotent stem cells (iPSCs), generating human models. We demonstrated PE's effectiveness and safety, marking the first successful application of PE for modeling VWMD. We found that all modeled mutations activate the s-ISR, indicating that this response is a common feature across VWMD mutations, and that it can be further amplified by stress-induced c-ISR and effectively suppressed by ISRIB. Mechanistically, we show that s-ISR hinders mutant iPSCs from achieving the high protein synthesis levels necessary for proper differentiation, expecially into astrocytes. This impairment disrupts their maturation process, directly linking s-ISR activation to the white matter abnormalities of VWMD.
    DOI:  https://doi.org/10.1038/s41419-025-08399-x
  16. Front Neurosci. 2025 ;19 1665272
    ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
    Chaitanya Kunja, Vaishali Kumar, Pradeep Kodam, Chamundeshwari Devi Gopu, Shuvadeep Maity.
      The endoplasmic reticulum (ER) and mitochondria are essential organelles that interact closely at specialized sites known as ER-mitochondria-associated membranes (MAMs). MAM is enriched with proteins from both the ER and mitochondria. ER stress sensors-inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) - are traditionally recognized for their roles in the unfolded protein response (UPR), which mitigates proteotoxic stress. However, recent studies reveal their non-canonical functions at MAMs, where they regulate calcium signaling, mitochondrial dynamics, and apoptosis through interactions with MAM-resident proteins. Disruption of these pathways is implicated in various diseases, particularly neurodegenerative disorders. This review highlights the emerging roles of IRE1 and PERK in preserving mitochondrial function and their relevance to neurodegeneration. It also examines pharmacological strategies targeting these proteins, which influence both UPR signaling and ER-mitochondrial communication, offering a comprehensive perspective on their roles in health and disease.
    Keywords:  ER stress sensors; ER-mitochondrial interactions; IRE1; UPR signaling; mitochondrial health; neurodegenerative diseases; pERK
    DOI:  https://doi.org/10.3389/fnins.2025.1665272
  17. Mol Genet Metab. 2025 Dec 27. pii: S1096-7192(25)00704-8. [Epub ahead of print]147(1): 109712
    Elevated cerebrospinal fluid 2-Hydroxybutyric acid in two siblings with aspartate-glutamate carrier 1 deficiency.
    Noemi Urquiza, Arthur Partikian, Stefan Bluml, Hirotomo Saitsu, Naomichi Matsumoto, Lindsay Williams Griffith, Rachel McGowan, Shoji Yano.
      The mitochondrial aspartate-glutamate carrier 1 (AGC1 or aralar) is a key component of the malate-aspartate shuttle (MAS), which transfers NADH-derived reducing equivalents from the cytosol into mitochondria to support oxidative phosphorylation. Disruption of MAS leads to cytosolic NADH accumulation, NAD+ depletion, and a reduced NAD+/NADH ratio, impairing redox-sensitive enzymes. AGC1 is primarily expressed in the central nervous system. AGC1 deficiency is a rare autosomal recessive disorder characterized by seizures, intellectual disability, and hypomyelination. The disorder impairs mitochondrial export of aspartate, thereby reducing neuronal synthesis of N-acetylaspartate (NAA), which is essential for myelination by oligodendrocytes. Consequently, hypomyelination is noted on MRI, and NAA appears decreased on MR spectroscopy (MRS). CASE STUDY: Two Hispanic male siblings (now 21y and 17y) with a homozygous SLC25A12 mutation (p.Gly398Val) presented with seizures, intellectual disability, hypotonic-ataxic cerebral palsy, and characteristic MRI/MRS findings. Their diagnosis was confirmed by whole exome sequencing when they were 9 and 4 years old, respectively. MRI showed cerebral atrophy and cortical dysplasia. MRS showed diffuse reduction in NAA and a consistent but unknown signal at 3.62 ppm. Aspartate supplementation did not result in any clinical or imaging improvement. Subsequently, both were treated with a modified Atkins/ketogenic diet with MCT oil in addition to antiseizure medications for eight years, with inconsistent dietary adherence. The elder brother has remained stable with some developmental progress, while the younger brother recently experienced mild regression following a period of developmental stability. Follow-up imaging showed no significant change. CSF organic acid analysis revealed elevated 2OH-butyrate, lactate, pyruvate, and acetoacetate, with low levels of glycolate, glyoxylate, and 5-oxoproline. Both brothers exhibited a marked preference for high-protein foods and an aversion to sweets from early childhood, mirroring dietary patterns commonly observed in citrin deficiency. DISCUSSION: We describe the two oldest known individuals with AGC1 deficiency. Their neuroimaging results remained largely stable over eight years of ketogenic therapy. The elder sibling showed modest progress, while the younger regressed in some motor milestones at age 16. Although blood and urine metabolomics were non-diagnostic, CSF organic acids revealed patterns suggestive of impaired redox balance, supporting mitochondrial dysfunction as a key feature of AGC1 deficiency.
    Keywords:  2-hydroxybutyric acid; AGC1; High protein diet preference; Malate-aspartate shuttle; Redox potential
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109712
  18. Biomolecules. 2025 Dec 16. pii: 1742. [Epub ahead of print]15(12):
    Systems-Level Integration of Multi-Omics Identifies Genetic Modifiers of TANGO2 Deficiency Disorder.
    Manuel Airoldi, Heather Bondi, Veronica Remori, Silvia Carestiato, Giovanni Battista Ferrero, Alfredo Brusco, Mauro Fasano.
      TANGO2 deficiency disorder is a rare autosomal recessive disease (~100 cases reported worldwide). Despite being caused by loss-of-function variants in the TANGO2 gene, patients exhibit marked phenotypic variability, including intrafamilial differences among individuals carrying identical variants. To uncover potential modifier mechanisms influencing disease severity, we developed an integrative Systems biology framework, combining exome sequencing, transcriptomics, variant effect prediction, and Human Phenotype Ontology mapping. This approach was applied to two siblings carrying identical compound heterozygous TANGO2 variants but opposite clinical outcomes: one severely affected and one asymptomatic. Personalized protein-protein interaction networks and combined univariate and multivariate analyses were employed to maximize specificity in this single-family comparison. In the affected sibling, a cumulative burden of common APOB variants, together with altered VLDLR, NTN1, and LDHA expression, implicated disrupted lipid metabolism and neurodevelopmental pathways. The asymptomatic sibling harbored a potentially protective 3'-UTR variant in EP300 and no APOB variant burden, supporting enhanced post-transcriptional regulation within developmental biology networks. These findings highlight lipid metabolism as a key pathway in TANGO2 deficiency pathophysiology and suggest autophagy and mitophagy as additional modifier mechanisms influencing phenotypic variability. Our integrative multi-omics framework provides a valuable strategy for elucidating genotype-phenotype relationships in rare diseases and supports personalized therapeutic approaches.
    Keywords:  TANGO2 deficiency disorder; genetic modifiers; multi-omics; network medicine
    DOI:  https://doi.org/10.3390/biom15121742
  19. Genes (Basel). 2025 Dec 15. pii: 1497. [Epub ahead of print]16(12):
    SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging.
    Kate Šešelja, Ena Šimunić, Sandra Sobočanec, Iva I Podgorski, Marija Pinterić, Marijana Popović Hadžija, Tihomir Balog, Robert Belužić.
      Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This review synthesizes evidence showing how SIRT3 loss in select "driver tissues"-notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary-initiates systemic aging through the release of cytokines, oxidized metabolites, and extracellular vesicles. We discuss molecular routes and mediators of senescence propagation, including the senescence-associated secretory phenotype (SASP), mitochondrial-derived vesicles, and circulating mitochondrial DNA, as well as sex-specific modulation of SIRT3 by hormonal and intrinsic factors. By integrating multi-tissue and sex-dependent data, we outline a framework in which SIRT3 activity defines the mitochondrial threshold separating local adaptation from systemic aging spread. Targeting SIRT3 and its NAD+-dependent network may offer a unified strategy to restore mitochondrial quality, dampen chronic inflammation, and therefore recalibrate the aging dynamics of an organism.
    Keywords:  NAD+ metabolism; SIRT3; aging drivers; extracellular vesicles; inflammaging; mitochondrial acetylation; senescence; sex differences; systemic aging
    DOI:  https://doi.org/10.3390/genes16121497
  20. J Genet Genomics. 2025 Dec 30. pii: S1673-8527(25)00351-0. [Epub ahead of print]
    Tiny genome with big impact: mitochondrial DNA in cardiovascular health.
    Yafang Yang, Jiaoyu Li, Lu Qian, Yuyan Xiong, Yi Yu.
      Cardiovascular diseases remain the leading cause of mortality worldwide. Mitochondrion, a key cellular organelle, harbors its own mitochondrial DNA (mtDNA) fundamental to cellular energy production through oxidative phosphorylation (OXPHOS). Beyond its canonical bioenergetic function, mtDNA integrity, copy number, and genetic variation play critical roles in maintaining cardiovascular function. This review provides a comprehensive overview of the multifaceted contributions of mtDNA to cardiovascular health and disease. We summarize the structural features and core biological functions of mtDNA, as well as the regulatory mechanisms governing its replication, biogenesis, and turnover. Particular emphasis is focused on mtDNA abnormalities, including point mutations, large-scale deletions, copy number alterations, and epigenetic modifications, and how these disturbances drive key pathogenic processes such as oxidative stress, chronic inflammation, apoptosis, and cellular senescence within the cardiovascular system. Furthermore, we highlight accumulating evidence linking mtDNA dysregulation to major cardiovascular disorders, including heart failure, atherosclerosis, and hypertension. Finally, we discuss the emerging diagnostic potential of circulating cell-free mtDNA and related mtDNA-derived metrics as non-invasive biomarkers, and outline therapeutic strategies aimed at preserving mtDNA integrity, modulating mtDNA content, or applying gene-based interventions to mitigate cardiovascular pathology.
    Keywords:  Mitochondrial DNA; cardiovascular diseases; diagnosis and therapy; inflammation; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.jgg.2025.12.009
  21. Circ Res. 2025 Dec 29.
    Novel DNJ Derivative Ameliorates Cardiac Hypertrophy by Targeting OPA1 and Restoring Mitochondrial Health.
    Xue Ding, Yangwei Jiang, Xiaochen Wang, Chujun Li, Zhengyi Kong, Lei Fu, Zhaoying Lei, Huajian Cai, Yufei Dong, Chengyu Shi, Xinwan Su, Tilo Kunath, Ziyi Wang, Damiano Buratto, Aifu Lin, Jianzhong Shao, Dong Zhang, Zhong Liu, Ping Liang, Ruhong Zhou, Qingfeng Yan.
       BACKGROUND: Pathological cardiac hypertrophy, an abnormal enlargement of cardiomyocytes and interstitial fibrosis in response to sustained injury or pressure overload, may lead to heart failure or even sudden death. Affected patients often also exhibit myocardial mitochondrial dysfunction and associated structural damage. Discovering more potent mitochondrial-targeting compounds may therefore hold great benefit, both for elucidating the mechanisms of cardiac hypertrophy and for treating affected patients.
    METHODS: A series of novel 1-deoxynojirimycin (DNJ) derivatives was designed based on the unique binding mode of DNJ with OPA1 (optic atrophy 1). Two-step phenotypic screening was then performed using patient-specific cytoplasmic hybrid cells and iPSC-derived cardiomyocytes to identify promising candidates. Molecular dynamics simulations, combined with proteomic, biochemical, and physiological assays, were used to assess potential therapeutic mechanisms for mitochondrial disorders. OPA1 mutant cell lines were established to test candidate compound target specificity. Pathological cardiac hypertrophy models were established in mice and rats through angiotensin II induction and abdominal aortic constriction, enabling comprehensive evaluation of the candidates' preventive and therapeutic efficacy.
    RESULTS: DNJ occupies a cavity formed by the GTPase domain of the OPA1 dimer, acting as an additional linker at the dimeric OPA1 interface. Here, we have designed and identified a novel DNJ derivative, DNJ5a. Compared with DNJ, DNJ5a exhibits enhanced in silico and in vitro binding specificity, providing additional anchor sites for direct OPA1 interaction. This interaction facilitates the stabilization of the OPA1 dimeric form to repair mitochondrial cristae damage and maintain inner membrane integrity. Comprehensive improvements in mitochondrial bioenergetics, Ca2+ homeostasis, mitophagy, and multidimensional functional responses are seen to result. In 2 rodent animal cardiac hypertrophy models, DNJ5a administration showed excellent preventive and therapeutic efficacy towards promoting mitochondrial health and cardiac function in vivo.
    CONCLUSIONS: Unlike conventional mitochondrial drugs, which act to alleviate symptoms, DNJ5a can specifically target OPA1-GTPase and comprehensively improve mitochondrial health to ameliorate cardiac hypertrophy. These findings underscore mitochondrial abnormality as a primary contributor to pathological cardiac remodeling and present OPA1 as a strong potential drug target. The underlying mechanism of this novel agonist DNJ5a may pave the way towards developing many other promising mitochondrial-targeted therapeutics.
    Keywords:  1-deoxynojirimycin; cardiomegaly; mitochondria; mitophagy; optic atrophy, autosomal dominant
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327407
  22. ACS Nano. 2025 Dec 30.
    Muscle-Targeted Nanocomposite Therapy Alleviates Age-Related Sarcopenia via Antioxidant and Metabolic Reprogramming.
    Zhang Liu, Zile Shen, Hengli Lu, Bingqiang Lu, Peng Zhang, Wenhao Chen, Guowei Huang, Xinyu Qu, Zhen Yu, Feng Chen, Wangfu Zang.
      Sarcopenia, a progressive skeletal muscle disorder marked by loss of mass and function, presents growing societal challenges due to limited therapeutic options. Here, we identify mitochondrial dysfunction and oxidative stress as central drivers of sarcopenia through integrated bioinformatics and clinical validation. To address this pathophysiology, we engineer a muscle-targeted nanocomposite (BP-PEG-MOTS-c, BM) combining mitochondrial-derived peptide MOTS-c with antioxidant black phosphorus nanosheets (BP). BM exhibits dual functionality: MOTS-c restores mitochondrial function, while BP synergistically amplifies ROS scavenging capacity. In cellular and murine models with age-related sarcopenia, BM treatment alleviates muscle dysfunction and muscle loss, concurrently normalizing mitochondrial function and reducing lipid peroxidation. Mechanistic profiling via RNA-seq reveals BM's activation of PI3K/AKT/Nrf2 and suppression of ROS/p38 MAPK signaling pathway, mediating antioxidant responses and maintenance of mitochondrial homeostasis. The nanocomposite demonstrats superior biocompatibility in toxicity assays, outperforming conventional delivery systems. Our findings establish that BM has been established as a promising mitochondrial redox modulator with translational potential for sarcopenia and related age-associated pathologies.
    Keywords:  black phosphorus nanosheets; metabolic reprogramming; mitochondria; reactive oxygen species; sarcopenia
    DOI:  https://doi.org/10.1021/acsnano.5c18226
  23. Sci Rep. 2025 Dec 29. 15(1): 44799
    Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells.
    Mai Kanai, Miyabi Goto, Shoko Itakura, Makiya Nishikawa, Kosuke Kusamori.
      Mitochondrial transplantation holds great promise as a therapeutic strategy; however, the mechanisms by which recipient cells interact with and internalize isolated mitochondria remain unclear. Therefore, in this study, we isolated functional mitochondria from mesenchymal stromal cells (MSCs) and characterized their biological activities and physicochemical properties. Additionally, effects of isolated mitochondria on MSC functions were evaluated. Treatment with isolated mitochondria promoted cell proliferation, improved cellular viability under stress conditions, and increased the oxygen consumption rate, indicating enhanced bioenergetic capacity. Uptake of isolated mitochondria by MSCs was visualized via fluorescence imaging and quantitatively assessed over time, showing progressive internalization within 24 h. To investigate the mechanism of mitochondrial uptake, endocytosis was chemically inhibited, which revealed that endocytic pathways contributed to the internalization of the isolated mitochondria. These findings suggest that MSCs incorporate isolated mitochondria via active uptake mechanisms and that the internalized mitochondria retain their functional activity. Collectively, our results provide critical evidence of mitochondrial internalization in MSCs and offer insights into the potential applications of mitochondrial therapy for various diseases.
    Keywords:  Biomedicine; Cellular uptake; Endocytosis; Mesenchymal stromal cell; Mitochondrial transplantation
    DOI:  https://doi.org/10.1038/s41598-025-28494-5
  24. Int J Mol Sci. 2025 Dec 14. pii: 12039. [Epub ahead of print]26(24):
    First Latin American Case of MLASA2 Caused by a Pathogenic Variant in the Anticodon-Binding Domain of YARS2.
    José Rafael Villafán-Bernal, Jhonatan Rosas-Hernández, Humberto García-Ortiz, Angélica Martínez-Hernández, Cecilia Contreras-Cubas, Israel Guerrero-Contreras, Hane Lee, Go Hun Seo, Alessandra Carnevale, Francisco Barajas-Olmos, Lorena Orozco.
      MLASA2 is a rare mitochondrial disorder with limited geographic representation in published medical literature. Here, we report the first confirmed case of MLASA2 in a Latin American 16-year-old male harboring a homozygous pathogenic variant p.(Asp311Glu) in the YARS2 gene. The patient presented with sideroblastic anemia and short stature, accompanied by other skeletal dysplasia features not previously associated with MLASA2, including epiphyseal dysplasia, rib edge widening, and poorly defined vertebral structures, but without lactic acidosis. Notably, the patient did not present exercise intolerance but recently exhibited reduced muscle strength. The p.(Asp311Glu) variant, located in the anticodon-binding domain of the mitochondrial tyrosyl-tRNA synthetase (Mt-TyrRS), was consistently predicted to be pathogenic by multiple in silico tools. Molecular modeling revealed that this variant destabilizes the 'KMSKS' motif, potentially compromising tRNA recognition fidelity and aminoacylation efficiency. Analysis of runs of homozygosity (ROH) revealed significantly elevated consanguinity (ROH: 31.93%), consistent with a consanguineous mating between biological parents. This case expands the geographic distribution of MLASA2, documents previously unreported phenotypes, suggests a novel pathogenic mechanism, and demonstrates the utility of genomic approaches for diagnosing rare mitochondrial disorders in the absence of complete clinical information and family history.
    Keywords:  MLASA2; YARS2; lactic acidosis; meta-analysis; sideroblastic anemia
    DOI:  https://doi.org/10.3390/ijms262412039
  25. bioRxiv. 2025 Dec 19. pii: 2025.12.17.694756. [Epub ahead of print]
    A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
    Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.
      Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.
    DOI:  https://doi.org/10.64898/2025.12.17.694756
  26. Heliyon. 2025 Feb 28. 11(4): e42797
    Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies.
    Dana Dobešová, Matúš Prídavok, Radana Brumarová, Aleš Kvasnička, Barbora Piskláková, Eliška Ivanovová, Katarína Brennerová, Jana Šaligová, Ľudmila Potočňáková, Simona Drobňaková, Jana Potočňáková, David Friedecký.
       Objective: This study aims to characterize the metabolic alterations in patients with inherited mitochondrial enzymopathies. We focused on wide-coverage targeted metabolomic, organic acid and lipidomic analyses of patients with TMEM70 deficiency (TMEM70d), short-chain acyl-CoA dehydrogenase deficiency (SCADd), and individuals with both deficiencies (TMEM70d-SCADd).
    Methods: Serum and urine samples were collected from patients with TMEM70d (n = 13), SCADd (n = 11), TMEM70d-SCADd (n = 3), and controls (n = 38). Analyses were conducted using high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Univariate and multivariate statistical evaluation was performed to identify significant metabolic differences between patient groups and controls.
    Results: Distinct metabolic profiles were observed in urine and serum samples of patients with TMEM70d, SCADd, and TMEM70d-SCADd compared to controls. Urinary metabolomics revealed significant elevations in butyrylcarnitine and metabolites related to branched-chain amino acid degradation in SCADd and TMEM70d-SCADd patients. Serum metabolomic analysis indicated alterations in pyruvate metabolism, citric acid cycle intermediates, and acylcarnitine metabolism in TMEM70d and TMEM70d-SCADd patients. Lipidomic analysis showed decreased levels of glycerophospholipids and sphingolipids across all patient groups.
    Conclusion: Patients with TMEM70d, SCADd, and TMEM70d-SCADd exhibit distinct metabolic signatures characterized by disturbances in energy metabolism, amino acid degradation, and lipid homeostasis. The combination of TMEM70d and SCADd leads to synergistic metabolic effects, emphasizing the importance of comprehensive metabolic profiling in understanding complex mitochondrial disorders and identifying potential biomarkers for diagnosis and treatment monitoring.
    Keywords:  Lipidomics; Metabolomics; Mitochondrial disorders; Oxidative phosphorylation; SCAD; TMEM70
    DOI:  https://doi.org/10.1016/j.heliyon.2025.e42797
  27. Neurol Sci. 2026 Jan 02. 47(1): 78
    Mild and late onset forms of type I 3-methylglutaconic aciduria presenting as isolated cerebellar ataxia without leukodystrophy: case reports and phenotype expansion.
    Flavie Borel, Christel Thauvin, Manuel Schiff, Yannis Duffourd, Frederic Tran Mau Them, Christophe Philippe, Fanny Mochel, Quentin Thomas.
       INTRODUCTION: Type I 3-Methylglutaconic Aciduria (MGCA1) is a metabolic disorder inherited in an autosomal recessive manner. It is caused by a deficiency in the 3-methylglutaconyl-CoA hydratase encoded by the AUH gene, leading to abnormal excretion of urinary organic acids. While the pediatric phenotype encompasses a spectrum ranging from isolated developmental delay to severe forms with leukodystrophy, developmental delay, spastic tetraplegia and movement disorders, the adult phenotype corresponds to a leukodystrophy with spastic ataxia, progressive dementia, and optic neuropathy. Due to its rarity, MGCA1 is most likely underdiagnosed, or diagnosed with an important delay, leading to inadequate care or genetic counselling. A better understanding of the disease's phenotype is thus required to facilitate its clinical and genetic diagnosis, in turn favoring clinical care and genetic counselling.
    METHODS AND RESULTS: We report two new MGCA1 patients, including an adult male patient with pure, late-onset, and progressive cerebellar ataxia, without optic neuropathy or leukodystrophy. A young female patient case is also reported with moderate developmental delay and leukodystrophy, offering 14-year follow-up data under carnitine supplementation. In both cases, urinary organic acid chromatography was critical to the diagnostic process by demonstrating abnormal and specific urinary organic acids excretion.
    DISCUSSION AND CONCLUSION: The description of new, mild and/or late-onset phenotypes expands the clinical and radiological spectrum of MGCA1. Our results show that late-onset MGCA1 patients may present with pure cerebellar ataxia without leukodystrophy, contrasting with current knowledge. These results support the fact that AUH should always be sequenced in patients with pure cerebellar ataxia, but also that urinary organic acid chromatography being a simple, rapid, and cost-effective test, should be performed as a first-tier analysis in all patients with unresolved neurological symptoms. The importance of identifying MGCA1 patients is reinforced by the possibility of implementing a low-risk and possibly effective therapy with low-protein diet and L-carnitine supplementation.
    Keywords:  3-Methylglutaconic aciduria; AUH; Cerebellar ataxia; Late-onset
    DOI:  https://doi.org/10.1007/s10072-025-08634-5
  28. Cell Signal. 2025 Dec 29. pii: S0898-6568(25)00762-4. [Epub ahead of print]139 112347
    ISG15 dysregulates endoplasmic reticulum-mitochondrial contacts and calcium homeostasis in Ataxia telangiectasia.
    Oygul Mirzalieva, Ryan E Reed, Arthur L Haas, Meredith A Juncker, Patrick Logarbo, Jennifer M Klein, David Worthylake, Shyamal D Desai.
      Dysregulation of endoplasmic reticulum and mitochondrial (ER:Mit) contacts and mitochondrial calcium (mitCa2+) homeostasis are found in several neurodegenerative disorders, including Ataxia Telangiectasia (A-T). However, the cellular basis of these defects remains unclear. Previously, we demonstrated that the aberrantly elevated Interferon-Stimulated Gene 15 (ISG15) pathway inhibits protein polyubiquitylation, its dependent protein turnover, and mitophagy pathways in A-T. Literature indicates that silencing of mitochondrial ubiquitin ligase 1 (MUL1) stabilizes mitofusin2 (MFN2) and attenuates mitCa2+ uptake from ER to Mit (mitCa2+influx) in primary neurons. We have replicated these findings in apparently healthy fibroblasts. We hypothesized that elevated ISG15 may inhibit ubiquitin-dependent MUL1-mediated degradation of MFN2 and dysregulate ER:Mit contacts and mitCa2+ homeostasis in A-T fibroblasts. Concurrently, MFN2 is stabilized in A-T, MUL1-silenced A-T, MUL1/ISG15-silenced A-T vs ISG15-silenced A-T fibroblasts. Moreover, the number of ER:Mit contacts is increased in A-T vs ISG15-silenced A-T fibroblasts. Notably, mitCa2+efflux is significantly attenuated in A-T vs ISG15-silenced A-T fibroblasts in which mitCa2+efflux is restored to levels comparable to those observed in normal fibroblasts. The mitCa2+efflux remains attenuated in MUL1 and MUL1/ISG15-silenced A-T fibroblasts. We conclude that ISG15 impairs MUL1/MFN2-mediated regulation of ER:Mit contacts and attenuates mitCa2+efflux, which may, in turn, cause Ca2+ overload-mediated mitochondrial damage in A-T. These findings suggest that ISG15 silencers may correct mitochondrial abnormalities and improve mitochondrial health in A-T patients and in those with other neurodegenerative disorders in which ISG15 is elevated, such as ALS.
    Keywords:  Ataxia telangiectasia; Ca(2+) homeostasis; ER:Mit contacts; Interferon-stimulated gene 15; MFN2; MUL1
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112347
  29. Sci Adv. 2026 Jan 02. 12(1): eady0628
    Perturbation of NAD(P)H metabolism with the LbNOX xenotopic tool extends lifespan and mitigates age-related changes.
    Shweta Yadav, Xingxiu Pan, Shengxi Li, Paige LaRae Martin, Ngoc Hoang, Kejin Chen, Aditi Karhadkar, Jatin Malhotra, Austin L Zuckerman, Subrata Munan, Markus K Klose, Lin Wang, Valentin Cracan, Andrey A Parkhitko.
      Aging involves widespread metabolic dysregulation, including a decline in total nicotinamide adenine dinucleotide (NAD) levels. While NAD precursor supplementation elevates total NAD levels, it does not reveal tissue-specific effects of an altered NADH [reduced form of NAD+ (oxidized NAD)]/NAD+ balance. To address this, we generated transgenic Drosophila expressing the genetically encoded xenotopic enzyme LbNOX, which converts NADH to NAD+. LbNOX expression modulated both NAD(H) and NADP(H) (reduced form of NAD phosphate) metabolites in a sex-dependent manner and rescued neuronal cell death induced by mutant αB-crystallin-associated reductive stress. We demonstrate that tissue-specific targeting of redox NAD metabolism shows distinct outcomes: Muscle-specific LbNOX expression confers stronger protection against paraquat-induced oxidative stress than whole-body expression, emphasizing tissue-dependent redox sensitivity. Notably, LbNOX expression in nonneuronal tissues restored youthful sleep patterns in aged flies. Together, these findings establish LbNOX as an efficient xenotopic tool for in vivo redox manipulation and reveal tissue- and sex-specific NAD(P)H mechanisms underlying aging, stress resilience, and sleep regulation, providing a framework for NAD-based interventions in aging.
    DOI:  https://doi.org/10.1126/sciadv.ady0628
  30. J Cell Biol. 2026 Mar 02. pii: e202505059. [Epub ahead of print]225(3):
    Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments.
    Michaela Medina, Ya-Ting Chang, Hamidreza Rahmani, Mark Frank, Zidan Khan, Daniel Fuentes, Frederick A Heberle, M Neal Waxham, Benjamin A Barad, Danielle A Grotjahn.
      Lipid bilayers form the basis of organellar architecture, structure, and compartmentalization in the cell. Decades of biophysical, biochemical, and imaging studies on purified or in vitro-reconstituted liposomes have shown that variations in lipid composition influence the physical properties of membranes, such as thickness and curvature. However, similar studies characterizing these membrane properties within the native cellular context have remained technically challenging. Recent advancements in cellular cryo-electron tomography (cryo-ET) imaging enable high-resolution, three-dimensional views of native organellar membrane architecture preserved in near-native conditions. We previously developed a "Surface Morphometrics" pipeline that generates surface mesh reconstructions to model and quantify cellular membrane ultrastructure from cryo-ET data. Here, we expand this pipeline to measure the distance between the phospholipid head groups of the membrane bilayer as a readout of membrane thickness. Using this approach, we demonstrate thickness variations both within and between distinct organellar membranes. We show that organellar membrane thickness positively correlates with other features, such as membrane curvedness, in cells. Further, we show that subcompartments of the mitochondrial inner membrane exhibit varying membrane thicknesses that are independent of whether the mitochondria are in fragmented or elongated networks. We also demonstrate that our technique, when applied to three-dimensional data, yields results that match existing measurements obtained from two-dimensional data of in vitro samples. Finally, we demonstrate that large membrane-associated macromolecular complexes exhibit distinct density profiles that correlate with local variations in membrane thickness. Overall, our updated Surface Morphometrics pipeline provides a framework for investigating how changes in membrane composition in various cellular and disease contexts affect organelle ultrastructure and function.
    DOI:  https://doi.org/10.1083/jcb.202505059
  31. Methods Mol Biol. 2026 ;2989 241-255
    Spinal Spheroids as Screening Platform for Peripheral Neuropathies.
    Elizabeth H Jacobs, Jessica Medina, Christopher Yanick, Renata Maciel, Mario Saporta.
      The lack of effective disease-modifying therapies for axonopathies highlights the need for novel preclinical models suitable for treatment development. Two-dimensional neuronal cultures lack the directional axonal distribution required to investigate length-dependent processes such as peripheral neuropathies. To optimize this well-established model system, we developed a robust human platform to study axonal morphology and physiology based on three-dimensional motor neuron cultures (i.e., spinal spheroids). We differentiate motor neurons from human induced pluripotent stem cells, purify them by magnetic sorting, and culture them in suspension until they form spheroids. Axons are allowed to grow out of plated spinal spheroids in a radial fashion at an average rate of 200 micrometers/day and reach up to 1 cm in length. This system is optimized for morphological analysis, including high content imaging, investigation of axonal protein expression, and time-lapse imaging of axonal transport.
    Keywords:  Charcot-Marie-Tooth disease; High content imaging; Induced pluripotent stem cells; Motor neurons; Neuropathy; Spinal spheroids
    DOI:  https://doi.org/10.1007/978-1-0716-4985-5_12
  32. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2508911123
    Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
    Isidora Molina-Riquelme, Gonzalo Barrientos, Leonhard Breitsprecher, Wileidy Gómez, Francisco Díaz-Castro, Silke Morris, Gonzalo Almarza, Andrea Del Campo, Luis Garrido-Olivares, Hugo E Verdejo, Olympia Ekaterini Psathaki, Karin B Busch, Verónica Eisner.
      Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide. Mitochondrial dysfunction is a hallmark of cardiovascular aging. Most of the heart's ATP is produced at the cristae, specialized subcompartments where oxidative phosphorylation (OXPHOS) takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and ultrastructural alterations of cristae in human and mouse hearts. We found that aged patients' hearts displayed reduced cristae density as seen by transmission electron microscopy (TEM), even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multiscale approach that included TEM and serial block-face scanning electron microscopy (SBF-SEM) showed that in aged mice's hearts, cristae undergo ultrastructural remodeling processes, resulting in a decrease in cristae density and width. Electron tomography suggests an apparent decline in cristae connectivity and an increase in fenestration size. These changes were linked to Opa1 downregulation, accompanied by reduced maximal OXPHOS respiration, but unrelated to alterations in the abundance of OXPHOS core subunits and ATP synthase assembly. Altogether, this indicates that alterations in cristae structure alone are sufficient to impair oxidative metabolism, which highlights its potential as an early signal of cardiac aging, even before noticeable changes in mitochondrial morphology occur.
    Keywords:  Opa1; aging; cristae; heart; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2508911123
  33. Genome Med. 2025 Dec 31.
    An integrated platform for concurrent structural and single-nucleotide variants improves copy-number detection and reveals pathogenic alleles in undiagnosed Mendelian families.
    Haowei Du, Ming Yin Lun, Lidiia Gagarina, Jesse D Bengtsson, Christopher M Grochowski, Michele G Mehaffey, James Paul Hwang, Shalini N Jhangiani, Sravya V Bhamidipati, Donna M Muzny, M Cecilia Poli, Sebastian Ochoa, Ivan K Chinn, Anna Lindstrand, Jennifer E Posey, Richard A Gibbs, Pengfei Liu, James R Lupski, Claudia M B Carvalho.
       BACKGROUND: Copy number variation (CNV) is a class of genomic structural variation (SV) that contributes to genomic disorders and can significantly impact health. Short-read genome sequencing (sr-GS) enables genome-wide SV calling which has been shown to increase diagnosis in unsolved rare disease families. The growing number of large sequencing cohort projects with sr-GS data available requires open free analytical tools that provide visualization of CNV and SV integrated calls associated with gene annotation, proband-parent trio analysis to enable prioritization of de novo variants, B-allele frequency (BAF) plots to support CNV calls, parent of origin assessment and mosaicism detection.
    METHODS: To support those needs, we developed VizCNV, an open-source platform that incorporates read depth and BAF to enable haplotype-aware CNV analysis. The tool incorporates multiple interactive view modes for SV concurrent calls and annotation tracks for analyzing chromosomal abnormalities [e.g., aneuploidy, segmental aneusomy, and chromosome translocations], gene exonic rearrangements and non-coding gene regulatory regions. In addition, VizCNV includes a built-in filter schema for trio genomes, prioritizing the detection of de novo CNVs. We optimized VizCNV using 1000 Genomes Project data and benchmarked its performance against a cohort containing CNVs validated by multiple technologies. Finally, we applied VizCNV to a molecularly unsolved primary immunodeficiency disease cohort (PIDD, n = 39) previously analyzed by exome sequencing.
    RESULTS: Upon computational optimization, VizCNV achieved approximately 82.3% recall and 76.3% precision for deletions > 10 kb. VizCNV accurately detected all 71 validated copy number gains and correctly indicated potential underlying genomic complexities. Haplotype-aware CNV analysis identified a meiosis I non-disjunction event (trisomy 21), three de novo CNVs at two unique loci and 48 inherited candidate CNVs in the PIDD cohort of which 42% (20/48) were validated by integrated CNV/BAF analysis. Moreover, genotype-phenotype analyses revealed that a compound heterozygous combination of a paternal 12.8 kb deletion of exon 5 and a maternal missense variant allele of DOCK8 are the molecular cause of one proband diagnosed with Hyper-IgE syndrome.
    CONCLUSIONS: VizCNV provides a robust and flexible platform for identification of aneuploidies, CNV, SV discovery and visualization of CNV and BAF data. It is also a useful tool to investigate features of genomic rearrangements such as parental origin which has implications for genetic counseling and mechanistic studies. The tool is freely available through https://doi.org/10.6084/m9.figshare.25869523.
    Keywords:  Deletions; Duplications; Genomic disorders; Mendelian diseases; Runs of homozygosity; Structural variation; Trisomy 21
    DOI:  https://doi.org/10.1186/s13073-025-01593-8
  34. Front Mol Biosci. 2025 ;12 1712573
    Mitochondrial dysfunction in Wilson disease: a systematic review and meta-analysis across human and animal models.
    Raya Amin, Valentina Medici, Erik D Fausak, Keren Sierra, Ieleen Li, Joshua Gong, Cecilia Giulivi.
       Background & Aims: Wilson disease (WD) is a genetic disorder of copper metabolism caused by ATP7B mutations, leading to hepatic and systemic copper accumulation. While lysosomes are early storage sites, mitochondria appear highly vulnerable to copper toxicity. We performed a systematic review and meta-analysis to assess mitochondrial outcomes in WD patients and animal models.
    Methods: PubMed, Scopus, and SciFinder were searched through 11 September 2025, for studies reporting hepatic mitochondrial endpoints in WD (in patients and models using mice, rats, and dogs). Outcomes included mitochondrial copper, morphology, oxidative stress, mtDNA copy number, ATP production, and respiratory Complex activities. Random-effects meta-analyses were conducted.
    Results: Thirteen studies met the inclusion criteria. Mitochondrial copper was consistently elevated (standardized mean difference ±standard error: 6.7 ± 0.9, P < 0.001), with ultrastructural abnormalities (4 ± 2, P = 0.012). Oxidative stress markers increased (2.9 ± 0.9, P = 0.001), while MnSOD and aconitase declined with disease progression. mtDNA copy number was reduced (-0.7 ± 0.3, P = 0.032). ATP synthesis (-1.5 ± 0.6, P = 0.023) and Complex activities (-1.0 ± 0.3, P = 0.001) were impaired, especially in older or symptomatic subjects. Citrate synthase activity increased (2.8 ± 0.9, P = 0.003), consistent with compensatory biogenesis. Several abnormalities appeared in presymptomatic or young animals.
    Conclusion: Across human and animal studies, hepatic mitochondria in WD exhibit copper accumulation, structural injury, impaired bioenergetics, oxidative stress, and mitochondrial genome loss. Mitochondrial dysfunction arises early and worsens with progression, highlighting it as a central pathogenic feature and therapeutic target.
    Keywords:  MtDNA copy number; bioenergetics; citrate synthase; complex IV; copper toxicity; liver metabolism; oxidative stress; translational hepatology
    DOI:  https://doi.org/10.3389/fmolb.2025.1712573
  35. Aging Cell. 2026 Jan;25(1): e70339
    Not Aging but Calorie Restriction Strongly Affects Protein Oxidation in Heart and Brain Mitochondria.
    Shipan Fan, Carina Ramallo-Guevara, Monika Frenzel, Shuichi Yanai, Sataro Goto, Michiru D Sugawa, Norbert A Dencher, Ansgar Poetsch.
      Aging is an inevitable consequence for all organisms. According to the mitochondrial free radical theory of aging (MFRTA), reactive oxygen species (ROS), which are predominantly generated in mitochondria, are assumed to play a key role. Calorie restriction (CR) delays aging by improving mitochondrial function; however, the molecular mechanisms underlying the effects of ROS and CR on mitochondria remain poorly understood. Oxidative protein modifications in mitochondrial proteins from the heart and cerebrum of young (6.5 months) and old (27 months) rats were quantified and the effects of short-term and lifelong CR interventions were investigated. Mass spectrometry was leveraged to achieve an unbiased and comprehensive analysis of various types of oxidative postranslational modifications (oxPTMs). Contrary to the MFRTA, aging did not cause significant increases in mitochondrial protein oxidation in the heart and cerebrum. CR markedly diminished the overall level of oxPTMs in the heart, particularly in transmembrane proteins. Similarly, the level of oxidative modification of transmembrane proteins in cerebrum was reduced by CR, whereas it perplexingly increased in mitochondrial proteins. The absolute level of oxidized mitochondrial protein was always higher in the heart than in the cerebrum under all conditions. Carbonylation, a prevalent marker of protein oxidation and aging, increased in the heart with age and was notably reduced by CR. However, this trend was not consistent in cerebrum or for some other types of oxPTMs. Therefore, protein oxidation in the heart and cerebrum exhibits distinct responses to chronological aging and dietary interventions, with the latter exerting a stronger influence.
    Keywords:  aging; calorie restriction; mitochondria; oxidative modification
    DOI:  https://doi.org/10.1111/acel.70339
  36. Front Neurol. 2025 ;16 1678595
    The metabolic-epigenetic interface: lysine succinylation orchestrates bidirectional crosstalk in neurodegenerative disorders.
    Fanglei Chai, Chong Liu, Yandong Liu, Wei Zou.
      Succinylation, a nexus between metabolism and epigenetic regulation, is a central factor in the onset and progression of neurodegenerative diseases (NDDs). Research has demonstrated a close association between NDDs and neuronal metabolic disorders. Succinylation regulates the interaction between energy metabolism and epigenetic networks, establishing the pathological mechanism of "metabolic-epigenetic bidirectional regulation." In metabolic stress, such as mitochondrial dysfunction or enhanced glycolysis, succinyl-CoA increases, causing uncontrolled succinylation. These modifications impair the function of proteins associated with synaptic plasticity, leading to disorders in synaptic transmission and neuronal damage. Concurrently, succinylation regulates the activity of enzymes involved in DNA methylation and epigenetic reprogramming, impairing neuronal recovery and creating a vicious cycle. This regulatory network displays bidirectional self-reinforcing characteristics. Metabolic disorders influence epigenetic states through succinylation. Epigenetic abnormalities inhibit the transcription of genes associated with mitochondrial metabolism, exacerbating energy metabolism defects and oxidative stress. This leads to irreversible degenerative changes in neurons. At the therapeutic level, targeting succinylation can disrupt the metabolic-epigenetic pathological loop and restore synaptic function. In short, understanding how succinylation is regulated may lead to new treatment options for neurodegenerative diseases.
    Keywords:  NDD; SIRT5; metabolic-epigenetic crosstalk; mitochondria; succinylation
    DOI:  https://doi.org/10.3389/fneur.2025.1678595
  37. STAR Protoc. 2025 Dec 26. pii: S2666-1667(25)00658-6. [Epub ahead of print]7(1): 104252
    Protocol to assess retinal metabolic flux of mice via stable isotope-resolved metabolomics.
    Georgy Komissarov, Kriti Pandey, Nicholas D Nolan, Thomas Winogrodzki, Daniel T Hass, Aykut Demirkol, Brian M Robbings, James B Hurley, Stephen H Tsang.
      Here, we present a protocol for evaluating glucose metabolism in mouse retinas and retinal pigment epithelium (RPE)-choroid tissue by tracking the incorporation of 13C6 from U-13C6-glucose with gas chromatography-mass spectrometry (GC-MS). We describe steps for incubating tissues in Krebs-Ringer bicarbonate solution and homogenizing tissues. We then detail procedures for extracting metabolites and determining isotopic labeling of intermediates in glycolysis and the tricarboxylic acid (TCA) cycle using GC-MS. The approach has been adapted to study glucose metabolism in various tissues, animal models, and genetic conditions. For complete details on the use and execution of this protocol, please refer to Nolan et al.1.
    Keywords:  Mass spectrometry; Metabolism; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2025.104252
  38. Biology (Basel). 2025 Dec 02. pii: 1728. [Epub ahead of print]14(12):
    Gatekeepers of the Germ Line: How Mitochondria Shape Reproductive Evolution in Metazoans.
    Yu-Tong Sun, Wan-Xi Yang.
      Mitochondria play essential roles for animal reproduction, influencing not only cellular energetics but also gamete quality, inheritance and evolutionary patterns. Currently, most research still focuses on chordates or mitochondrial diseases and their impact on the health of germ cells. However, few studies focus on integrative synthesis that connect comparative morphology, inheritance mechanisms and evolutionary theory. In this review, we integrate cross-phyla evidence to explore two interconnected dimensions: the fate of mitochondria during gametogenesis and the strategy shaping their evolution. We compare mitochondrial morphology, distribution, and metabolic strategies in gametogenesis, revealing how these traits align with reproductive modes and ecological adaptations. Then we further discuss how mitochondrial genome evolution, bottleneck effects and mito-nuclear coevolution contribute to germline stability and maternal inheritance. Special attention is given to exceptional systems such as Doubly Uniparental Inheritance (DUI) in bivalves, which challenges conventional mode of strictly maternal transmission and illuminates the flexibility of mito-nuclear evolution. Altogether, these perspectives highlight mitochondria as gatekeepers and evolutionary recorders in the reproductive systems across metazoans, providing a unifying framework for future research across ecology, evolution and molecular biology.
    Keywords:  Doubly Uniparental Inheritance (DUI); gametogenesis; mito-nuclear coevolution; mitochondria; mitochondria evolution
    DOI:  https://doi.org/10.3390/biology14121728
  39. Am J Case Rep. 2025 Dec 29. 26 e950967
    Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights.
    Shu Liu, Wei Lu, Lin Yang, Xiubin Tong, Xiu Xu, Huiping Li.
      BACKGROUND Translocase of the outer mitochondrial membrane 7 (TOMM7) encodes a subunit of the mitochondrial translocase complex, which has a critical role in stabilizing the complex and regulating mitochondrial function. Rare individual case reports have identified homozygous TOMM7 mutations associated with Garg-Mishra progeroid syndrome (GMPGS), characterized by dwarfism, facial dysmorphia, developmental delay, and macular scarring. However, few therapeutic interventions have been documented. CASE REPORT We describe a 2-year-old Han boy from China with severe growth retardation who carries a homozygous TOMM7 mutation (p.Pro29Leu), inherited from consanguineous parents; he has a confirmed diagnosis of GMPGS. Because of growth stagnation, the child has been receiving long-acting recombinant human growth hormone since 31 months of age. After 10 months of treatment, his length increased by 3.8 cm (change in standard deviation score [SDS] of -0.34). This modest decline in SDS sharply contrasted with the precipitous drop of 1.28 SDS during the 10 months before treatment; it represented distinct improvement from the near-complete growth arrest observed between 24 and 31 months of age. CONCLUSIONS This case highlights the clinical characteristics of children with TOMM7 mutations and offers a potential strategy for managing growth retardation associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.12659/AJCR.950967
  40. J Fluoresc. 2026 Jan 03.
    High-Photostability Perylene-Derived Probe Enables Accurate Dual-Modality Imaging of Mitochondrial Membrane Potential.
    Fei Peng, Xiangnan Ai, Ran Chai, Bin Hao, Baoxiang Gao.
      Mitochondrial membrane potential (MMP) is a key indicator of mitochondrial function and cellular health. Fluorescence intensity-based methods are widely used for MMP monitoring, where probe photostability is critical for accurate quantification. To improve imaging reliability, we developed a photostable mitochondrial-targeted probe, PDI-TPP, by linking perylene diimide (PDI) with triphenylphosphonium (TPP). To the best of our knowledge, this is the first report of PDI being rationally designed and synthesized as a FRET donor for MMP sensing. Acting as a FRET donor, PDI-TPP pairs with SiR-BA, which is synthesized by conjugating silicon-rhodamine with butyric acid, to achieve dual-modality imaging through both fluorescence intensity ratio and lifetime. Compared to our previous donor OR-C8, PDI-TPP shows significantly enhanced photostability, reducing photobleaching artifacts and enabling dynamic visualization of MMP changes. This work provides a more accurate tool for mitochondrial imaging and functional studies.
    Keywords:  Dual-modality; FRET; Fluorescence intensity; Fluorescence lifetime; Mitochondrial membrane potential; Perylene diimide
    DOI:  https://doi.org/10.1007/s10895-025-04567-6
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