bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–12–28
fifty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.
  2. Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
  3. Turnover and Quality Control of Mitochondrial DNA.
  4. Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
  5. Stroke-like lesion and status epilepticus in a child with NARS2-related combined oxidative phosphorylation deficiency 24.
  6. A systematic analysis of mitochondrial aminoacyl tRNA synthetase variants in a rare disease cohort.
  7. Biomarkers.
  8. Basic Science and Pathogenesis.
  9. Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
  10. From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
  11. Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35.
  12. A role for Fis1 in dendritic development.
  13. Mechanisms of Intracellular Selection of Mitochondrial DNA.
  14. Basic Science and Pathogenesis.
  15. Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis.
  16. A reversible feedback mechanism regulating mitochondrial heme synthesis.
  17. Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.
  18. The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
  19. Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
  20. TAG-PL: A Universal Proximity Labeling Platform for Mapping Mitochondrial Proteomes and Organelle Interactions under Stress.
  21. Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.
  22. Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
  23. Proximity Labeling Reveals RNA-Binding Proteins Associating with the Human Mitochondrial Import Receptor TOMM20.
  24. Model organisms in POLG-related disorders: insights from yeast to multicellular systems.
  25. Mitochondrial Reticulum in Skeletal Muscles: Proven and Hypothetical Functions.
  26. Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism.
  27. Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
  28. A new subset of mitochondrial-derived vesicles perform inter-mitochondrial communications.
  29. Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.
  30. Unveiling mitochondrial and PANoptosis-related biomarkers for premature ovarian insufficiency.
  31. Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle.
  32. Targeting mitochondrial autophagy for anti-aging.
  33. Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
  34. Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.
  35. Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.
  36. Basic Science and Pathogenesis.
  37. Editorial: Insights in aging, metabolism and redox biology: 2024.
  38. Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
  39. A Novel Variant in the TAMM41-Associated Mitochondrial Myopathy.
  40. Cerebellar deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia.
  41. Ca2+-Dependent Mitochondrial Permeability Transition Pore: Structure, Properties, and Role in Cellular Pathophysiology.
  42. Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.
  43. Insights into PINK1/Parkin function and dysfunction from Drosophila models.
  44. Mitochondrial control of fuel switching via carnitine biosynthesis.
  45. Basic Science and Pathogenesis.
  46. Cardiolipin's multifaceted role in immune response: a focus on interacting proteins.
  47. Basic Science and Pathogenesis.
  48. ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
  49. Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
  50. Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway.
  51. Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
  52. Expert consensus on the combined screening of genes and biomarkers for neonatal diseases.
  53. Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.
  54. GLOBAL LOSS OF SELENOCYSTEINE LYASE IN MICE DRIVES LIPID ACCUMULATION IN BROWN ADIPOCYTES.
  55. Implementing electronic informed consent in rare disease genomics.
  1. J Transl Med. 2025 Dec 23. 23(1): 1415
    Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.
    Lei Lyu, Beibei Qie, Yanjie He, Feilong Chen, Bao Liu.
      Mitochondria function as the primary energy hubs of cells and possess semi-autonomous genetic characteristic. Mutations in mitochondrial DNA (mtDNA) frequently lead to severe illness and even premature death. The rapid advancement of gene therapy offers promising potential for correcting such disorders. This review first aims to delineate the mechanisms of gene therapy strategies applicable to mitochondrial diseases, including the allotopic expression of mtDNA in the nucleus, mitochondrial-targeted nuclease cleavage, and mtDNA-targeted base editing. It also discusses in detail the clinical efficacy of mtDNA allotopic expression and the preclinical progress of other strategies. Furthermore, the unique physiological features of mitochondria, such as heteroplasmy and independent molecular transport mechanisms, pose distinct challenges for the clinical implementation of mitochondrial gene therapy strategies. Accordingly, this review elaborates on the current limitations of each approach. Finally, it highlights potential optimization directions to address these challenges, emphasizing that understanding heteroplasmy dynamics and their corresponding phenotypes, ensuring the safe delivery and tissue-specific expression of therapeutic elements, and maintaining long-term therapeutic specificity and efficiency are essential for the clinical translation of mitochondrial gene therapy.
    Keywords:  Allotopic expression; Base editing; Mitochondrial DNA; Mitochondrial disorders; Nuclease
    DOI:  https://doi.org/10.1186/s12967-025-07420-3
  2. Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727
    Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
    Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.
      Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2025.116727
  3. Biochemistry (Mosc). 2025 Dec;90(12): 1849-1861
    Turnover and Quality Control of Mitochondrial DNA.
    Wolfram S Kunz.
      The quantitative content of mitochondrial DNA (mtDNA) - a multicopy circular genome - is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).
    Keywords:  determinants of cellular mtDNA content; mtDNA degradation; mtDNA maintenance; mtDNA maintenance disorders; mtDNA replication
    DOI:  https://doi.org/10.1134/S0006297925602485
  4. Autophagy. 2025 Dec 26.
    Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
    Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.
      Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.
    Keywords:  ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons
    DOI:  https://doi.org/10.1080/15548627.2025.2610450
  5. Front Neurol. 2025 ;16 1731858
    Stroke-like lesion and status epilepticus in a child with NARS2-related combined oxidative phosphorylation deficiency 24.
    Song Su, Wandong Hu, Yong Liu, Qiong Lang, Hongwei Zhang.
       Introduction: The NARS2 gene encodes mitochondrial asparaginyl-tRNA synthetase, and biallelic pathogenic variants have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24), an autosomal recessive mitochondrial disorder characterized by highly heterogeneous clinical manifestations. This study retrospectively analyzed the clinical and genetic findings of a Chinese infant presenting with status epilepticus and explored potential genotype-phenotype correlations.
    Methods: Clinical data, laboratory tests, neuroimaging, and disease course of the proband were reviewed. Whole-exome sequencing (WES) and copy-number variation (CNV) analysis were performed to identify causative variants in NARS2. Candidate variants were assessed by population database screening and literature review.
    Results: The proband, a 9-month-old girl, presented with status epilepticus, global developmental delay, increased muscle tone, elevated serum lactate and myocardial enzyme levels. Brain magnetic resonance imaging (MRI) revealed a focal cerebral lesion consistent with a metabolic or stroke-like infarction, as well as delayed myelination. WES identified compound heterozygous NARS2 variants: a large exon 6-11 deletion and a novel missense variant c.467T>C (p.Leu156Ser), inherited in an autosomal recessive manner. Both variants were absent from public population databases and published literature. Notably, cerebral infarction has not been previously reported in NARS2-related disorders, suggesting a potential expansion of the clinical spectrum.
    Discussion: Review of previously reported NARS2 variants indicates that both missense and loss-of-function mutations can lead to variable disease severity depending on residual enzyme activity. This case broadens the phenotypic and mutational spectrum of NARS2-associated COXPD24 and highlights the importance of evaluating large exon deletions and novel variants in infants with early-onset mitochondrial encephalopathy and epileptic manifestations.
    Keywords:  COXPD24; NARS2; infarction-like lesion; mitochondrial disease; status epilepticus
    DOI:  https://doi.org/10.3389/fneur.2025.1731858
  6. Eur J Hum Genet. 2025 Dec 27.
    A systematic analysis of mitochondrial aminoacyl tRNA synthetase variants in a rare disease cohort.
    Thiloka E Ratnaike, M Eren Kule, Ida Paramonov, Leslie Matalonga, Kiran Polavarapu, Catarina Olimpio, Rita Horváth.
      Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenotypically heterogenous but often present with significant neurological features such as childhood-onset encephalopathy and seizures. As such, these conditions are a diagnostic challenge. We present an approach that systematically quantifies phenotypic similarity of individuals with an mt-aaRS variant to published cases, to aid variant interpretation, in RD-Connect-a large Europe-wide rare disease cohort. Across 98 individuals with a mt-aaRS gene of interest, we prioritised 38 individuals with 63 variants following bioinformatic and manual analyses. We additionally reviewed Exomiser prioritisation using a pre-defined gene list for neurological disorders within the RD-Connect Genome-Phenome Analysis Platform (GPAP). We were able to generate likely diagnoses in 11 individuals and VUS findings in 13 individuals, following careful phenotype similarity analysis using a phenotype-genotype dataset generated from 234 published individuals. Four of these 24 individuals did not have an Exomiser-ranked gene variant in the GPAP. Therefore, this approach, using individual-level curated phenotype-genotype data to support variant interpretation, can highlight potentially significant variants that may not be captured by current pipelines. This workflow can be replicated in other heterogeneous rare diseases to support clinical practice.
    DOI:  https://doi.org/10.1038/s41431-025-01990-y
  7. Alzheimers Dement. 2025 Dec;21 Suppl 2 e104338
    Biomarkers.
    Shampa Ghosh, Krishna Kumar Singh, Amit Kumar Pandey, Suchita Jha, Jitendra Kumar Sinha.
       BACKGROUND: Mitochondrial dysfunction is an integral feature of both aging and neurodegenerative diseases, where it significantly contributes to disease progression. It is, therefore, of the utmost importance to understand the underlying mechanisms so that effective therapeutic approaches can be developed. This article delves into specific pathways where mitochondrial dysfunction occurs in aging and neurodegenerative conditions in the hope of discovering potential targets for intervention.
    METHODS: A comprehensive literature review was done to synthesize current knowledge on mitochondrial dysfunction in ageing and neurodegeneration. It focused on the key cellular and molecular pathways that include changes in mitochondrial structure and function, disruptions in energy metabolism, and their impact on cellular homeostasis.
    RESULTS: In short, the overall data point to complex interactions between the processes of aging, neurodegenerative disease and mitochondrial dysfunction. During aging, mitochondria become functionally less effective, characterized by decreased ATP levels, impaired oxidative phosphorylation and increased reactive oxygen species production. Different neurodegenerative diseases- Alzheimer's disease, Parkinson's disease, Huntington's disease-had specific abnormalities in mitochondria, including deficient mitophagy, altered dynamics of mitochondria, and mutation in mitochondrial DNA. These cause neuronal cell death and accelerate progression of the diseases.
    CONCLUSION: This study elucidates the diverse mechanisms that connect mitochondrial dysfunction with both ageing and neurodegenerative diseases. Various pathways identified in this review are considered critical areas for therapeutic intervention aimed at preserving mitochondrial integrity and subsequently reducing detrimental impact of ageing and neurodegeneration on cellular function. These mechanisms offer more complex avenues for research into these critical pathways that should lead to novel treatments for age-related and neurodegenerative conditions.
    DOI:  https://doi.org/10.1002/alz70856_104338
  8. Alzheimers Dement. 2025 Dec;21 Suppl 1 e102364
    Basic Science and Pathogenesis.
    Sara Yunta-Sánchez, Regina Mengual-Fenollar, Juan Pedro Bolaños, Rubén Quintana-Cabrera.
       BACKGROUND: In the nervous system, mitochondria can be transferred between neural cells through intercellular tunneling nanotubes (TNTs), microvesicles, or as free organelles. This transfer not only alters the mitochondrial content and respiration of recipient neural cells but also triggers a profound rewiring of their physiology, with glial cells and immune responses playing key roles in this reconfiguration.
    METHOD: Primary co-cultures of neurons and glial cells, along with in vivo analysis of mitochondrial transfer in mouse brains, were monitored using kinetic microscopy, flow cytometry, and metabolic flux analyses to explore the physiological changes in neural cells. Mitochondrial DNA (mtDNA) transmission was tracked through RT-PCR and ARMS-PCR to examine hierarchical transfer and acquisition.
    RESULT: Communication between neural cells, particularly through TNTs, shows dynamic mitochondrial transfer, regulated by mitochondrial transport, fusion, and fission events. These events respond to structural and signaling changes in intercellular communication, mainly via TNTs. As a result, transmitted mitochondria reconfigure the content, metabolism, and mtDNA composition in recipient neurons and astrocytes. Notably, we observe a significant role of microglia and astrocytes upon mitochondrial acquisition in mouse brains, suggesting inflammatory events that may coordinate mitochondrial transfer as key regulators of metabolic rewiring and cognitive effects in the nervous system.
    CONCLUSION: Our findings provide evidence that a multilayered mitochondrial transfer is a critical mechanism for reconfiguring neural metabolism, immune responses, and overall neural physiology.
    DOI:  https://doi.org/10.1002/alz70855_102364
  9. Front Neurol. 2025 ;16 1657852
    Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
    Gülhan Karakaya Molla, Özlem Ünal Uzun, Hanım Babazade Agakisili, Emine Genç, Zümrüt Arslan Gülten, Tarık Yıldırım, Aydan Sezgin Ersoy, Belkıs Ak, Aliye Gülbahçe, Sevil Yıldız, Nafiye Emel Çakar, Meryem Karaca, Tanyel Zübarioğlu, Burcu Öztürk Hişmi, Şahin Erdöl, Hasan Önal, Bülent Kara, Gülden Fatma Gökçay.
       Introduction: Stroke-like episodes (SLE) are defined as events characterized by the sudden onset of neurological symptoms with clinical manifestations similar to those of a stroke. However, they are distinguished by the presence of radiological lesions that do not conform to single vascular territory. MELAS syndrome, which is characterized by metabolic encephalopathy, lactic acidosis, and SLE, has been identified as the first genetically defined and most widely known mitochondrial cause of SLE. It has been demonstrated that SLE may occur in the course of a variety of mitochondrial diseases, including those that are the result of nuclear DNA mutations.
    Objective: In this retrospective, multicenter, observational cohort study, we sought to determine the clinical, radiological, EEG, and genetic characteristics of patients with mitochondrial gene mutations presenting with SLE and the frequency and treatment of SLE.
    Methods: Thirty-four patients with a genetically diagnosed mitochondrial disease from 9 paediatric metabolic disease centres in the Marmara Region of Turkey were included in the study, of whom 13 pateints had SLEs. Demographic characteristics, symptoms, clinical features, cranial MRI, EEG findings, and genetic characteristics were evaluated.
    Conclusion: In this study, stroke-like episodes in genetically defined mitochondrial disorders were most frequently observed in MELAS and POLG mutations, and rarely in CoQ10 deficiency, Leigh syndrome cases. Cranial MRI findings are often frontotemporal in location and inconsistent with vascular distribution, and focal epileptiform activity on EEG are diagnostically significant. In MELAS, clinical improvement was observed in patients when L-arginine was initiated in the acute period. The findings emphasise that SLE should be evaluated in the differential diagnosis of sudden onset neurological symptoms in mitochondrial diseases.
    Keywords:  CoQ10 deficiency; MELAS; POLG mutations; mitochondrial diseases; stroke-like episodes
    DOI:  https://doi.org/10.3389/fneur.2025.1657852
  10. J Child Neurol. 2025 Dec 23. 8830738251404115
    From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
    Sofia Corbaz, Daniela Alejandra Pibernus, Mariana Amina Loos, María Mercedes Pérez, María Celeste Buompadre, Francisco Martín García, María Paula Rodriguez, Carlos Rugilo, Marisa Armeno, Go Hun Seo, Rin Khang, Cristina Noemi Alonso, Hilda Verónica Aráoz.
      Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.
    Keywords:  Ketogenic diet; Leigh syndrome; PDHA1; mitochondrial disease; pyruvate dehydrogenase deficiency
    DOI:  https://doi.org/10.1177/08830738251404115
  11. bioRxiv. 2025 Dec 16. pii: 2025.12.12.693842. [Epub ahead of print]
    Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains the highest energy phosphate bond above ATP, and has diverse biological functions, including glycolysis, gluconeogenesis, and glyceroneogenesis. Although PEP is generally considered a cytosolic intermediate, it can also be synthesized within mitochondria by the mitochondria-localized carboxykinase (PCK2, also known as M-PEPCK). However, the mechanism by which mitochondrial PEP is delivered to the cytosolic compartment and caters to cell-specific requirements remains elusive. Here, we identify SLC25A35, a previously uncharacterized mitochondrial inner-membrane protein, as the long-sought carrier responsible for mitochondrial PEP efflux. SLC25A35 is highly expressed in lipogenic cells, such as adipocytes, which employ the mitochondrial pyruvate-to-PEP bypass, and is upregulated by lipogenic stimuli. Reconstitution studies by proteo-liposomes, together with structural analyses, demonstrated specific PEP transport by SLC25A35 in a pH gradient-dependent manner. Importantly, loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, the glycerol backbone in triglyceride, resulting in reduced glycerolipid synthesis while preserving substrate oxidation in the TCA cycle. Furthermore, blockade of SLC25A35 in the liver of obese mice markedly decreased glycerolipid accumulation, ameliorated hepatic steatosis, and improved systemic glucose homeostasis. Together, the present study identifies mitochondrial PEP transport via SLC25A35 as a metabolic checkpoint of fatty acid esterification, offering a selective target for "lipogenic mitochondria" to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and Type 2 diabetes.
    DOI:  https://doi.org/10.64898/2025.12.12.693842
  12. Sci Rep. 2025 Dec 23.
    A role for Fis1 in dendritic development.
    Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.
      Mitochondrial ATP production and calcium handling are critical for metabolic regulation and neurotransmission. Thus, the formation and maintenance of the mitochondrial network is a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously revealed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Therefore, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo, and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 activity regulates mitochondrial morphological and functional features that influence dendritic tree arborization and connectivity.
    DOI:  https://doi.org/10.1038/s41598-025-33557-8
  13. Biochemistry (Mosc). 2025 Dec;90(12): 1919-1928
    Mechanisms of Intracellular Selection of Mitochondrial DNA.
    Georgii Muravyov, Dmitry A Knorre.
      Eukaryotic cells contain multiple mitochondrial DNA (mtDNA) molecules. Heteroplasmy is coexistence in the same cell of different mtDNA variants competing for cellular resources required for their replication. Here, we review documented cases of emergence and spread of selfish mtDNA (i.e., mtDNA that has a selective advantage in a cell but decreases cell fitness) in eukaryotic species, from humans to baker's yeast. The review discusses hypothetical mechanisms enabling preferential proliferation of certain mtDNA variants in heteroplasmy. We propose that selfish mtDNAs have significantly influenced the evolution of eukaryotes and may be responsible for the emergence of uniparental inheritance and constraints on the mtDNA copy number in germline cells.
    Keywords:  heteroplasmy; intracellular selection; mitochondrial DNA; mitophagy; mtDNA quality control; selfish gene
    DOI:  https://doi.org/10.1134/S0006297925603296
  14. Alzheimers Dement. 2025 Dec;21 Suppl 1 e100949
    Basic Science and Pathogenesis.
    Anusruti Sabui, Prasad Tammineni.
       BACKGROUND: Mitochondria are essential organelle for neuronal homeostasis. They supply ATP and buffer calcium at synaptic terminals. The complex structural geometry of neurons poses a unique challenge in transporting mitochondria to synaptic terminals. Anterograde mitochondrial transport is driven by kinesin motors whereas retrograde transport is driven by cytoplasmic dynein. Despite the importance of presynaptic mitochondria, how and whether axonal mitochondrial transport and distribution are altered in tauopathy neurons remain poorly studied.
    METHOD: We studied mitochondrial transport and distribution in neurons expressing the tauopathy-associated P301L mutant protein. Quantitative analyses of mitochondrial motility and abundance were performed using live-cell imaging and biochemical assays. We also investigated the interaction between mitochondria and motor proteins, alongside mathematical modeling to evaluate motor activity changes.
    RESULT: P301L neurons exhibited a significant reduction in anterograde mitochondrial transport, with no change observed in retrograde transport. This led to decreased axonal mitochondrial abundance in P301L neurons. Biochemical analyses revealed a reduction in mitochondrial association with kinesin in P301L cells. Interestingly, mathematical modelling of transport dynamics suggested a compensatory increase in dynein activity to maintain retrograde flux.
    CONCLUSION: Our findings demonstrate that decreased kinesin-mediated anterograde transport coupled with sustained retrograde transport might reduce axonal mitochondrial density in tauopathy neurons. This imbalance may contribute to synaptic deficits observed in Alzheimer's disease and other tauopathies.
    DOI:  https://doi.org/10.1002/alz70855_100949
  15. Nat Commun. 2025 Dec 21.
    Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis.
    Jeffrey C Hsiao, Douglas M Warui, Jason J Kwon, Margaret B Dreishpoon, Nolan R Bick, Tamra Blue-Lahom, David E Root, Squire J Booker, Peter Tsvetkov.
      Cuproptosis is a recently described form of regulated cell death triggered by ionophore-induced copper (Cu) overload in mitochondria. It is critically dependent on ferredoxin 1 (FDX1), a mitochondrial iron-sulfur cluster containing protein that acts as an electron shuttle. FDX1 reduces ionophore-bound Cu(II) to Cu(I), thereby triggering its release, and promotes mitochondrial protein lipoylation, which is directly targeted by the released copper to drive cell death. Despite the pivotal role of FDX1 in cuproptosis, the structural determinants underlying its distinct functions remain unclear. To address this, we performed deep mutational scanning on FDX1 and find that two conserved solvent-exposed residues, D136 and D139, on alpha helix 3 are essential for both cuproptosis and lipoylation. Charge-reversal mutations at these positions abolish FDX1's ability to induce cuproptosis and support lipoylation in cells, despite retaining full enzymatic activity in vitro. Guided by structural and genomic analyses, we further identify dihydrolipoamide dehydrogenase (DLD), the E3 subunit of lipoylated complexes as an alternative FDX1 reductase both in cells and in vitro. Together, these findings establish the acidic alpha helix 3 of FDX1 as a critical interface for its upstream regulation and suggest that FDX1's roles in cuproptosis and in lipoylation are both structurally and functionally linked.
    DOI:  https://doi.org/10.1038/s41467-025-67869-0
  16. J Biol Chem. 2025 Dec 22. pii: S0021-9258(25)02941-2. [Epub ahead of print] 111089
    A reversible feedback mechanism regulating mitochondrial heme synthesis.
    Iva Chitrakar, Alexis B Roberson, Pedro H Ayres-Galhardo, Breann L Brown.
      Proper heme biosynthesis is essential for numerous cellular functions across nearly all life forms. In humans, dysregulated heme metabolism is linked to multiple blood diseases, neurodegeneration, cardiovascular disease, and metabolic disorders. Erythroid heme production begins with the rate-limiting enzyme Aminolevulinic Acid Synthase (ALAS2) in the mitochondrion. Although prior studies discuss the regulation of ALAS2 in the nucleus and cytoplasm, its modulation as a mature mitochondrial matrix enzyme remains poorly understood. We report that heme binds mature human ALAS2 with high affinity, acting as a reversible mixed inhibitor that reduces enzymatic activity. Structural modeling supports the hypothesis that two flexible regions of ALAS2 interact with heme, locking the enzyme in an inactive conformation and occluding the active site. Our work reveals a negative feedback mechanism for heme synthesis, offering insights into the spatial regulation of ALAS2 and the maturation of the essential heme cofactor.
    Keywords:  Heme; aminolevulinic acid; enzyme inhibition; enzymology; erythropoiesis; heme regulatory motif; protein structure and function; pyridoxal 5-phosphate
    DOI:  https://doi.org/10.1016/j.jbc.2025.111089
  17. Am J Physiol Renal Physiol. 2025 Dec 22.
    Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.
    Kyle Feola, Andrea Henning Venable, Mina Rasouli, Julie Do, Tatyana Broomfield, Claire Llamas, Dana Straus, Joshua C Russell, Prashant Mishra, Behzad Najafian, Sarah C Huen.
      The metabolic health of the kidney is directly correlated to the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel the diverse functions of the kidney is limited by the kidney's structural and functional heterogeneity, especially in key metabolic organelles like the mitochondria. As the kidney contains many different cell types, we sought to determine the intra-renal mitochondrial heterogeneity that contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique, MITO-Tag, to isolate kidney cell-type specific mitochondria. Here, we investigated mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag transgene was combined with Slc34a1-CreERT2, Ggt1-Cre, or Pvalb-Cre transgenes to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting.
    Keywords:  cellular metabolic heterogeneity; kidney; metabolism; mitochondria; tubular epithelium
    DOI:  https://doi.org/10.1152/ajprenal.00235.2025
  18. bioRxiv. 2025 Dec 16. pii: 2025.12.13.693635. [Epub ahead of print]
    The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
    Bryanna Shao, Bartosz Kula, Han Le, Prasanna Venkhatesh, Prasanna Katti, Andrea G Marshall, Siddharth Chittaranjan, Suraj Thapilyal, Namdar Hari Kalpana, C Nivedya, Adam Roszczyk, Harrison Mobley, Mason Killion, Emelina St John, Pamela Martin, Benjamin Rodrigiuez, Markis' Hamilton, LaCara Bell, Sunjay M Wyckoff, Laurent A Moran, Mark Philips, David Hubert, Briar Tomeau, Jeremiah M Afolabi, Annet Kirabo, Ismary Blanco, Samantha Reasonover, Lauren E Drake, Ethan S Lippmann, Chantell Evans, Monica M Santisteban, Taneisha G Cheairs, Sepiso Mesenga, Celestine Wanjalla, Jennifer Gaddy, Ronald McMillan, Calixto P Hernandez Perez, Htet Htet Paing, Jenny C Schafer, Bret Mobley, Julia Berry, Amber Crabtree, Oleg Kovtun, Shawn Goodwin, Edgar Garza Lopez, Chandravanu Dash, Dao-Fu Dai, Tyne W Miller-Fleming, Antentor Hinton, Nathan A Smith.
      Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2025.12.13.693635
  19. Epigenomics. 2025 Dec 23. 1-18
    Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
    Phyo W Win, Julia Nguyen, Elly H Shin, Tyler S Nagano, Brent Selimi, Katie Hong, Anahita M Meybodi, Bradley P Yates, Emma V Burke, David E Carter, Gregory A Newby, Charles Newcomb, Dan E Arking, Christina A Castellani.
       AIMS: Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease.
    MATERIALS AND METHODS: Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harboring a mitochondrial transcription factor A (TFAM) knockout generated via CRISPR-Cas9, and matched control lines.
    RESULTS: We identified 2924 differentially methylated sites, 67 differentially methylated regions, and 102 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 24 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand signaling pathway, ABCD1/2 gene activity, and cell signaling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression.
    CONCLUSIONS: We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodeling relevant to development, aging, and complex disease.
    Keywords:  Mitochondria; epigenome; mitochondrial DNA; mitochondrial DNA copy number; transcriptome
    DOI:  https://doi.org/10.1080/17501911.2025.2603883
  20. J Proteome Res. 2025 Dec 23.
    TAG-PL: A Universal Proximity Labeling Platform for Mapping Mitochondrial Proteomes and Organelle Interactions under Stress.
    Enming Miao, Xuyang Yue, Zhixiong Tao, Hongqiang Qin, Mingliang Ye.
      Mitochondrial dysfunction induces numerous diseases, yet current proximity labeling methods require gene transfection and membrane potential-sensitive probes, limiting their use in hard-to-transfect cells and disease models. We developed TAG-PL (Tailored Antibody-Guided Proximity Labeling), a transfection-free approach for in-depth mapping of the mitochondrial proteome, achieving >90% specificity and identifying >450 mitochondrial proteins─more than the coverage of existing nontransfection methods. Applied to heat-stressed macrophages, TAG-PL revealed dynamic mitochondrial proteome remodeling, including antioxidant responses and metabolic shifts during heat stress. Notably, we discovered physical interactions between stress granules and mitochondria, identifying 10 interaction mediators (including MSRA and UBA1). These findings establish stress granules as regulatory hubs for organelle dynamics and immune responses. TAG-PL's high performance and broad applicability across diverse sample types, particularly immune cells and tissues, make it a powerful tool for dissecting mitochondrial function in disease models without genetic manipulation.
    Keywords:  SG−mitochondria interaction; antibody-guided proximity labeling; mitochondrial proteome
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00855
  21. Commun Biol. 2025 Dec 22.
    Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.
    Yvan Campos, Gustavo Palacios, Elida Gomero, Diantha van de Vlekkert, Krishnan Venkataraman, Jaison John, Jason Andrew Weesner, Randall Wakefield, Xiaohui Qiu, Ricardo Rodriguez-Enriquez, Stephanie Rockfield, Jeroen Demmers, Joseph T Opferman, Cam Robinson, Khaled Khairy, Tulio Bertorini, Gerard C Grosveld, Alessandra d'Azzo.
      High-energy-demanding tissues, such as skeletal muscle, rely on mitochondrial proteostasis for proper function. Two key quality-control mechanisms -the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles- help maintain mitochondrial proteostasis, but whether these processes interact remains unclear. Here, we show that CRL5Ozz and its substrate, Alix, localize to mitochondria and together regulate the levels and distribution of the mitochondrial solute carrier Slc25A4, which is essential for ATP production. In Ozz-/- or Alix-/- mice, skeletal muscle mitochondria exhibit similar morphological abnormalities, including swelling and dysmorphism, along with partially overlapping metabolomic alterations. We demonstrate that CRL5Ozz ubiquitinates Slc25A4, targeting it for proteasomal degradation, while Alix facilitates Slc25A4 loading into exosomes for lysosomal degradation. Loss of Ozz or Alix in vivo disrupts the steady-state levels of Slc25A4, impairing mitochondrial metabolism and triggering a switch in muscle fiber composition from oxidative, mitochondria-rich slow to glycolytic fast fibers.
    DOI:  https://doi.org/10.1038/s42003-025-09363-3
  22. Mol Neurobiol. 2025 Dec 27. 63(1): 329
    Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
    Mahalaxmi Iyer, Masako Kinoshita, Dibbanti HariKrishna Reddy, Harysh Winster Suresh Babu, Vikas Lakhanpal, Mukesh Kumar Yadav, Jayalakshmi Krishnan, Vignesh Palanivel, Salmanul Faris, Khushboo Chauhan, Balachandar Vellingiri.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in dopamine depletion and impaired motor function. Growing evidence implicates mitochondrial dysfunction as a central driver of PD pathogenesis with many PD-associated genes and proteins localized are localized near mitochondria and they also have major functions in proper functioning of mitochondria. Among mitochondrial regulators, the transcriptional co-activator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) orchestrates oxidative stress response, mitochondrial biogenesis and inflammatory pathways whereas mitochondrial transcription factor A (TFAM) is essential for maintaining mitochondrial DNA (mtDNA) integrity and copy number variations. Dysregulation of TFAM contributes to mtDNA stress mediated oxidative stress and neurodegeneration whereas experimental studies demonstrate that TFAM overexpression or enzyme replacement enhances neuronal survival and functions. Therefore, in this review we have highlighted the PGC-1α-TFAM regulatory axis as a central hub linking mitochondrial dysfunction, neuroinflammation and oxidative stress in PD. We further discuss therapeutic opportunities aimed at modulating PGC-1α and TFAM to restore mitochondrial homeostasis, underscoring their potential as promising yet underexplored targets for slowing or halting PD progression.
    Keywords:  Mitochondria; PGC-1α; Parkinson’s Disease; TFAM; Therapeutics
    DOI:  https://doi.org/10.1007/s12035-025-05611-z
  23. J Proteome Res. 2025 Dec 22.
    Proximity Labeling Reveals RNA-Binding Proteins Associating with the Human Mitochondrial Import Receptor TOMM20.
    Saira Akram, Katharina I Zittlau, Karan Sharma, Julia C Fitzgerald, Nisha Rafiq, Boris Maček, Ralf-Peter Jansen.
      The import of most mitochondrial proteins requires that their precursor proteins be bound by the peripheral receptor proteins TOM20, TOM22, and TOM70. Budding yeast TOM20 and TOM70 have been extensively studied regarding their interaction partners and recognized substrates; however, little data is available for metazoan cells. Using APEX2-based proximity labeling, we created association profiles for human TOMM20 and TOMM70 in HeLa cells. We focused particularly on their interactions with RNA-binding proteins (RBPs) because there is evidence of RNA association with the mitochondrial outer membrane (MOM) and of local translation at the mitochondrial surface, however, these processes are poorly understood. Our results demonstrate that several RBPs and translation factors preferentially associate with TOMM20 rather than TOMM70. These include SYNJ2BP, a previously identified membrane-bound RBP that binds and protects mRNA encoding mitochondrial proteins. Inhibiting translation with puromycin increased the association of these RBPs with TOMM20 compared to TOMM70. This suggests that TOMM20, but not TOMM70, may play a role in maintaining cellular homeostasis during translation stress by retaining protective RBPs and translation-related proteins at the MOM.
    Keywords:  APEX2; SYNJ2BP; TOMM20; TOMM70; mitochondrial import; proteomics; proximity labeling
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00905
  24. Cell Death Dis. 2025 Dec 26.
    Model organisms in POLG-related disorders: insights from yeast to multicellular systems.
    Raquel Brañas Casas, Giovanni Risato, Alessandro Zuppardo, Carlo Viscomi, Francesco Argenton, Mara Doimo, Nicola Facchinello, Natascia Tiso.
      Mitochondrial genetic diseases are complex disorders that impair cellular energy production, leading to diverse clinical manifestations across multiple organ systems. These diseases arise from mutations in either mitochondrial DNA or nuclear DNA. Among nuclear DNA-related cases, mutations in POLG and POLG2, which encode subunits of mitochondrial DNA polymerase γ, are particularly significant, causing conditions such as Alpers-Huttenlocher syndrome and progressive external ophthalmoplegia. Model organisms have been instrumental in elucidating POLG-related disease mechanisms and advancing therapeutic strategies. Saccharomyces cerevisiae (budding yeast) provided insights into fundamental mitochondrial functions, while Caenorhabditis elegans (roundworm) helped explore POLG's roles in multicellular organisms. Drosophila melanogaster (fruit fly) has been pivotal in studying neurological aspects, and Mus musculus (mouse) models contributed to understanding systemic effects in mammals. Recently, Danio rerio (zebrafish) has emerged as a promising vertebrate model for drug screening, due to its optical transparency and genetic tractability. Each model system offers unique advantages, collectively bridging the gap between basic research and clinical applications. This review will examine in vivo models used in POLG disorder research, highlighting their contributions to understanding disease mechanisms and therapeutic advancements.
    DOI:  https://doi.org/10.1038/s41419-025-08366-6
  25. Biochemistry (Mosc). 2025 Dec;90(12): 1957-1969
    Mitochondrial Reticulum in Skeletal Muscles: Proven and Hypothetical Functions.
    Lora E Bakeeva, Valeriya B Vays, Irina M Vangeli, Chupalav M Eldarov, Vasily A Popkov, Ljubava D Zorova, Savva D Zorov, Dmitry B Zorov.
      The mitochondrial reticulum of skeletal muscles has been characterized in the 1970-80s. It has been suggested and then proven its role is delivering energy in a form of transmembrane potential on the mitochondrial inner membrane throughout the cell volume, followed by ATP synthesis by the mitochondrial ATP synthase. However, the data on the mitochondrial ultrastructure still remains a subject to criticism. To exclude the possibility of artifacts caused by the sample preparation for electron microscopy, we compared the structure of mitochondria in the ultrathin sections of muscle fibers observed by electron microscopy and in intact fibers stained with a membrane potential-dependent dye and visualized by confocal microscopy. The comparison was carried out for mice and naked mole rats known for their superior longevity. The obtained results confirmed previous findings regarding the structure of mitochondrial reticulum. A model suggesting the functioning of giant mitochondria as intracellular structures preventing tissue hypoxia was proposed.
    Keywords:  hypoxia; membrane potential; mitochondria; mouse; naked mole rat; oxygen transport; reticulum; ultrastructure
    DOI:  https://doi.org/10.1134/S000629792560190X
  26. bioRxiv. 2025 Dec 19. pii: 2025.12.18.695286. [Epub ahead of print]
    Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism.
    Dengbao Yang, Gemma Molinaro, Nadine Nijem, Chuanhai Zhang, Dylen Penny, Meijuan Bai, Mei-Jung Lin, Xiaodong Wen, Salvador Pena, Janaka Wansapura, Maria Gaitanou, Rebecca Matsas, Boyuan Wang, Hamid Baniasadi, Yan Han, Jay Gibson, Kimberly Huber, Xing Zeng.
      Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo . Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.
    DOI:  https://doi.org/10.64898/2025.12.18.695286
  27. bioRxiv. 2025 Dec 22. pii: 2025.12.12.694056. [Epub ahead of print]
    Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
    Marina R Hanna, Madison Yarbrough, Melanie Gil, James Costanzo, Vivian Gama.
      Myeloid Cell Leukemia-1 (MCL-1) is canonically an anti-apoptotic protein that is crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B-cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural stem cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation, and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to swollen mitochondria with disorganized cristae and destabilization of the OPA1-MICOS machinery that maintains inner membrane architecture. These structural defects are accompanied by impaired lipid droplet accumulation and altered expression of β-oxidation enzymes, revealing a tight link between cristae architecture and metabolic competence. Functionally, in the absence of caspase-mediated cell death, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings identify MCL-1 as a modulator of cristae organization, linking lipid metabolism to neural progenitor fate. This work establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights the non-canonical MCL-1 functions as critical regulators of human brain development.
    DOI:  https://doi.org/10.64898/2025.12.12.694056
  28. Mol Biol Cell. 2025 Dec 24. mbcE25040188
    A new subset of mitochondrial-derived vesicles perform inter-mitochondrial communications.
    Priyanka Adla, Vani Bshivakumar, Dheeraj Pathak, Ushodaya Mattam, Prasad Tammineni, Thanuja Krishnamoorthy, Naresh B V Sepuri.
      Mitochondria have a fascinating array of tools in their armory for maintaining cellular homeostasis, of which the formation of Mitochondrial-Derived Vesicles (MDVs) is the least energy-intensive. MDVs have become the 'go-to' vesicles for mitochondria to perform functions such as ferrying damaged mitochondrial proteins to lysosomes and regulating peroxisomal morphology. In a corollary to the increasing number of MDV functions, the discovery of MDV subsets has also increased. However, all the known MDV communications have been from mitochondria to other organelles. Using purified mitochondria from rat liver, we show that MDVs can be generated in vitro, and proteomic analyses reveal that liver MDVs are enriched in metabolic proteins mirroring the liver's metabolic hub status. Intriguingly, live cell imaging studies in HepG2 cells reveal a new subset of MDVs that are TOMM70+ve but TOMM20-ve. This subset of MDVs harbors metabolic enzymes, such as ALDH7A1, an aldehyde dehydrogenase. Remarkably, this class of MDVs facilitates communication between mitochondria, revealing a previously unknown communication channel. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-04-0188
  29. Mol Brain. 2025 Dec 25.
    Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.
    Akihiko Nishijima, Mutsumi Yokota, Soichiro Kakuta, Akihiro Yamaguchi, Kei-Ichi Ishikawa, Hideyuki Okano, Wado Akamatsu, Nobutaka Hattori, Masato Koike.
      Mitochondrial dysfunction and abnormalities in mitochondrial quality control contribute to the development of neurodegenerative diseases. Parkinson's disease is a neurodegenerative disease that causes motor problems mainly due to the loss of dopaminergic neurons in the substantia nigra pars compacta. Axonal mitochondria in neurons reportedly differ in properties and morphologies from mitochondria in somata or dendrites. However, the function and morphology of axonal mitochondria in human dopaminergic neurons remain poorly understood. To define the function and morphology of axonal mitochondria in human dopaminergic neurons, we newly generated tyrosine hydroxylase (TH) reporter (TH-GFP) induced pluripotent stem cell (iPSC) lines from one control and one PRKN-mutant patient iPSC lines and differentiated these iPSC lines into dopaminergic neurons in two-dimensional monolayer cultures or three-dimensional midbrain organoids. Immunostainings with antibodies against axonal and dendritic markers showed that axons could be better distinguished from dendrites of dopaminergic neurons in the peripheral area of three-dimensional midbrain organoids than in two-dimensional monolayers. Live-cell imaging and correlative light-electron microscopy in peripheral areas of midbrain organoids derived from control TH-GFP iPSCs demonstrated that axonal mitochondria in dopaminergic neurons had lower membrane potential and were shorter in length than those in non-dopaminergic neurons. Although the mitochondrial membrane potential did not significantly differ between dopaminergic and non-dopaminergic neurons derived from PRKN-mutant patient lines, these differences tended to be similar to those in control lines. These results were also largely consistent with those of our previous study on somatic mitochondria. The findings of the present study indicate that midbrain organoids are an effective tool to distinguish axonal from dendritic mitochondria in dopaminergic neurons. This may facilitate the analysis of axonal mitochondria to provide further insights into the mechanisms of dopaminergic neuron degeneration in patients with Parkinson's disease.
    Keywords:  Axonal mitochondria; Dopaminergic neurons; Electron microscopy; Live-cell imaging; Midbrain organoids
    DOI:  https://doi.org/10.1186/s13041-025-01268-w
  30. J Ovarian Res. 2025 Dec 22. 18(1): 297
    Unveiling mitochondrial and PANoptosis-related biomarkers for premature ovarian insufficiency.
    Zhen Ma, Hong Sun.
      
    Keywords:  Biomarker; Mitochondria; PANoptosis; Premature ovarian insufficiency
    DOI:  https://doi.org/10.1186/s13048-025-01839-4
  31. Comp Biochem Physiol A Mol Integr Physiol. 2026 Jan;pii: S1095-6433(25)00143-6. [Epub ahead of print]311 111944
    Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle.
    Mélanie Boël, Yann Voituron, Damien Roussel.
      Here, we investigate whether the elevated mitochondrial H2O2 release in small mammals arises from a tradeoff between NAD-dependent enzymes, which synthesizes NADH to support high oxidative phosphorylation, and NADP-dependent enzymes, which generates NADPH to detoxify H2O2 within the matrix. We measured the activities of NAD- and NADP-dependent enzymes in skeletal muscle mitochondria from mammal species ranging from 4 g to 600 kg. The activities of the two most active NADPH-producing enzymes increased, whereas NAD-dependent enzyme activities declined with body mass. Therefore, small mammals prioritize NADH synthesis at the expense of NADPH, increasing the oxidative cost of mitochondrial metabolism.
    Keywords:  Allometry; Mammals; Mitochondria; NADPH; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.cbpa.2025.111944
  32. Cell Death Discov. 2025 Dec 24.
    Targeting mitochondrial autophagy for anti-aging.
    Wenjun Shan, Yuling Liu, Ruying Tang, Longfei Lin, Hui Li, Hongjun Yang.
      Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.
    DOI:  https://doi.org/10.1038/s41420-025-02913-y
  33. Mol Ther. 2025 Dec 24. pii: S1525-0016(25)01064-0. [Epub ahead of print]
    Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
    Sandra R Bacman, Wendy Shoop, C Spencer Henley-Beasley, Rhese Thompson, Jose Domingo Barrera-Paez, Lise-Michelle Theard, Monica Rodriguez-Silva, Cassandra Gorsuch, Elisabeth R Barton, Carlos T Moraes.
      Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load which was maintained up to forty-two weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.041
  34. Nat Commun. 2025 Dec 23.
    Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.
    Yiwei Peng, Datong Gao, Yiliang Yang, Yitian Du, Zhenzhen Yang, Jiajia Li, Meng Lin, Yanxia Zhou, Xinru Li, Xianrong Qi.
      Inspired by the non-transmembrane transfer of mitochondria in cell-to-cell communications, herein, we report an original exploration to accelerate mitochondrial intercellular transport, and its application to exogenous cargo delivery. We discover that deliberate PINK1-targeted mitophagy downregulation elevates mitochondrial transit capacity via multifaceted drivers-morphological adaptation, metabolic reprogramming, and respiratory enhancement. Capitalizing on this, we engineer high-speed mitochondrial vehicles for photosensitizer hitchhiking, with spatiotemporal tracking elucidating its dynamic intercellular transit and physiological impacts. Through mitochondria's communication network-tunneling nanotubes (TNTs), the mitochondria-photosensitizer cotransporter achieves reinforced intercellular delivery, thereby inducing deep tumor penetration and enhanced photodynamic killing. Our work establishes a transformative mitochondria-hitchhiking platform for overcoming biological barriers in drug delivery and provides mechanistic insights into manipulating intercellular organelle transport for therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-025-67837-8
  35. EMBO Mol Med. 2025 Dec 22.
    Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.
    Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yairis Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.
      Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.
    Keywords:  Corpus Callosum; Leigh Syndrome; Neural Stem Cells; Postnatal Neurogenesis; Subventricular Zone
    DOI:  https://doi.org/10.1038/s44321-025-00367-4
  36. Alzheimers Dement. 2025 Dec;21 Suppl 1 e104475
    Basic Science and Pathogenesis.
    Thi Kim Oanh Nguyen, Sergey A Trushin, Mark Ostroot, Oscar Ramirez-Molina, Eugenia Trushina.
       BACKGROUND: Although novel treatments targeting amyloid-beta (Aβ) have been recently approved by the FDA, there remains a critical need for alternative therapeutic strategies to delay the onset and progression of Alzheimer's disease (AD). Mitochondrial dysfunction and disrupted brain energy homeostasis are key hallmarks of early-stage AD. Developing treatments that address these deficits could offer substantial benefits. We identified mitochondrial complex I (mtCI) as a druggable target and demonstrated that its mild inhibition using the small molecule CP2 improves brain energy homeostasis, restores synaptic and cognitive function, and activates neuroprotective signaling in AD mouse models. However, the mechanistic link between mtCI inhibition, glucose metabolism, and energy homeostasis remains unclear.
    METHODS: Cellular energy metabolism was assessed in neuroblastoma SH-SY5Y cells expressing mutant human APP protein (APPswe) and in control cells. Glycolytic function, mitochondrial energetics, and fatty acid β-oxidation (FAO) were measured using a Seahorse Analyzer. Glucose transporter (GLUT) translocation to the cell surface was evaluated using flow cytometry and immunofluorescence staining. Protein expression changes were analyzed via Western blot, and glucose uptake was quantified with the Glucose Uptake-Glo™ assay. Additionally, metabolic flux analysis using 13C-labeled glucose and targeted metabolomics by mass spectrometry were performed to measure specific metabolites.
    RESULTS: APPswe cells displayed significant reductions in glycolysis and spare respiratory capacity, indicative of impaired mitochondrial energy production under stress. These deficits were accompanied by reduced glucose uptake, which was partially compensated by an increase in FAO. At concentrations relevant to in vivo treatments, CP2 acutely enhanced GLUT translocation to the cell surface, increasing glucose uptake within one hour. Enhanced glucose utilization in OXPHOS machinery was confirmed by inhibition of PDH phosphorylation and increased conversion of pyruvate to acetyl-CoA, fueling the TCA cycle and generating critical signaling metabolites essential for gene regulation. These mechanisms were mediated by AMPK.
    CONCLUSION: Our findings suggest that mild inhibition of mtCI activates multiple neuroprotective mechanisms, including improved glucose metabolism and energy homeostasis. These consistent results in human cells and AD mouse models highlight the translational potential of this therapeutic approach for AD.
    DOI:  https://doi.org/10.1002/alz70855_104475
  37. Front Aging. 2025 ;6 1750125
    Editorial: Insights in aging, metabolism and redox biology: 2024.
    Ruben K Dagda, Jianhua Zhang.
      
    Keywords:  NAD+; ROCK inhibitor; autophagy and mitophagy; lactate; lifestyles including sleep/fasting/exercise; mitochondria and mitochondrial DNA; neurodegeneration; rapamycin
    DOI:  https://doi.org/10.3389/fragi.2025.1750125
  38. Front Med. 2025 Dec 26.
    Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
    Guoling Zeng, Rongpei Liu, Xiaotian Li, Zhaoqi Lv, Lei Cui, Xiong Zhang, Jianyong Wang.
      Mitochondrial disorders are highly heterogeneous and can manifest as a spectrum of clinically heterogeneous disorders that affect multiple organ systems. Herein, we report a Chinese female patient carrying mitochondrial DNA m.3243A>G mutation who sequentially experienced myoclonic epilepsy with ragged red fibers, mitochondrial neurogastrointestinal encephalomyopathy, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. This report expands the current understanding of phenotypic heterogeneity in mitochondrial disorders.
    Keywords:  m.3243A>G; mitochondrial disorders; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF)
    DOI:  https://doi.org/10.1007/s11684-025-1186-7
  39. Am J Med Genet A. 2025 Dec 23.
    A Novel Variant in the TAMM41-Associated Mitochondrial Myopathy.
    Cristiane Araujo Martins Moreno, Clara Camelo Gontijo, Alulin Tacio Quadros Santos Monteiro Fonseca, Rita Horvath, David Schlesinger, Edmar Zanoteli.
      Pathogenic variants in TAMM41 were recently linked to mitochondrial myopathy, presenting with neonatal hypotonia, generalized weakness, developmental delay, ptosis, and ophthalmoparesis. Here, we present a long-term follow-up of an additional case, a Brazilian patient harboring a novel TAMM41 variant in compound heterozygosity with a previously described pathogenic variant. Patient exhibited mild developmental delay, acquired independent gait, but subsequently developed motor regression and weakness associated with recurrent infections, severe axial involvement, and marked restrictive pulmonary dysfunction. Muscle biopsy revealed decreased COX and SDH staining, which may serve as an important diagnostic clue for this condition. This case expanded the genetic spectrum of TAMM41-related mitochondrial myopathy and provided a brief review of disorders associated with reduced SDH staining.
    DOI:  https://doi.org/10.1002/ajmga.70034
  40. Brain Res Bull. 2025 Dec 24. pii: S0361-9230(25)00516-7. [Epub ahead of print] 111704
    Cerebellar deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia.
    Lauren N Miterko-Myers, Lauren E Peacoe, Lita Duraine, Zhongyuan Zuo, Roy V Sillitoe.
      Deep brain stimulation (DBS) improves motor function in a growing list of movement diseases including Parkinson's disease, dystonia, and tremor. There is evidence that DBS may also be effective in ataxia. It is not known why DBS is effective, but modulating cell activity and conferring neuroprotection are hypothesized to underlie its benefits. Understanding the effects of DBS on neurons is paramount to extending its clinical use in the treatment of various motor and non-motor diseases. Here, we stimulated the cerebellum of Car8 waddles (Car8wdl) mice, given the cerebellum's important role in ataxia pathophysiology. Using transmission electron microscopy, we tested the effects of therapeutic neuromodulation on Purkinje cell subcellular structures, including the mitochondria and their proximity to the endoplasmic reticulum (ER). In the absence of stimulation, we found increased putative mitochondria-ER contacts in Car8wdl Purkinje cells as well as mitochondrial size and density alterations. Low-frequency cerebellar DBS rescued mitochondrial density, but not size or putative contacts in Car8wdl Purkinje cells. Although increased mitochondrial density and sustained ER contact are specific to DBS treatment, they do not determine efficaciousness. These data uncover a mode of intracellular plasticity in Purkinje cells after stimulation, enhancing our mechanistic understanding of DBS for cerebellar disorders.
    Keywords:  CAR8; Cerebellum; Deep Brain Stimulation; Endoplasmic Reticulum; Mitochondria; Purkinje cell; Transmission Electron Microscopy
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111704
  41. Biochemistry (Mosc). 2025 Dec;90(12): 1789-1810
    Ca2+-Dependent Mitochondrial Permeability Transition Pore: Structure, Properties, and Role in Cellular Pathophysiology.
    Konstantin N Belosludtsev, Mikhail V Dubinin, Natalia V Belosludtseva.
      The Mitochondrial Permeability Transition pore (MPT pore) activated by Ca2+ ions is a phenomenon that has long been the subject of intense study. Cyclophilin D-dependent opening of the MPT pore in mitochondria in response to calcium overload and oxidative stress leads to swelling of the mitochondrial matrix, depolarization of the inner membrane and dysregulation of ion homeostasis. These processes are accompanied by damage to mitochondrial membranes and, ultimately, to cell death. Despite decades of research, the molecular identity of the MPT pore remains unclear. Currently, the inner membrane proteins - ATP synthase and adenine nucleotide translocator (ANT) - are considered to be its key structural components, along with the regulatory protein cyclophilin D. The involvement of the MPT pore in the progression of various pathological conditions and diseases, as well as in a number of physiological processes, such as the regulation of cellular bioenergetics and rapid release of Ca2+, is widely discussed. This review summarizes modern molecular genetic data on the putative structure of the MPT pore, traces the evolution of views on its functioning - from interpreting it as a simple experimental artifact to its recognition as a putative key regulator of energy metabolism - and also considers the mechanisms of its regulation and its multifaceted pathophysiological role.
    Keywords:  Ca2+; F0F1–ATP synthase; MPT pore; adenine nucleotide translocator; cell death; cyclophilin D; diabetes mellitus; mitochondria; neurodegenerative diseases; neuromuscular diseases
    DOI:  https://doi.org/10.1134/S0006297925602369
  42. Mol Neurodegener. 2025 Dec 22.
    Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.
    Di Hu, Xiaoyan Sun, Xin Qi.
       BACKGROUND: Mitochondrial dysfunction and α-Synuclein (αSyn) aggregation are defining features of Parkinson's disease (PD), yet the mechanistic link between them remains poorly understood. Although our previous findings suggest that the interaction between αSyn and ClpP (a mitochondrial matrix protease) contributes to PD progression, the pathogenic and therapeutic relevance of this interaction remains elusive.
    METHODS: We employed biochemical and cell biological approaches to investigate how αSyn and ClpP are mutually regulated. Additionally, we determined the pathogenic impact of αSyn-ClpP interaction by using decoy peptide CS2 in αSyn-PFF inoculated primary neurons, PD patient iPSC-derived dopaminergic neurons, and a transgenic mouse model of PD carrying αSyn-A53T mutation.
    RESULTS: We identified mitochondrial protease ClpP as a key regulator of αSyn pathology. We show that αSyn interacts with ClpP through its non-amyloid-β component (NAC) domain, leading to impaired ClpP activity and mitochondrial proteotoxic stress. ClpP, in turn, negatively regulates αSyn aggregation and propagation by stabilizing its native tetrameric form. To interrupt this pathogenic interaction, we developed a decoy peptide, CS2, which binds the NAC domain of αSyn and restores ClpP function. CS2 treatment reduced mitochondrial oxidative stress and αSyn neurotoxicity in neuronal cultures, primary cortical neurons inoculated with αSyn preformed fibrils, and dopaminergic neurons derived from PD patient iPSCs. In mThy1-hSNCA transgenic mice, subcutaneous administration of CS2 restored ClpP levels, decreased αSyn pathology and neuroinflammation, and improved both cognitive and motor function.
    CONCLUSION: These findings highlight the αSyn-ClpP interaction as a druggable target and support CS2 as a potential disease-modifying therapy for PD and related synucleinopathies.
    Keywords:  ClpP; Decoy peptide inhibitor; Mitochondrial dysfunction; Mitochondrial proteostasis; Parkinson’s disease; Protein–protein interaction; αSyn aggregation
    DOI:  https://doi.org/10.1186/s13024-025-00918-w
  43. Biochem J. 2025 Dec 23. pii: BCJ20253459. [Epub ahead of print]483(1):
    Insights into PINK1/Parkin function and dysfunction from Drosophila models.
    Seoyoung Park, Nikita Kozhushko, Thomas H Wight, Alexander J Whitworth.
      Loss-of-function mutations in PINK1 and PRKN cause familial forms of Parkinson's disease (PD). In vitro studies have revealed incredible insights into the molecular and cell-biological function of these genes, which have focused predominantly on mitophagy - the autophagic degradation of damaged mitochondria. The mechanisms of PINK1/Parkin function ultimately require investigation in an in vivo context using classic genetic approaches in animal models. In this context, Drosophila models have proven to be remarkably informative, in part due to robust phenotypes arising from null mutations. They have revealed important insights into the function of the Pink1 and parkin orthologues, much of which has proven to be conserved in humans. The simplicity, speed and genetic tractability make Drosophila an excellent in vivo model to interrogate the physiological functions of Pink1 and parkin and to rapidly test emerging hypotheses arising from in vitro work. They also represent a powerful model with which to explore the pathological consequences of Pink1/parkin loss in a whole-organism context. In this regard, several themes have emerged from recent studies that likely have significance for the neurodegenerative process in humans, including aberrant activation of immune signalling and consequent inflammation, disruptions to gut integrity and disturbed mitochondrial calcium handling. In this review, we evaluate the current evidence regarding the mechanism(s) of Pink1/parkin-mediated mitochondrial turnover in Drosophila, and discuss the potential implications of recent developments on the consequences of Pink1/parkin mutations and how these may inform the pathogenesis of PD.
    Keywords:   Drosophila ; PINK1; Parkin; Parkinson’s disease; autophagy; calcium signalling; immune signalling; mitochondria; mitophagy; mtDNA; neurodegeneration
    DOI:  https://doi.org/10.1042/BCJ20253459
  44. bioRxiv. 2025 Dec 20. pii: 2025.12.16.694762. [Epub ahead of print]
    Mitochondrial control of fuel switching via carnitine biosynthesis.
    Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Anthony Verkerke, Alexander Banks, Sheng Tony Hui, Lijun Sun, Jin-Seon Yook, Rose Witte, Shingo Kajimura.
      Metabolic adaptation to environmental changes, such as fasting and cold exposure, involves a dynamic shift in fuel utilization from glucose to fatty acid oxidation, a process that relies on carnitine-mediated fatty acid oxidation in mitochondria. While dietary sources of animal origin (e.g., red meat) contribute to the carnitine pool, de novo carnitine synthesis from trimethyllysine (TML) is essential, particularly for those whose dietary sources are vegetables and fruits that contain negligible amounts of carnitine. However, the molecular pathway of de novo carnitine synthesis and its physiological significance remain poorly understood. Here, we showed that SLC25A45 is a mitochondrial TML carrier that controls de novo carnitine biosynthesis in vivo. Genetic loss of SLC25A45 results in systemic carnitine and acylcarnitine deficiency, leading to impaired fatty acid oxidation and thermogenesis during cold adaptation, while promoting glucose catabolism. Notably, Slc25a45-deficient mice maintained a high respiratory exchange ratio and impaired lipid mobilization following treatment with a GLP1 receptor agonist (GLP-1RA), rendering them resistant to GLP-1RA-induced adipose tissue loss. Together, the present study identifies SLC25A45 as a regulatory checkpoint in fuel switching during adaptation, with implications for systemic energy balance and response to GLP-1RA-mediated anti-obesity therapy.
    DOI:  https://doi.org/10.64898/2025.12.16.694762
  45. Alzheimers Dement. 2025 Dec;21 Suppl 1 e103262
    Basic Science and Pathogenesis.
    Büşra Şengül, Zuhal Yurttaş, Tugay Çamoğlu, Bilge Nur Bilge, Sümeyra Ildız, Nazlıcan İlhan, Erdinc Dursun, Duygu Gezen-Ak.
       BACKGROUND: Mitochondrial dysfunction in energy metabolism is considered one of the early features of neurodegenerative diseases (1). In Parkinson's disease (PD), mitochondrial functions are among the earliest disrupted neurodegeneration pathways (2). The translocation of alpha-synuclein (α-syn), encoded by the SNCA gene, the major protein of Lewy bodies seen in PD, to mitochondria has been demonstrated (3). Although the importance of α-syn in PD pathology is known, its specific roles within mitochondria must be better understood (4). In this study, we aimed to investigate the regulatory effects of SNCA gene overexpression on the expression of mitochondrial DNA (mtDNA) encoded genes.
    METHOD: Human astrocytes were transfected with a plasmid carrying the SNCA gene and SNCA was overexpressed. The group transfected with the MOCK plasmid was used as a control. RNA isolations were performed 24 and 48 hours after SNCA transfection. Following cDNA synthesis, the expression of 13 respiratory complex genes encoded by mtDNA, two mitochondrial rRNA genes, and three mitochondrial tRNA genes was investigated using qRT-PCR. Statistical analysis of the results was performed using a one-way ANOVA test with GraphPad Prism 8.
    RESULT: After 24 hours of SNCA transfection, the expression of MTND2 (* p <0.05) and MTtRNA3 (* p <0.05; ** p <0.01) increased in the SNCA overexpression group compared to both the MOCK group and the control group. After 48 hours of SNCA transfection, in the SNCA group, mRNA expression levels of MTCYB, MTCO3, MTtRNA1, and MTD-loop were statistically significantly increased compared to the MOCK group (* p <0.05).
    CONCLUSION: These findings indicate that alpha-synuclein overexpression can modulate the expression of mitochondrial genes, highlighting its potential role in mitochondrial dysfunction associated with Parkinson's disease. This study provides new insights into the molecular interactions between alpha-synuclein and mitochondrial gene regulation, offering a basis for future investigations into its contribution to neurodegeneration in PD.
    DOI:  https://doi.org/10.1002/alz70855_103262
  46. Front Immunol. 2025 ;16 1680326
    Cardiolipin's multifaceted role in immune response: a focus on interacting proteins.
    Zhuodong Chai, Yuqi Zhou, Sukria Hossain, Khanh Huynh, Sahelosadat Hajimirzaei, Yan Zhang, Jiaqian Qi, Guoying Zhang, Zhenyu Li, Yinan Wei.
      Cardiolipin is a unique and essential phospholipid that plays a pivotal role in cellular function. In eukaryotic cells, it is predominantly localized within the mitochondrial membranes, with the highest concentration in the inner mitochondrial membrane (IMM). Recent studies have highlighted the multifaceted role of cardiolipin in immune regulation. This review aims to provide a comprehensive overview of specific proteins that directly interact with cardiolipin and to elucidate how these interactions underlie its diverse and critical functions in innate immunity. In addition, we discuss the involvement of cardiolipin in various pathological conditions in which its protein interactions contribute to immune dysregulation.
    Keywords:  cardiolipin; inflammasome; innate immunity; protein-lipid interaction; pyroptosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1680326
  47. Alzheimers Dement. 2025 Dec;21 Suppl 1 e107448
    Basic Science and Pathogenesis.
    Jose Torrellas, Aravindraja Chairmandurai, Adamantios Mamais, Matthew J LaVoie, Paramita Chakrabarty.
       BACKGROUND: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, particularly the G2019S and R1441C variants, are the most prevalent genetic determinants of Parkinson's disease (PD). LRRK2 is increasingly recognized for its roles in immune signaling, with studies suggesting that interferon-gamma (IFNγ), a master immune regulator, may modulate its activity. Based on these findings, we hypothesize a synergistic interaction between LRRK2 mutations and IFNγ.
    METHOD: To explore this hypothesis, we utilized neurons derived from human induced pluripotent stem cells (iPSCs) harboring homozygous G2019S or R1441C LRRK2 mutations, with isogenic wildtype (WT) controls. After differentiation into neurons, cells were treated with recombinant human IFNγ or control media on day 17 of culture and harvested after 6 hours of treatment. Six experimental conditions were analyzed: (WT + IFNγ, WT + Control, G2019S + IFNγ, G2019S + Control, R1441C + IFNγ, R1441C + Control) We analyzed these experiments using immunoblotting and immunofluorescence methods to assess interferon-pathways, tau phosphorylation, and LRRK2 substrate engagement.
    RESULT: Using a dose-dependent paradigm, we optimized the minimum IFNγ dose to achieve maximal target engagement (STAT1 and phosphorylated-STAT1, pSTAT1). All three genotypes responded to IFNγ, producing equivalent levels of pSTAT1, confirming activation of the JAK-STAT pathway. We found that at baseline, levels of pSer202 tau (CP13) levels were moderately increased in both G2019S- and R1441C-LRRK2 relative to WT-LRRK2. IFNγ treatment increased CP13 levels in both G2019S- and R1441C-LRRK2, with the CP13 induction higher in G2019S-LRRK2 while WT-LRRK2 neurons did not show elevated CP13 following IFNγ treatment. IFNγ treatment phosphorylated Threonine73 on Rab10 (a LRRK2 substrate) more efficiently in G2019S-LRRK2 neurons compared to R1441C-LRRK2. We did not observe a genotype-dependent effect of IFNγ on phosphorylation of Ser106 on Rab12, another LRRK2 substrate.
    CONCLUSION: Our data indicates a LRRK2 genotype related response of LRRK2 neurons to IFNγ stimulus. This data lays the groundwork for future studies to dissect mechanisms of neuronal vulnerability in PD and the interplay between LRRK2 mutations and disease pathways.
    DOI:  https://doi.org/10.1002/alz70855_107448
  48. Biochemistry (Mosc). 2025 Dec;90(12): 1929-1943
    ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
    Anna S Lapashina, Danila O Tretyakov, Boris A Feniouk.
      Oxidative phosphorylation in mitochondria is the main source of ATP in most eukaryotic cells. Concentrations of ATP, ADP, and AMP affect numerous cellular processes, including macromolecule biosynthesis, cell division, motor protein activity, ion homeostasis, and metabolic regulation. Variations in ATP levels also influence concentration of free Mg2+, thereby extending the range of affected reactions. In the cytosol, adenine nucleotide concentrations are relatively constant and typically are around 5 mM ATP, 0.5 mM ADP, and 0.05 mM AMP. These concentrations are mutually constrained by adenylate kinases operating in the cytosol and intermembrane space and are further linked to mitochondrial ATP and ADP pools via the adenine nucleotide translocator. Quantitative data on absolute adenine nucleotide concentrations in the mitochondrial matrix are limited. Total adenine nucleotide concentration lies in the millimolar range, but the matrix ATP/ADP ratio is consistently lower than the cytosolic ratio. Estimates of nucleotide fractions show substantial variability (ATP 20-75%, ADP 20-70%, AMP 3-60%), depending on the organism and experimental conditions. These observations suggest that the 'state 4' - inhibition of oxidative phosphorylation in the resting cells due to the low matrix ADP and elevated proton motive force that impedes respiratory chain activity - is highly unlikely in vivo. In this review, we discuss proteins regulating ATP levels in mitochondria and cytosol, consider experimental estimates of adenine nucleotide concentrations across a range of biological systems, and examine the methods used for their quantification, with particular emphasis on the genetically encoded fluorescent ATP sensors such as ATeam, QUEEN, and MaLion.
    Keywords:  ADP; ATP; ATP synthase; ATeam; adenine nucleotide translocator (ANT); mitochondria
    DOI:  https://doi.org/10.1134/S0006297925603338
  49. Cells. 2025 Dec 09. pii: 1956. [Epub ahead of print]14(24):
    Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
    Surim Bang, So-Hyun Choi, Seung Min Jeong.
      Mitochondrial fatty acid oxidation (FAO) has long been recognized as a central pathway for energy production, providing acetyl-CoA, NADH, and FADH2 to sustain cellular growth and survival. However, recent advances have revealed that FAO exerts far broader roles beyond bioenergetics. FAO contributes to redox balance by generating NADPH for antioxidant defense, regulates protein acetylation through acetyl-CoA availability, and modulates stress signaling pathways to support cellular adaptation under nutrient or genotoxic stress. These emerging insights establish FAO as a metabolic hub that integrates energy homeostasis with redox regulation, epigenetic modification, and stress responses. Dysregulation of FAO has been increasingly implicated in aging and diverse pathologies, including cellular senescence, obesity, cancer and fibrosis. In this review, we highlight recent findings and provide an updated perspective on the expanding roles of mitochondrial FAO in stress responses and aging, with particular emphasis on its potential as a therapeutic target in age-associated diseases.
    Keywords:  acetylation; age-related diseases; fatty acid oxidation; redox homeostasis; stress response
    DOI:  https://doi.org/10.3390/cells14241956
  50. Cell Death Discov. 2025 Dec 23. 11(1): 563
    Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway.
    Teresa Campbell, Jesse Slone, Jimmy Vu, Wensheng Liu, Li Yang, Adam Dourson, Luis F Queme, Michael P Jankowski, Taosheng Huang.
      Loss-of-function variants in the ferredoxin reductase (FDXR) gene result in a primary mitochondrial disease in humans, involving abnormal mitochondrial iron accumulation. However, the molecular mechanism is not fully understood. To better understand the underlying pathology of FDXR-related disease, we generated a mouse model corresponding to the hotspot variant found in humans. We demonstrated increased lipid peroxidation in the inner mitochondrial and plasma membranes, resulting in susceptibility to ferroptosis. Closer examination revealed that disruption of the NRF2 pathway and its target gene SLC7A11 appear to play important roles in this pathogenic process. Finally, administration of the NRF2 activator omaveloxolone, which was recently approved by the FDA for treatment of Friedreich's ataxia, helps mitigate the pathogenesis. Together, our results suggest that ferroptosis is a novel underlying mechanism of FDXR-related disease and that activation of NRF2 could be an immediate, viable treatment option for individuals with FDXR-related disease and other conditions involving aberrant iron metabolism.
    DOI:  https://doi.org/10.1038/s41420-025-02840-y
  51. Cell Death Discov. 2025 Dec 20.
    Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
    Ping Zhang, Peng Huang, Qiongye Dong, Juan Luo, Guanghui Cui, Xin Guo, Minghua Li, Xia Long, Hongyu Zhang, Wei V Zheng, Peng Cui.
      Parkinson's disease (PD) is a challenging neurodegenerative disorder. Recently, therapy of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has emerged as a significant advancement in regenerative medicine. Melatonin (MT), acting as a mitochondrial targeting hormone, exhibits neuroprotective properties in neurodegenerative diseases and modulates stem cell differentiation through mitochondrial dynamics. However, the precise mechanism by which MT influences dopaminergic (DA) neuronal differentiation in hiPSCs through regulating mitochondrial dynamics remains unclear. In this study, we developed and optimized a technical protocol for the in vitro functional neuronal differentiation of hiPSCs. Our findings demonstrate that MT enhances the differentiation potential of hiPSCs toward neuroectoderm and significantly improves the efficiency of NSCs differentiation into DA neurons by more than three times within hiPSCs. Using the specific MT receptor inhibitor, Luzindole, we confirmed its inhibitory effect on MT-mediated promotion of neural differentiation. Mechanistically, we propose that MT enhances functional DA neuron differentiation from hiPSCs by activating mitochondrial dynamics-mediated WNT/β-catenin signaling pathways. Additionally, we elucidated the critical role of mitofusin2 (MFN2) in enhancing the directed differentiation of DA neurons from hiPSCs. In vivo studies validated the efficacy of MT-treated hiPSC-derived DA progenitor cells in regenerating tyrosine hydroxylase (TH)-positive DA neurons and improving motor function in a MPTP-induced mouse model of Parkinson's disease. In conclusion, this study highlights the potential clinical relevance of MT-enhanced differentiation of hiPSCs into DA neurons, offering promising implications for the treatment of PD.Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41420-025-02906-x
  52. World J Pediatr. 2025 Dec 26.
    Expert consensus on the combined screening of genes and biomarkers for neonatal diseases.
    Xin-Wen Huang, Ting Zhang, Zhen-Zhen Hu, Zhi-Guo Wang, Xiao-Ping Luo, Yan-Ling Yang, Lian-Shu Han, Xue-Fan Gu, Guang-Ren Xiao, Bao-Sheng Zhu, Ru-Lai Yang, Wei-Peng Wang, Yong-Lan Huang, Jian-Hui Jiang, Hua Wang, Guo-Li Tian, Qiao-Ling Sun, Xin-Mei Mao, Bin Yu, Wen-Bin Zhu, Pi-Liang Chen, Hai-Li Hu, Hui-Ming Yan, Jing Liu, Wen-Ying Nie, Feng Wang, Ren Cai, Tao Jiang, Xiao-Hua Wang, Fa-Liang Xu, Yu-Lin Zhou, Jian-Ping Yang, Lin Zou, Wei Wen, Yuan-Yuan Kong, Ming-Cai Ou, Ya-Guo Zhang, Yan-Qin Ying, Rong Qiang, De-Hua Zhao, Chen-Lu Jia, Zhi-Xin Zhang, Ben-Qing Wu, Hui Zou, Zheng-Yan Zhao.
       BACKGROUND: Newborn screening (NBS) through disease biomarkers has significantly reduced severe outcomes of congenital disorders. Moreover, exploratory newborn genetic screening programs are increasingly being implemented. This consensus, developed by multidisciplinary experts, aims to standardize the combined screening of genes and biomarkers for neonatal diseases in China, balancing ethical, technical, and clinical considerations.
    DATA SOURCES: This consensus synthesizes evidence from peer-reviewed literature (PubMed, CNKI, etc.) up to 2024 and integrates clinical experiences from multidisciplinary experts in neonatology, genetics, and laboratory medicine, focusing on disease biomarker-based NBS, newborn genetic screening, and the clinical utility of combined screening.
    RESULTS: The consensus defines principles for combined screening: (1) disease/gene selection: 154 disease-causing genes covering 67 inherited metabolic disorders (e.g., amino acid metabolism disorders, organic acid metabolism disorders), prioritized by treatability, onset age (< 5 years), and cost-effectiveness; (2) methodology: integrating dried blood spot biomarker analysis with next-generation sequencing-based targeted capture (coverage > 300 ×), validated by MLPA/Sanger and long-range sequencing for complex variants (e.g., CYP21A2, SLC25A13); and (3) operational workflow: standardized workflows for informed consent, sample collection/delivery, and result interpretation, with dual reporting of marker and genetic findings within 15 days. Positive cases require family verification and/or other genetic sequencing techniques.
    CONCLUSIONS: This consensus establishes a practical framework for integrating marker and genetic screening, aiming to improve diagnostic accuracy and achieve rapid and effective interventions, thereby saving lives and reducing the occurrence of severe complications. Implementation requires interdisciplinary collaboration and ongoing quality control to maximize clinical utility.
    Keywords:  Combined screening; Disease biomarker; Genetic screening; Newborn screening
    DOI:  https://doi.org/10.1007/s12519-025-00996-2
  53. EMBO Rep. 2025 Dec 22.
    Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.
    Anne E van Vlimmeren, Lauren C Tang, Ziyuan Jiang, Abhishek Iyer, Rashmi Voleti, Konstantin Krismer, Jellert T Gaublomme, Marko Jovanovic, Neel H Shah.
      Missense mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, are common in several developmental disorders and cancers. While many mutations disrupt auto-inhibition and hyperactivate SHP2, several do not enhance catalytic activity. Both activating and non-activating mutations could potentially drive pathogenic signaling by altering SHP2 interactions or localization. We employed proximity-labeling proteomics to map the interaction networks of wild-type SHP2, ten clinically relevant mutants, and SHP2 bound to an inhibitor that stabilizes its auto-inhibited state. Our analyses reveal mutation- and inhibitor-dependent alterations in the SHP2 interactome, with several mutations also changing localization. Some mutants show increased mitochondrial localization and impact mitochondrial function. This study provides a resource for exploring SHP2 signaling and offers new insights into the molecular basis of SHP2-driven diseases. Furthermore, this work highlights the capacity for proximity-labeling proteomics to detect missense-mutation-dependent changes in protein interactions and localization.
    Keywords:  Mitochondria; PTPN11; Protein-Protein Interaction; TurboID; Tyrosine Phosphatase
    DOI:  https://doi.org/10.1038/s44319-025-00674-4
  54. Am J Physiol Endocrinol Metab. 2025 Dec 26.
    GLOBAL LOSS OF SELENOCYSTEINE LYASE IN MICE DRIVES LIPID ACCUMULATION IN BROWN ADIPOCYTES.
    Briana K Shimada, Ashley N Ogawa-Wong, Antonio G Soares, Kayla A Hallam, Princess Jd Santiago, Kaitlyn Saelua, Kescher K Nakahara-Akita, Daniel J Torres, John D Brockman, Suguru Kurokawa, Kris Ewell, Miyoko T Bellinger, Pamela Toh, Gabriela Lagatta Pamplona Remedios, Naghum Alfulaij, Sydonie M Swanson, Ali Seyedali, Ann Marie Zavacki, Marla J Berry, Lucia A Seale.
      The enzyme selenocysteine (Sec) lyase (SCLY) decomposes Sec releasing selenide for the synthesis of selenoproteins, which contain Sec in their primary structure and participate in strong redox reactions, maintaining redox balance. We previously showed global disruption of the Scly gene (Scly KO) in mice leads to obesity. Targeted deletion of Scly in Agrp neurons enhances energy expenditure and brown adipose tissue (BAT) activation, augmenting leanness. We hypothesized that Scly KO mice develop obesity due to failure of BAT-controlled mechanisms of energy expenditure due to redirection of Sec to an alternative pathway. We analyzed BAT from male Scly KO mice on Se-adequate (0.25 ppm) and Se-deficient (0.08 ppm) diets for morphology, Se content, selenoprotein expression, thyroid hormones, and additional Sec-utilizing pathways. We found that BAT of Scly KO mice was enlarged, with lower Se levels, and substantial whitening on a Se-adequate diet. This phenotype worsened on low Se and coincided with a mild impairment in adapting to cold exposure. BAT whitening coincided with an increase in triglycerides and reduced 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) and cholesterol. BAT selenoproteins regulating energy metabolism DIO2, GPX1, and GPX4 were significantly decreased. DIO2 reduction corresponded with an increase in thyroxine (T4), thyroid stimulating hormone (TSH), and reduction in heat-producer uncoupling protein 1 (UCP1). Downregulation of GPX4 did not affect ferroptosis in the BAT. Therefore, the whitened BAT of the Scly KO mouse is a multifactorial process involving the disruption of BAT function through changes to selenoproteins involved in energy metabolism.
    Keywords:  BAT; energy metabolism; obesity; selenocysteine lyase; selenoproteins
    DOI:  https://doi.org/10.1152/ajpendo.00213.2025
  55. Sci Rep. 2025 Dec 23. 15(1): 44419
    Implementing electronic informed consent in rare disease genomics.
    Katja Ekholm, Annelie Augustinsson, Johan Sundström, Christian Johansen, Maria Storgärds, Lena Ljöstad, Fulya Taylan, Eva Ekblom, Stephanie Juran, Marlene Ek, Charlotta Ingvoldstad Malmgren, Maria Johansson Soller, Mikaela Friedman, Sofia Thunström, Lovisa Lovmar, Ann Nordgren, Hans Ehrencrona, Anna Lindstrand.
      
    Keywords:  Electronic informed consent (eConsent); Genomics; Rare diseases; Whole-genome sequencing
    DOI:  https://doi.org/10.1038/s41598-025-32740-1
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