bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–03–30
seventeen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. A human brain map of mitochondrial respiratory capacity and diversity.
  2. Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.
  3. The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
  4. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  5. A map of mitochondrial biology reveals the energy landscape of the human brain.
  6. The fate of mitochondrial respiratory complexes in aging.
  7. Mitochondrial DNA variants revealed by whole exome sequencing: from screening to diagnosis and follow-up.
  8. Organoids as 3D Models for Studying Exogenous Mitochondrial Transplantation.
  9. Can the Supplementation of Oocytes with Extra Copies of mtDNA Impact Development Without Being Transmitted? A Molecular Account.
  10. Diverse Phenotypes of Mitochondrial Disease With Varying Levels of Heteroplasmy.
  11. Hypertrophic Cardiomyopathy Through the Lens of Mitochondria.
  12. First map of human brain mitochondria is 'groundbreaking' achievement.
  13. Riboflavin transporter deficiency: AAV9-SLC52A2 gene therapy as a new therapeutic strategy.
  14. Adult-onset Leigh syndrome with recurrent seizures and peripheral neuropathy due to the 9176T > C mutation: a case report and literature review.
  15. Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA.
  16. A novel early onset spinocerebellar ataxia 13 BAC mouse model with cerebellar atrophy, tremor, and ataxic gait.
  17. Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
  1. Nature. 2025 Mar 26.
    A human brain map of mitochondrial respiratory capacity and diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .
    DOI:  https://doi.org/10.1038/s41586-025-08740-6
  2. Nat Commun. 2025 Mar 22. 16(1): 2839
    Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.
    Shu-Jiao Li, Qian-Wen Zheng, Jie Zheng, Jin-Bao Zhang, Hui Liu, Jing-Jing Tie, Kun-Long Zhang, Fei-Fei Wu, Xiao-Dong Li, Shuai Zhang, Xin Sun, Yan-Ling Yang, Ya-Yun Wang.
      Cerebellar ataxia is the primary manifestation of cerebellar degenerative diseases, and mitochondrial dysfunction in Purkinje cells (PCs) plays a critical role in disease progression. In this study, we investigated the feasibility of mitochondria transplantation as a potential therapeutic approach to rescue cerebellar neurodegeneration and elucidate the associated mechanisms. We constructed a conditional Drp1 knockout model in PCs (PCKO mice), characterized by progressive ataxia. Drp1 knockout resulted in pervasive and progressive apoptosis of PCs and significant activation of surrounding glial cells. Mitochondrial dysfunction, which triggers mitophagy, is a key pathogenic factor contributing to morphological and functional damage in PCs. Transplanting liver-derived mitochondria into the cerebellum of 1-month-old PCKO mice improved mitochondrial function, reduced mitophagy, delayed apoptosis of PCs, and alleviated cerebellar ataxia for up to 3 weeks. These findings demonstrate that mitochondria transplantation holds promise as a therapeutic approach for cerebellar degenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-025-58189-4
  3. Biomolecules. 2025 Mar 18. pii: 433. [Epub ahead of print]15(3):
    The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
    Paola Zanfardino, Alessandro Amati, Mirko Perrone, Vittoria Petruzzella.
      Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.
    Keywords:  autophagy; mTOR signaling; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases; oxidative phosphorylation; proliferation; senescence
    DOI:  https://doi.org/10.3390/biom15030433
  4. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  5. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  6. Trends Cell Biol. 2025 Mar 26. pii: S0962-8924(25)00042-X. [Epub ahead of print]
    The fate of mitochondrial respiratory complexes in aging.
    Hanna Salmonowicz, Karolina Szczepanowska.
      While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.
    Keywords:  OXPHOS; age-associated diseases; dysfunction; mitochondria; protein complexes, aging hallmarks
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.008
  7. Neurogenetics. 2025 Mar 26. 26(1): 38
    Mitochondrial DNA variants revealed by whole exome sequencing: from screening to diagnosis and follow-up.
    Sebastian Skoczylas, Tomasz Płoszaj, Karolina Gadzalska, Monika Gorządek, Paulina Jakiel, Ewa Juścińska, Maria Malarska, Magdalena Traczyk-Borszyńska, Hanna Biezynska, Magdalena Rychlik, Agata Pastorczak, Agnieszka Zmysłowska.
      Mutations in mitochondrial DNA play a crucial role in several diseases, but interpreting the clinical significance of mitochondrial DNA variants is challenging due to heteroplasmy, age-related loss of variants and evolving phenotypes. The aim of study was to identify mitochondrial pathogenic variants and explore their potential future association with specific phenotypes in patients during their lifetime, for both known and novel variants. We used a Python pipeline to analyse exome sequencing data from 418 patients (median age: 15 years; 52.9% males and 47.1% females), mostly diagnosed with neurological disorders, developmental and intellectual disabilities, behavioural and sensory disorders, cardiovascular and metabolic abnormalities, renal diseases and others. Screening identified 1,000 unique variants with heteroplasmy levels greater than 10% and 192 unique variants with 1-10% heteroplasmy, excluding hypervariable regions. Among these variants, four confirmed pathogenic variants were detected according to MITOMAP (m.1555 A > G, m.3243 A > G, m.9035T > C, and m.11778G > A), each identified in one patient. The application of pathogenicity and frequency criteria led to the identification of three unique variants and one in monozygotic twin sister with low levels of heteroplasmy, which were confirmed by next-generation sequencing. Finally, one of them, the variant m.15897G > A, was recognised as likely pathogenic (PP3, PS2). Our study highlights the complexity of diagnosing mitochondrial diseases associated with mtDNA mutations and emphasises the need for a comprehensive genotype-phenotype approach to correctly identify causal variants.
    Keywords:  Mitochondrial diseases; Whole exome sequencing; mtdna; mtdna variants
    DOI:  https://doi.org/10.1007/s10048-025-00820-z
  8. Adv Exp Med Biol. 2025 Mar 26.
    Organoids as 3D Models for Studying Exogenous Mitochondrial Transplantation.
    Ismail Eş, Oner Ulger.
      Mitochondria play a critical role in cellular communication, cell proliferation, and apoptosis, which make them essential to maintaining cellular health. Recently, mitochondrial transplantation has emerged as a promising therapeutic approach to treat conditions such as ischemia, neurodegenerative diseases, and cardiovascular disorders by restoring mitochondrial function in damaged cells. Despite its potential, understanding mitochondrial behavior in vivo remains challenging; however, organoid models, which are three-dimensional structures derived from stem cells that mimic human tissues, offer a solution to study mitochondrial function and transplantation strategies under controlled conditions. These models are particularly necessary in studies, as they can replicate disease conditions and consequently enable researchers to investigate mitochondrial dynamics and therapeutic integration. Developing organoid systems optimized for mitochondrial transplantation requires exploring factors that influence mitochondrial uptake, refining transplantation strategies, and understanding their role in cellular regeneration in order to advance in the field of mitochondrial research.
    Keywords:  3D cell culture models; Delivery methods in organoids; Mitochondria; Mitochondrial transplantation; Organoids
    DOI:  https://doi.org/10.1007/5584_2025_857
  9. Int J Mol Sci. 2025 Mar 18. pii: 2746. [Epub ahead of print]26(6):
    Can the Supplementation of Oocytes with Extra Copies of mtDNA Impact Development Without Being Transmitted? A Molecular Account.
    Justin C St John, Eryk Andreas, Alexander Penn.
      The introduction of extra copies of mitochondrial DNA (mtDNA), whether autologous or heterologous, into oocytes at the time of fertilisation or through other assisted reproductive technologies, such as nuclear transfer, is a contentious issue. The primary focus has been on whether third-party mtDNA is transmitted to the offspring and if it impacts offspring health and well-being. However, little attention has focused on whether the introduction of extra copies of mtDNA will interfere with the balance established between the nuclear and mitochondrial genomes during oogenesis and as the developing embryo establishes its own epigenetic imprint that will influence mature offspring. Whilst we determined that sexually mature offspring generated through mtDNA supplementation did not inherit any-third party mtDNA, they exhibited differences in gene expression from three tissues derived from three separate embryonic lineages. This resulted in a number of pathways being affected. In each case, the differences were greater in the heterologous and autologous comparison than when comparing all supplemented offspring against non-supplemented offspring. Many of the changes in gene expression were coupled to differential DNA methylation across tissues, some of which were tissue-specific, with high levels observed in the heterologous against autologous comparison. An analysis of DNA methylation in blastocyst-stage embryos pointed to changes in patterns of DNA methylation that were transmitted through to the offspring. Our results indicated that extra copies of mtDNA may not be transmitted if introduced at low levels, but the changes induced by supplementation that occur in DNA methylation and gene expression in the blastocyst have a profound effect on tissues.
    Keywords:  DNA methylation; gene expression; mtDNA; offspring; oocyte; segregation; supplementation; transmission
    DOI:  https://doi.org/10.3390/ijms26062746
  10. JCEM Case Rep. 2025 Apr;3(4): luaf020
    Diverse Phenotypes of Mitochondrial Disease With Varying Levels of Heteroplasmy.
    Rebecca John, Aaron Chapla, Geeta Chacko, Sangeetha Yoganathan, Maya Mary Thomas, Nihal Thomas.
      Mitochondrial diseases have a wide spectrum of clinical presentations. Heteroplasmy, the presence of wild type and mutated mitochondrial deoxyribonucleic acid (DNA) in a single cell, is typical of mitochondrial disorders. It can show varying levels between cells of the same tissue, between organs in a single individual as well as between members of the same family. We describe below a woman who presented to us for management of pancreatic diabetes. Her daughter had a history of recurrent bouts of myopathy; evaluation was suggestive of having a mitochondrial etiology. Subsequently, mitochondrial genetic testing revealed positivity for m.3243A>G variant with a heteroplasmy of 45% in the blood in the daughter and 15% in the proband. We highlight how differences in the heteroplasmy and threshold levels among members of the same family resulted in a variable spectrum of clinical disease. Family screening of members identified with mitochondrial disease is of utmost significance to ensure early diagnosis and therapy.
    Keywords:  diabetes mellitus; heteroplasmy; mitochondrial diseases; muscular diseases
    DOI:  https://doi.org/10.1210/jcemcr/luaf020
  11. Biomedicines. 2025 Feb 28. pii: 591. [Epub ahead of print]13(3):
    Hypertrophic Cardiomyopathy Through the Lens of Mitochondria.
    Tatiana V Kirichenko, Ivan V Zhivodernikov, Maria A Kozlova, Alexander M Markin, Vasily V Sinyov, Yuliya V Markina.
      The mechanisms of pathogenesis of hypertrophic cardiomyopathy are associated with mutations in the sarcomere genes of cardiomyocytes and metabolic disorders of the cell, including mitochondrial dysfunction. Mitochondria are characterized by the presence of their own DNA and enzyme complexes involved in oxidative reactions, which cause damage to mitochondrial protein structures and membranes by reactive oxygen species. Mitochondrial dysfunctions can also be associated with mutations in the genes encoding mitochondrial proteins and lead to a violation of protective functions such as mitophagy, mitochondrial fusion, and fission. Mutations in myofibril proteins can negatively affect mitochondria through increased oxidative stress due to an increased need for ATP. Mitochondrial dysfunction is associated with impaired ATP synthesis and cardiac contractility, leading to clinical manifestations of hypertrophic cardiomyopathy. The current review was designed to characterize the role of mitochondria in the pathogenesis of hypertrophic cardiomyopathy based on published data; the search for publications was based on the analysis of articles including the keywords "hypertrophic cardiomyopathy, mitochondria, dysfunction" in the PubMed and Scopus databases up to January 2025.
    Keywords:  hypertrophic cardiomyopathy; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/biomedicines13030591
  12. Nature. 2025 Mar 26.
    First map of human brain mitochondria is 'groundbreaking' achievement.
    Nora Bradford.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00848-z
  13. Front Cell Neurosci. 2025 ;19 1523773
    Riboflavin transporter deficiency: AAV9-SLC52A2 gene therapy as a new therapeutic strategy.
    Cecilia Mei, Valentina Magliocca, Xin Chen, Keith Massey, Anai Gonzalez-Cordero, Steven J Gray, Marco Tartaglia, Enrico Silvio Bertini, Stefania Corti, Claudia Compagnucci.
      Riboflavin transporter deficiency syndrome (RTD) is a rare childhood-onset neurodegenerative disorder caused by mutations in SLC52A2 and SLC52A3 genes, encoding the riboflavin (RF) transporters hRFVT2 and hRFVT3. In the present study we focused on RTD Type 2, which is due to variants in SLC52A2 gene. There is no cure for RTD patients and, although studies have reported clinical improvements with administration of RF, an effective treatment is still unavailable. Here we tested gene augmentation therapy on RTD type 2 patient-derived motoneurons using an adeno-associated viral vector 2/9 (AAV9) carrying the human codon optimized SLC52A2 cDNA. We optimized the in vitro transduction of motoneurons using sialidase treatment. Treated RTD motoneurons showed a significant increase in neurite's length when compared to untreated samples demonstrating that AAV9-SLC52A2 gene therapy can rescue RTD motoneurons. This leads the path towards in vivo studies offering a potential treatment for RTD patients.
    Keywords:  gene therapy; human pluripotent stem cells; morphological neuronal phenotyping; motoneuronal differentiation; neurodegenerative autosomal recessive disease
    DOI:  https://doi.org/10.3389/fncel.2025.1523773
  14. BMC Neurol. 2025 Mar 26. 25(1): 128
    Adult-onset Leigh syndrome with recurrent seizures and peripheral neuropathy due to the 9176T > C mutation: a case report and literature review.
    Yashi Liao, Yaxin Lai, Xinxin Chen, Shanshan Zhao.
       BACKGROUND: Leigh syndrome (LS) is an inherited form of mitochondrial encephalopathy associated with various gene mutations of the oxidative phosphorylation system, typically occurring in infancy or early childhood and resulting in disability or even death. However, few late-onset cases have been reported.
    OBJECTIVE: The objective of this case report was to investigate the radiological and clinical characteristics of an adult patient diagnosed with Leigh syndrome.
    CASE PRESENTATION: This article describes a patient who presented with recurrent generalized seizures, peripheral neuropathy and hypertension and was ultimately diagnosed with Leigh syndrome with a mitochondrial gene variant, c.9176T > C (p.Leu217Pro), in 20,315 of the MT-ATP6 gene. Here, we discuss the possible pathogenesis of its clinical manifestations according to the related literature and review the current therapeutic approaches and prognosis of LS.
    CONCLUSION: A possible diagnosis of LS should be taken into consideration when patients with characteristic neuroimaging findings of LS demonstrate recurrent seizures, peripheral neuropathy, or hypertension, and genetic analysis should be carried out for differential diagnosis.
    Keywords:  Basal ganglia; Hypertension; Leigh syndrome; MT-ATP6 gene; Mitochondrial diseases; Peripheral neuropathy; Recurrent seizure
    DOI:  https://doi.org/10.1186/s12883-025-04135-2
  15. Nat Biotechnol. 2025 Mar 25.
    Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA.
    Yuhang Fan, Wenchao Xu, Bao-Qing Gao, Huichao Qin, Xiaoyi Wu, Jia Wei, Qingyang Ni, Lina Zhou, Jiangchao Xiang, Jing Wu, Bei Yang, Li Yang, Jia Chen.
      Transcription activator-like effector-linked deaminases (TALEDs) use their single-stranded DNA (ssDNA)-specific adenosine deaminase TadA8e to mediate A-to-G editing in mitochondrial DNA (mtDNA). The working mechanism of this process is unknown, hindering the development of more effective TALEDs. Here we reveal that TALED-mediated A-to-G editing relies on the formation of an ssDNA region through base excision repair (BER), which is triggered by double-stranded DNA-specific cytidine deaminase (DddA)-induced C-to-U deamination. We develop a series of enhanced TALEDs (eTALED6s) with increased editing efficiency by replacing DddA with the high-activity variant DddA6 and fusing human uracil DNA glycosylase to TadA8e. By further engineering TadA8e, the resulting eTALED6Rs induces efficient on-target editing with reduced bystander editing and off-target editing at the DNA and RNA levels. Lastly, we use eTALED6 and eTALED6R to install a pathogenic mutation in mtDNA. Revealing the mechanism of TALED-mediated A-to-G editing demonstrates that enhancing BER increases editing efficiency.
    DOI:  https://doi.org/10.1038/s41587-025-02608-w
  16. Exp Anim. 2025 Mar 20.
    A novel early onset spinocerebellar ataxia 13 BAC mouse model with cerebellar atrophy, tremor, and ataxic gait.
    Junxiang Yin, Jerelyn A Nick, Swati Khare, Heidi E Kloefkorn, Ming Gao, Michael Wu, Jennifer White, James L Resnick, Kyle D Allen, Harry S Nick, Michael F Waters.
      Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant neurological disorder caused by mutations in KCNC3. Our previous studies revealed that KCNC3 (Potassium Voltage-Gated Channel Subfamily C Member 3)mutation R423H results in an early-onset form of SCA13. Previous biological models of SCA13 include zebrafish and Drosophila but no mammalian systems. More recently, mouse models with Kcnc3 mutations presented behavioral abnormalities but without obvious pathological changes in the cerebellum, a hallmark of patients with SCA13. Here, we present a novel transgenic mouse model by bacterial artificial chromosome (BAC) recombineering to express the full-length mouse Kcnc3 expressing the R424H mutation. This BAC-R424H mice exhibited behavioral and pathological changes mimicking the clinical phenotype of the disease. The BAC-R424H mice (homologous to R423H in human) developed early onset clinical symptoms with aberrant gait, tremor, and cerebellar atrophy. Histopathological analysis of the cerebellum in BAC-R424H mice showed progressive Purkinje cell loss and thinning of the molecular cell layer. Additionally, Purkinje cells of BAC-R424H mice showed significantly lower spontaneous firing frequency with a corresponding increase in inter-spike interval compared to that of wild-type mice. Our SCA13 transgenic mice recapitulate both neuropathological and behavioral changes manifested in human SCA13 R423H patients and provide an advantageous approach to understanding the role of voltage-gated potassium channel in cerebellar morphogenesis and function. This mammalian in vivo model will lead to further understanding of the R423H allelic form of SCA13 from the molecular to the behavioral level and serve as a platform for testing potential therapeutic compounds.
    Keywords:  KCNC3; Purkinje cells; R424H; Spinocerebellar ataxia 13; cerebellar atrophy
    DOI:  https://doi.org/10.1538/expanim.24-0118
  17. Cell Death Dis. 2025 Mar 27. 16(1): 214
    Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
    Lucia Barazzuol, Tetiana Tykhonenko, Tia L Griffiths, Alessio Vagnoni, Marisa Brini, Tito Calì.
      Organelle contact sites are crucial for cellular function, enabling the exchange of lipids, ions, and other molecules between different organelles. The ability to track these contact sites in vivo has been significantly advanced by the development of SPLICS (Split-GFP-based Contact Site Sensors) reporters, which have provided unprecedented insights into the intricate network of organelle communication. This innovative and powerful tool allows the real-time visualization of different organelle interactions in living cells and in vivo thus unraveling the complexity of their dynamic in the context of cellular homeostasis. Recent studies highlighted the dynamic nature of organelle contact sites either in terms of tethering/untethering and of movement of the contact itself in time and space: whether unique temporal behaviors and contact site-specific dynamics of different organelle interactions exist is currently unknown. In this study, we investigated the spatiotemporal distribution of various organelle contact sites using time-lapse in vitro and in vivo imaging and discovered an evolutionarily conserved dynamic pattern among different contact sites, influenced by the specific partner organelles involved. These findings highlight the importance of spatial and temporal regulation at organelle contact sites, which may underlie their diverse physiological functions. The discovery of contact site-specific dynamics opens new avenues for understanding the regulation of organelle interactions in health and disease, with potential implications for developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-025-07511-5
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