bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–01–19
eightteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
  2. Friedreich ataxia: what can we learn from non-GAA repeat mutations?
  3. When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder.
  4. Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
  5. Intrinsic neuronal resilience as a tool for therapeutic discovery.
  6. Longitudinal analysis of anthropometric measures over 5 years in patients with Friedreich ataxia in the EFACTS natural history study.
  7. Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.
  8. Mitochondrial Complex I Deficiency: Unraveling the Relevance of NDUFAF1 in Pediatric Hypertrophic Cardiomyopathy.
  9. Targeting mitophagy in neurodegenerative diseases.
  10. ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
  11. Reacting to reductive stress at the mitochondrial import gate.
  12. In vivo base editing extends lifespan of a humanized mouse model of prion disease.
  13. mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
  14. Mechanistic Target of Rapamycin Signaling Activity in the Human Placenta Across Gestation and in Maternal Obesity.
  15. Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
  16. Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
  17. Mitochondrial segmentation and function prediction in live-cell images with deep learning.
  18. Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial.
  1. Acta Pharm Sin B. 2024 Dec;14(12): 5435-5450
    Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
    Yi Wang, Nahui Liu, Lifan Hu, Jingsong Yang, Mengmeng Han, Tianjiao Zhou, Lei Xing, Hulin Jiang.
      Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
    Keywords:  Complex I defect; Engineered mitochondria; Idebenone; Leber's hereditary optic neuropathy; Mitochondrial disease; Mitochondrial function; Mitochondrial transfer; Nanoparticle
    DOI:  https://doi.org/10.1016/j.apsb.2024.08.007
  2. Neurodegener Dis Manag. 2025 Jan 15. 1-10
    Friedreich ataxia: what can we learn from non-GAA repeat mutations?
    David R Lynch, M Shen, Robert B Wilson.
      Friedreich ataxia (FRDA) is a slowly progressive neurological disease resulting from decreased levels of the protein frataxin, a small mitochondrial protein that facilitates the synthesis of iron-sulfur clusters in the mitochondrion. It is caused by GAA (guanine-adenine-adenine) repeat expansions in the FXN gene in 96% of patients, with 4% of patients carrying other mutations (missense, nonsense, deletion) in the FXN gene. Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient. In this review, we propose explanations for such phenotypes based on the potential for activities of frataxin other than enhancement of iron-sulfur cluster synthesis, as well as crucial future experiments for fully understanding the role of frataxin in cells.
    Keywords:  GRP75; Triplet repeat; frataxin; iron sulfur cluster; mitochondrion; point mutation
    DOI:  https://doi.org/10.1080/17582024.2025.2452147
  3. J Child Neurol. 2025 Jan 17. 8830738241313081
    When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder.
    Ahmet Koçak, Emek Uyur Yalçin, Nilüfer Eldeş Hacifazlioğlu, İbrahim Taş, Rahşan Göçmen, Bahadır Konuşkan.
      Mitochondrial complex I transfers electrons from NADH (nicotinamide adenine dinucleotide) to ubiquinone, facilitating ATP synthesis via a proton gradient. Complex I defects are common among the mitochondrial diseases, especially in childhood. NDUFA12, located in complex I's transmembrane domain, is not directly involved in catalytic activity, but the NDUFA mutations are associated with Leigh syndrome and complex I defects. Complex I deficiency typically manifests as bilateral brainstem lesions and presents with dystonia, hypotonia, and optic nerve damage. This article discusses a patient with an NDUFA12 mutation resembling neuromyelitis optica spectrum disorder clinically and radiologically, highlighting the importance of considering NDUFA12 mutations in dystonia and optic neuritis diagnoses, particularly in neuromyelitis optica spectrum disorder cases that do not respond to standard treatments. Further research on NDUFA12 variants is needed for a better understanding of their phenotypic spectrum and to enhance diagnostic accuracy.
    Keywords:  Leigh syndrome; NDUFA12; mitochondrial complex I; mitochondrial disease; neuromyelitis optica; symmetric brainstem lesion
    DOI:  https://doi.org/10.1177/08830738241313081
  4. Nat Metab. 2025 Jan 16.
    Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
    Jonathan R Brestoff, Keshav K Singh, Katia Aquilano, Lance B Becker, Michael V Berridge, Eric Boilard, Andrés Caicedo, Clair Crewe, José Antonio Enríquez, Jianqing Gao, Åsa B Gustafsson, Kazuhide Hayakawa, Maroun Khoury, Yun-Sil Lee, Daniele Lettieri-Barbato, Patricia Luz-Crawford, Heidi M McBride, James D McCully, Ritsuko Nakai, Jiri Neuzil, Martin Picard, Alexander G Rabchevsky, Anne-Marie Rodriguez, Shiladitya Sengupta, Alexander J Sercel, Toshio Suda, Michael A Teitell, Alain R Thierry, Rong Tian, Melanie Walker, Minghao Zheng.
      Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.
    DOI:  https://doi.org/10.1038/s42255-024-01200-x
  5. Brain. 2025 Jan 15. pii: awaf010. [Epub ahead of print]
    Intrinsic neuronal resilience as a tool for therapeutic discovery.
    Stefania Corti, Eva Hedlund.
      
    DOI:  https://doi.org/10.1093/brain/awaf010
  6. Eur J Neurol. 2025 Jan;32(1): e70011
    Longitudinal analysis of anthropometric measures over 5 years in patients with Friedreich ataxia in the EFACTS natural history study.
    EFACTS study group
       BACKGROUND: Friedreich ataxia is a rare neurodegenerative disorder caused by frataxin deficiency. Both underweight and overweight occur in mitochondrial disorders, each with adverse health outcomes. We investigated the longitudinal evolution of anthropometric abnormalities in Friedreich ataxia and the hypothesis that both weight loss and weight gain are associated with faster disease progression.
    METHODS: Participants were drawn from the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS). Age- and sex-specific BMI and height scores were calculated using the KIGGS-BMI percentiles for children. Height correction was applied for scoliosis. Longitudinal data were analysed using linear mixed effects models and incremental standard deviation scores and growth mixture models identified subclasses with varying BMI trajectories.
    RESULTS: Five hundred and forty-three adults and fifty-nine children were assessed for up to 5 years. In children, severe underweight (26%), underweight (7%), severe short stature (16%) and short stature (23%) were common. The corrected BMI percentile was stable in children, although 48% had negative incremental BMI scores over 1 year and 63% over 3 years versus 10%/year in a normal reference cohort. Overweight was common in adults (19%), with a slight increase in BMI over time. Longer GAA repeat size was linked to lower BMI in adults. Weight trajectory was not associated with ataxia progression in adults.
    CONCLUSION: Significant anthropometric abnormalities were identified, with underweight and short stature prevalent in children and overweight in adults. These findings highlight the need for regular nutritional monitoring and interventions to manage underweight in children and promote healthy weight in adults.
    Keywords:  Friedreich ataxia; body height; body mass index; natural history; underweight
    DOI:  https://doi.org/10.1111/ene.70011
  7. iScience. 2025 Jan 17. 28(1): 111496
    Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.
    Irena J J Muffels, Richard Rodenburg, Hanneke L D Willemen, Désirée van Haaften-Visser, Hans Waterham, Niels Eijkelkamp, Sabine A Fuchs, Peter M van Hasselt.
      Traditional classification by clinical phenotype or oxidative phosphorylation (OXPHOS) complex deficiencies often fails to clarify complex genotype-phenotype correlations in mitochondrial disease. A multimodal functional assessment may better reveal underlying disease patterns. Using imaging flow cytometry (IFC), we evaluated mitochondrial fragmentation, swelling, membrane potential, reactive oxygen species (ROS) production, and mitochondrial mass in fibroblasts from 31 mitochondrial disease patients. Significant changes were observed in 97% of patients, forming two overarching groups with distinct responses to mitochondrial pathology. One group displayed low-to-normal membrane potential, indicating a hypometabolic state, while the other showed elevated membrane potential and swelling, suggesting a hypermetabolic state. Literature analysis linked these clusters to complex I stability defects (hypometabolic) and proton pumping activity (hypermetabolic). Thus, our IFC-based platform offers a novel approach to identify disease-specific patterns through functional responses, supporting improved diagnostic and therapeutic strategies.
    Keywords:  Biological sciences; Genetics; Health sciences; Human genetics; Medicine; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.111496
  8. Am J Med Genet A. 2025 Jan 16. e63994
    Mitochondrial Complex I Deficiency: Unraveling the Relevance of NDUFAF1 in Pediatric Hypertrophic Cardiomyopathy.
    Silvia Kalantari, Daniele Veraldi, Davide Politano, Antonia Apicella, Riccardo Castagnoli, Thomas Foiadelli, Fulvio D'Abrusco, Elisa Giorgio, Angela Berardinelli, Alessia Claudia Codazzi, Gianluigi Marseglia, Enza Maria Valente, Fabio Sirchia.
      Hypertrophic cardiomyopathy (HCM) is rare in childhood, but it is associated with significant morbidity and mortality. Genetic causes of HCM are mostly related to sarcomeric genes abnormalities; however, syndromic, metabolic, and mitochondrial disorders play an important role in its etiopathogenesis in pediatric patients. We here describe a new case of apparently isolated HCM due to mitochondrial assembly factor gene NDUFAF1 biallelic variants (c.631C > T and an intragenic deletion encompassing exon 3, NM_016013.4). Alterations of this nuclear gene have been associated to Mitochondrial complex I deficiency, nuclear type 11 (OMIM *618234). We here report the fourth case of a child affected by complex I deficiency due to alterations in NDUFAF1 gene. His clinical features appear simpler when compared to the other cases described in the medical literature, increasing our knowledge regarding the highly heterogeneous clinical presentation associated with this disorder.
    Keywords:  NDUFAF1; hypertrophic cardiomiopathy; mitochondrial complex I deficiency
    DOI:  https://doi.org/10.1002/ajmg.a.63994
  9. Nat Rev Drug Discov. 2025 Jan 14.
    Targeting mitophagy in neurodegenerative diseases.
    Odetta Antico, Paul W Thompson, Nicholas T Hertz, Miratul M K Muqit, Laura E Parton.
      Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.
    DOI:  https://doi.org/10.1038/s41573-024-01105-0
  10. iScience. 2025 Jan 17. 28(1): 111544
    ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
    Kashif Shaikh, Melissa Bowman, Sarah M McCormick, Linlin Gao, Jiawen Zhang, Jesse White, John Tawil, Arun Kapoor, Ravit Arav-Boger, Christopher C Norbury, Edward W Harhaj.
      ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.
    Keywords:  Cell biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111544
  11. Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]
    Reacting to reductive stress at the mitochondrial import gate.
    Sylvie Callegari.
      A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.
    Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
  12. Nat Med. 2025 Jan 14.
    In vivo base editing extends lifespan of a humanized mouse model of prion disease.
    Meirui An, Jessie R Davis, Jonathan M Levy, Fiona E Serack, John W Harvey, Pamela P Brauer, Catherine P Pirtle, Kiara N Berríos, Gregory A Newby, Wei-Hsi Yeh, Nikita Kamath, Meredith Mortberg, Yuan Lian, Michael Howard, Kendrick DeSouza-Lenz, Kenia Guzman, Aaron Thai, Samantha Graffam, Alissa A Coffey, Jeannine Frei, Sarah E Pierce, Jiri G Safar, Benjamin E Deverman, Eric Vallabh Minikel, Sonia M Vallabh, David R Liu.
      Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain. Systemic injection of dual-adeno-associated virus PHP.eB encoding BE3.9max and single guide RNA installing PRNP R37X resulted in 37% average installation of the desired edit, 50% reduction of PrP in the mouse brain and 52% extension of lifespan in transgenic human PRNP mice inoculated with pathogenic human prion isolates representing the most common sporadic and genetic subtypes of prion disease. We further engineered base editing systems to achieve improved in vivo potency and reduced base editor expression in nontargeting tissues, resulting in 63% average PrP reduction in the mouse brain from a 6.7-fold lower viral dose, with no detected off-target editing of anticipated clinical significance observed in either human cells or mouse tissues. These findings support the potential of in vivo base editing as one-time treatment for prion disease.
    DOI:  https://doi.org/10.1038/s41591-024-03466-w
  13. Cell Rep. 2025 Jan 13. pii: S2211-1247(24)01530-4. [Epub ahead of print]44(1): 115179
    mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
    Brittany Q Pham, Sang Ah Yi, Alban Ordureau, Heeseon An.
      One critical aspect of cell proliferation is increased nucleotide synthesis, including pyrimidines. Pyrimidines are synthesized through de novo and salvage pathways. Prior studies established that the mammalian target of rapamycin complex 1 (mTORC1) promotes pyrimidine synthesis by activating the de novo pathway for cell proliferation. However, the involvement of mTORC1 in regulating the salvage pathway remains unclear. Here, we report that mTORC1 controls the half-life of uridine cytidine kinase 2 (UCK2), the rate-limiting enzyme in the salvage pathway. Specifically, UCK2 is degraded via the CTLH-WDR26 E3 complex during mTORC1 inhibition, which is prevented when mTORC1 is active. We also find that UCK1, an isoform of UCK2, affects the turnover of UCK2 by influencing its cellular localization. Importantly, altered UCK2 levels through the mTORC1-CTLH E3 pathway affect pyrimidine salvage and the efficacy of pyrimidine analog prodrugs. Therefore, mTORC1-CTLH E3-mediated degradation of UCK2 adds another layer of complexity to mTORC1's role in regulating pyrimidine metabolism.
    Keywords:  CP: Metabolism; CP: Molecular biology; CTLH; UCK2; WDR26; YPEL5; degradomics; mTOR; mTORC1; pyrimidine; pyrimidine salvage; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2024.115179
  14. Biol Reprod. 2025 Jan 13. pii: ioaf007. [Epub ahead of print]
    Mechanistic Target of Rapamycin Signaling Activity in the Human Placenta Across Gestation and in Maternal Obesity.
    Katie L Bidne, Kathryn E Erickson, Theresa L Powell, Thomas Jansson.
      The mechanistic target of rapamycin (mTOR) system is vital to placental development, formation, and function. Alterations in this system in the placenta have been associated with altered fetal growth. However, changes in placental mTOR signaling across gestation are poorly understood. We collected 81 human placental samples from 4-40 weeks' gestation to test the hypothesis that placental mTOR signaling activity increases over gestation and is activated in maternal obesity in early gestation. Proteins involved in upstream mTOR regulation and mTORC1/2 downstream signaling were quantified using immunoblotting in placentas of male or female fetuses. Readouts of mTORC1 activation, phospho-rpS6 and phospho-4EBP1 were highest in first trimester and decreased across gestation. Phosphorylation of AKT (308 and 473) increased over gestation. Interestingly, abundance of cytochrome c oxidase I and mitochondrial ATP synthase, key subunits of mitochondrial complexes III/IV and V, respectively, were elevated in first trimester obese placentas compared to control, but only in placenta from female fetuses. We suggest that the high placental mTOR signaling activity in early pregnancy may be related to the high anabolism and active trophoblast proliferation and invasion in the second half of the first trimester. In addition, we conclude that maternal obesity has only limited impact on this key placental signaling pathway across gestation in women.
    Keywords:  first trimester; maternal-fetal exchange; pregnancy; signal transduction; trophoblast
    DOI:  https://doi.org/10.1093/biolre/ioaf007
  15. Nat Metab. 2025 Jan 15.
    Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
    Janine Tutas, Marianna Tolve, Ebru Özer-Yildiz, Lotte Ickert, Ines Klein, Quinn Silverman, Filip Liebsch, Frederik Dethloff, Patrick Giavalisco, Heike Endepols, Theodoros Georgomanolis, Bernd Neumaier, Alexander Drzezga, Guenter Schwarz, Bernard Thorens, Graziana Gatto, Christian Frezza, Natalia L Kononenko.
      Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.
    DOI:  https://doi.org/10.1038/s42255-024-01196-4
  16. J Physiol. 2025 Jan 14.
    Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
    Ludovica Tommasin, Andrea Carrer, Federica Boscolo Nata, Elena Frigo, Federico Fogolari, Giovanna Lippe, Michela Carraro, Paolo Bernardi.
      The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+-dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Unexpectedly, ANT-dependent PT at pH 6.5 could also be stimulated by benzodiazepine-423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co-immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process. KEY POINTS: We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT). At pH 7.4, bongkrekate had little effect on Ca2+-dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Benzodiazepine-423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT-dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. ANT could be co-immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.
    Keywords:  ATP synthase; adenine nucleotide translocator; calcium; mitochondria; permeability transition
    DOI:  https://doi.org/10.1113/JP287147
  17. Nat Commun. 2025 Jan 16. 16(1): 743
    Mitochondrial segmentation and function prediction in live-cell images with deep learning.
    Yang Ding, Jintao Li, Jiaxin Zhang, Panpan Li, Hua Bai, Bin Fang, Haixiao Fang, Kai Huang, Guangyu Wang, Cameron J Nowell, Nicolas H Voelcker, Bo Peng, Lin Li, Wei Huang.
      Mitochondrial morphology and function are intrinsically linked, indicating the opportunity to predict functions by analyzing morphological features in live-cell imaging. Herein, we introduce MoDL, a deep learning algorithm for mitochondrial image segmentation and function prediction. Trained on a dataset of 20,000 manually labeled mitochondria from super-resolution (SR) images, MoDL achieves superior segmentation accuracy, enabling comprehensive morphological analysis. Furthermore, MoDL predicts mitochondrial functions by employing an ensemble learning strategy, powered by an extended training dataset of over 100,000 SR images, each annotated with functional data from biochemical assays. By leveraging this large dataset alongside data fine-tuning and retraining, MoDL demonstrates the ability to precisely predict functions of heterogeneous mitochondria from unseen cell types through small sample size training. Our results highlight the MoDL's potential to significantly impact mitochondrial research and drug discovery, illustrating its utility in exploring the complex relationship between mitochondrial form and function within a wide range of biological contexts.
    DOI:  https://doi.org/10.1038/s41467-025-55825-x
  18. Brain Commun. 2025 ;7(1): fcae478
    Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial.
    Burak Yulug, Ozlem Altay, Xiangyu Li, Lutfu Hanoglu, Seyda Cankaya, Halil A Velioglu, Simon Lam, Hong Yang, Ebru Coskun, Ezgi Idil, Zubeyir Bayraktaroglu, Rahim Nogaylar, Ahmet Ozsimsek, Serkan Yildirim, Ismail Bolat, Metin Kiliclioglu, Cemil Bayram, Nursena Yuksel, Ozlem O Tozlu, Muhammad Arif, Saeed Shoaie, Ahmet Hacimuftuoglu, Cheng Zhang, Jens Nielsen, Hasan Turkez, Jan Borén, Mathias Uhlén, Adil Mardinoglu.
      Parkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).
    Keywords:  Parkinson’s disease; combined metabolic activators; multi-omics; systems biology
    DOI:  https://doi.org/10.1093/braincomms/fcae478
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