bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–09–14
sixty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mending a mother's mitochondrial DNA.
  2. Mitochondrial Transplantation Therapy: A Novel Approach in the Era of Organelle-Centered Regenerative Medicine.
  3. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  4. Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data.
  5. The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
  6. SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
  7. Preclinical and first-in-human evidence of 4-hydroxybenzoic acid for mitochondrial COQ2 deficiency.
  8. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
  9. Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.
  10. Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
  11. A Perspective on the Role of Mitochondrial Biomolecular Condensates (mtBCs) in Neurodegenerative Diseases and Evolutionary Links to Bacterial BCs.
  12. ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
  13. Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
  14. Emerging strategies, applications and challenges of targeting NAD+ in the clinic.
  15. Bacteria-Mitochondria Cross-talk: How Microbes Regulate Mitochondrial Dynamics and Bioenergetics of Host Cells.
  16. Age-related changes in cardiolipin profile and functional consequences of altered fatty acid supply.
  17. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  18. The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
  19. Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
  20. Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
  21. Phosphomimetic experiments do not support a causal role for TFAM phosphorylation in mtDNA elimination in sperm.
  22. Mitochondria-Associated Pathways in Cancer and Precancerous Conditions: Mechanistic Insights.
  23. Defective mitochondrial quality control in the aging of skeletal muscle.
  24. Ligand-Enzyme Interaction Modeling of Missense Variants Implicated in Mitochondrial HMG-CoA Synthase Deficiency.
  25. Mechanism of Na+ ions contribution to the generation and maintenance of a high inner membrane potential in mitochondria.
  26. Acute refractory chorea as a novel phenotype of NARS2 gene mutation-related mitochondrial disorder.
  27. Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.
  28. Activator of apoptosis harakiri (HRK) localisation at mitochondria alters mitochondrial morphology independently of other BCL-2 proteins.
  29. Mitochondria mechanosensing: The powerhouse fueling cellular force signaling.
  30. ABCA7 variants impact phosphatidylcholine and mitochondria in neurons.
  31. Protective role of Bre1 in mitochondrial function and energy metabolism in Drosophila models of Parkinson's disease.
  32. MetabOCT: a clinical trial looking for a metabolomic signature predicting the onset of Leber's hereditary optic neuropathy in healthy MtDNA mutations carriers.
  33. LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
  34. Carriers of m.3243A>G Who Receive Transplant Must be Closely Monitored for Possible Mitochondrial Toxicity of Required Immunosuppressants.
  35. Comprehensive review on alcohol-induced protein modifications in hepatic mitochondrial membranes and their functional implications.
  36. The potential of mitochondrial transfer as the modifying therapy for osteoarthritis.
  37. The Solve-RD Solvathons as a pan-European interdisciplinary collaboration to diagnose patients with rare disease.
  38. Structure and mechanism of the mitochondrial calcium transporter NCLX.
  39. An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.
  40. OXPHOS complex deficiency in congenital myopathy: A systematic review.
  41. Incorporating Rare Disease Growth Monitoring Into Routine Practice to Improve Early Recognition and Diagnosis of Genetic Conditions.
  42. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 deficiency with severe hyperglycemia in a child: A rare case report.
  43. Next-Gen Neuroprotection in Glaucoma: Synergistic Molecules for Targeted Therapy.
  44. Mitochondrial Gene Regulation and Pain Susceptibility: A Multi-Omics Causal Inference Study.
  45. Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
  46. CRABS-ROC, A Respirometry Protocol For Overcoming Substrate Limitations, Reveals Excess Brain Mitochondrial Complex I Capacity.
  47. Mitochondria delay action potential propagation.
  48. Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.
  49. Mitochondrial Transport Proteins in Cardiovascular Diseases: Metabolic Gatekeepers, Pathogenic Mediators and Therapeutic Targets.
  50. Muscle Memory of Exercise Optimizes Mitochondrial Metabolism to Support Skeletal Muscle Growth.
  51. A mitochondria targeted nitroreductase-sensitive self-immolative spacer as an efficient shuttle for uncharged amine-based molecules.
  52. Ferric derisomaltose augments intrinsic skeletal muscle electron transport chain activity in heart failure: A FERRIC-HF II molecular substudy.
  53. Mitochondrial lipidome's fatty acid profile and peroxidation index are programmed tissue-specific traits.
  54. Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review.
  55. IL-1β restrains its own apoptosis-promoting activity via NF-κB (RelA) Ser276/p62-mediated elimination of damaged mitochondria in Chondrocytes.
  56. Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.
  57. Updates on Parkinson's Disease.
  58. Synthetic data can benefit medical research - but risks must be recognized.
  59. Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.
  60. Current Therapeutic Strategies in Parkinson's Disease: Future Perspectives.
  61. Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female.
  1. Nat Med. 2025 Sep 12.
    Mending a mother's mitochondrial DNA.
    Mike May.
      
    DOI:  https://doi.org/10.1038/d41591-025-00056-2
  2. Front Biosci (Landmark Ed). 2025 Aug 18. 30(8): 37006
    Mitochondrial Transplantation Therapy: A Novel Approach in the Era of Organelle-Centered Regenerative Medicine.
    Ha Rim Shin, Gaheon Lee, Kyung Hwa Kim.
      Mitochondria play crucial roles in maintaining health and influencing disease progression by acting as central regulators of cellular homeostasis and energy production. Dysfunctions in mitochondrial activity are increasingly recognized as key contributors to various pathologies, ultimately impacting healthspan and disease outcomes. However, traditional treatments often do not restore damaged mitochondria to a healthy state. Mitochondrial transplantation, a cellular organelle-based therapy in which mitochondria are introduced into a recipient, has emerged as a novel concept in next-generation therapeutics that overcomes the limitations of current cell-based treatments. This review highlights the unique properties of mitochondria as therapeutic agents, including their ability to restore cellular functions and treat a wide range of diseases. In this review, we focus on the unique role of mitochondria in the regulation of stem cell functions, including stem cell fate, self-renewal, and differentiation. Various perspectives have been explored to better understand mitochondrial transplantation therapy, which harnesses the capacity of mitochondria as living drugs in regenerative medicine, as an innovative strategy to bridge the gap between cell therapy and organelle-based treatments and overcome current clinical barriers.
    Keywords:  mesenchymal stem cell; mitochondrial dysfunction; mitochondrial transplantation; organelle transplantation; regenerative medicine
    DOI:  https://doi.org/10.31083/FBL37006
  3. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  4. Ann Clin Transl Neurol. 2025 Sep 12.
    Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data.
    Ian W McKeague, Kristin Engelstad, Yue Ge, Amber Tucker, Shufang Li, Jasim Uddin, Ziwei Zhao, John L P Thompson, Michio Hirano.
       OBJECTIVE: Therapeutic development for mitochondrial diseases, rare genetic disorders with pathogenic defects of oxidative phosphorylation, is hindered by unsatisfactory outcome measures. To address this problem, we provide the first clinical application of a novel, bias-adjusted outcome measure of acceleration across a range of subjects' activities to assess nucleoside therapy for thymidine kinase 2 deficiency, an ultra-rare autosomal recessive mitochondrial disease.
    METHODS: Data were collected from treated patients in an ongoing phase 2 clinical trial who served as their own controls. If there is a treatment effect, time-in-activity curves for these patients will increase over successive clinic visits. We used a combination of functional data analysis and longitudinal mixed-effects linear regression, adjusted for age and gender, to test for the effect of treatment length on time-in-activity.
    RESULTS: For 14 patients with at least two assessments 6 months apart, we found a significant overall improvement of time-in-activity due to treatment. Improvement was especially significant at two individual activity levels within the range (0.14 and 2 g). In longitudinal analyses, using data on time-in-activity at these two levels for all clinic visits of 19 subjects, the effect of treatment length on time-in-activity was highly significant at both 0.14 g (0.04, CI 0.01-0.08, p = 0.023) and 2 g (0.01, 0.00-0.02, p = 0.013).
    INTERPRETATION: This small-N exploratory analysis using a new accelerometer-based activity measure featuring powerful data reduction and adjustment for circadian rhythms and other biases finds that nucleoside therapy may increase activity levels in thymidine kinase 2 deficiency patients.
    Keywords:  accelerometer; mitochondrial disease; outcome measure; thymidine kinase 2 deficiency
    DOI:  https://doi.org/10.1002/acn3.70180
  5. Front Biosci (Landmark Ed). 2025 Aug 27. 30(8): 27634
    The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
    Solenn Plouzennec, Juan Manuel Chao de la Barca, Arnaud Chevrollier.
      The bioenergetic machinery of the cell is protected and structured within two layers of mitochondrial membranes. The mitochondrial inner membrane is extremely rich in proteins, including respiratory chain complexes, substrate transport proteins, ion exchangers, and structural fusion proteins. These proteins participate directly or indirectly in shaping the membrane's curvature and facilitating its folding, as well as promoting the formation of nanotubes, and proton-rich pockets known as cristae. Recent fluorescent super-resolution images have demonstrated the strong dynamics of these events, with constant remodeling processes. The mitochondrial outer membrane itself is also highly dynamic, interacting with the endoplasmic reticulum and its environment to ensure a rapid diffusion of surface components throughout the mitochondrial networks. All these movements occur besides migration, fusion, and fission of the mitochondria themselves. These dynamic events at the level of mitochondrial membranes are primarily dependent on their unique lipid composition. In this review, we discuss the latest advances in phospholipid research, focusing on their metabolism and role in mitochondrial dynamics. This process emphasizes the importance of interactions with the endoplasmic reticulum and mitochondrial matrix enzymes, extending its relevance to lipid sources, in particular, cardiolipins and phosphatidylethanolamines at the cellular, tissue and even whole-organism level. Given the expanding array of characterized mitochondrial functions, ranging from calcium homeostasis to inflammation and cellular senescence, research in the field of mitochondrial lipids is particularly significant. As mitochondria play a central role in various pathological processes, including cancer and neurodegenerative disorders, lipid metabolism may offer promising therapeutic approaches.
    Keywords:  dynamic; lipids; membrane; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.31083/FBL27634
  6. J Cell Biol. 2025 Oct 06. pii: e202406017. [Epub ahead of print]224(10):
    SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
    Rachel Shannon, Yadu Balachandran, Xindi Wang, Maxime Boutry, Hong Xie, Peter K Kim, William S Trimble.
      Mitochondria continually undergo fission to maintain their network and health. Nascent fission sites are marked by the ER, which facilitates actin polymerization to drive calcium flux into the mitochondrion and constrict the inner mitochondrial membrane. Septins are a major eukaryotic cytoskeleton component that forms filaments that can both directly and indirectly modulate other cytoskeleton components, including actin. Septins have been implicated in mitochondrial fission; however, a connection between septins and the regulation of cytoskeletal machinery driving fission is not known. We find that SEPTIN9 is present at mitochondrial fission sites from its early stages with the ER and prior to the fission factor dynamin-related protein 1 (DRP1). SEPTIN9 has an isoform-specific role in fission, dependent on its N-terminal interaction to activate a Rho guanine nucleotide exchange factor, ARHGEF18. Without SEPTIN9, mitochondrial calcium influx is impaired, indicating SEPTIN9-containing octamers play a critical role in the early stages of fission.
    DOI:  https://doi.org/10.1083/jcb.202406017
  7. Brain. 2025 Sep 10. pii: awaf334. [Epub ahead of print]
    Preclinical and first-in-human evidence of 4-hydroxybenzoic acid for mitochondrial COQ2 deficiency.
    Felix Distelmaier, Julia Corral-Sarasa, Laura Jiménez-Sánchez, María Elena Díaz-Casado, Melanie Rohmann, Annette Seibt, Diran Herebian, Sander H J Smits, Juliane Münch, Ertan Mayatepek, Jörg Breitkreutz, Ralf A Husain, Sergio López-Herrador, Pilar González-García, Luis C López.
      Primary coenzyme Q (CoQ) deficiency is a mitochondrial disorder with variable clinical presentation and limited response to standard CoQ10 supplementation. Recent studies suggest that 4-hydroxybenzoic acid (4-HBA), a biosynthetic precursor of CoQ, may serve as a substrate enhancement treatment in cases caused by pathogenic variants in COQ2, a gene encoding a key enzyme in CoQ biosynthesis. However, it remains unclear whether 4-HBA is required throughout life to maintain health, whether it offers advantages over CoQ10 treatment, and whether these findings are translatable to humans. Here, we demonstrate that lifelong 4-HBA supplementation in a murine model carrying the pathogenic Coq2A252V variant is well tolerated and prevents the onset of mitochondrial encephalopathy. In contrast, withdrawal of 4-HBA leads to progressive neurological decline. Notably, while conventional CoQ10 supplementation transiently ameliorated cardiac dysfunction, it failed to prevent fatal neurological deterioration. Guided by these preclinical findings, we initiated a first-in-human individual therapeutic trial with 4-HBA in a 3-year-old boy with genetically confirmed primary CoQ10 deficiency due to compound heterozygous pathogenic COQ2 variants. The patient presented with a Leigh-like syndrome characterized by bilateral brain lesions, developmental delay, muscular hypotonia, failure to thrive, lactic acidosis, and steroid-resistant nephrotic syndrome. Despite high-dose oral CoQ10 supplementation, clinical response had been minimal. Prior to clinical application, patient-derived fibroblasts were treated in vitro with 4-HBA, resulting in a marked increase in endogenous CoQ10 levels. Following the initiation of oral 4-HBA treatment, the patient experienced rapid and sustained remission of proteinuria, improved renal hyperfiltration, and a gradual increase in serum CoQ10 concentrations. No adverse effects were observed during a six-month follow-up. Clinically, the patient showed notable improvements in motor skills, language acquisition, cognitive alertness, and overall development, accompanied by significant gains in growth and nutritional status. Clinical recovery was also reflected by improved scores on the Newcastle Paediatric Mitochondrial Disease Scale. These findings support 4-HBA as a promising targeted metabolic treatment for COQ2-related CoQ deficiency and highlight the need for further clinical investigation.
    Keywords:  4-hydroxybenzoic acid; COQ2; coenzyme Q deficiency; mitochondrial diseases; pharmacological therapy; therapeutic trial
    DOI:  https://doi.org/10.1093/brain/awaf334
  8. Nat Metab. 2025 Sep 09.
    Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
    Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.
      The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01358-y
  9. Mol Cell. 2025 Sep 03. pii: S1097-2765(25)00701-4. [Epub ahead of print]
    Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.
    Jiangchao Xiang, Wenchao Xu, Jing Wu, Yaxin Luo, Chengyu Liu, Yaofeng Hou, Jia Chen, Bei Yang.
      DddA-derived cytosine base editor (DdCBE) couples transcription activator-like effector (TALE) arrays and the double-stranded DNA (dsDNA)-specific cytidine deaminase DddA to target mitochondrial DNA (mtDNA) for editing. However, structures of DdCBE in action are unavailable, impeding its mechanistic-based optimization for high-precision-demanding therapeutic applications. Here, we determined the cryo-electron microscopy (cryo-EM) structures of DdCBE targeting two native mitochondrial gene loci and combined editing data from systematically designed spacers to develop WinPred, a model that can predict DdCBE's editing outcome and guide its design to achieve high-precision editing. Furthermore, structure-guided engineering of DddA narrowed the editing window of DdCBE to 2-3 nt while minimizing its off-target (OT) editing to near-background levels, thereby generating accurate DdCBE (aDdCBE). Using aDdCBE, we precisely introduced a Leber hereditary optic neuropathy (LHON)-disease-related mutation into mtDNA and faithfully recapitulated the pathogenic conditions without interference from unintended bystander or OT mutations. Our work provides a mechanistic understanding of DdCBE and establishes WinPred and aDdCBE as useful tools for faithfully modeling or correcting disease-related mtDNA mutations.
    Keywords:  DdCBE; DddA engineering; cryo-EM structure; editing precision; editing window; mitochondrial DNA; mitochondrial disease modeling
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.016
  10. Redox Biol. 2025 Sep 04. pii: S2213-2317(25)00372-6. [Epub ahead of print]86 103859
    Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
    Nada Ahmed Selim, Andrew P Wojtovich.
      Mitochondria are central to cellular function, acting as metabolic hubs that regulate energy transduction to communicate cellular status. A key component of this energetic regulation is the mitochondrial membrane potential (MMP), a charge separation across the inner mitochondrial membrane generated by the electron transport chain. Beyond MMP's canonical role in driving ATP synthesis, MMP acts as a dynamic signaling hub. MMP rapidly adjusts to acute changes in cellular energy demand and undergoes sustained modifications during developmental processes, such as neuronal remodeling. Changes in MMP influence reactive oxygen species (ROS) production, calcium handling, and mitochondrial quality control, enabling localized and time-sensitive regulation of cellular function. In neurons, changes in MMP coordinate synaptic plasticity by linking metabolic state to structural changes at synapses. This review highlights the non-canonical roles of MMP in signal integration, spatial organization, and stress adaptation, providing a broader framework for understanding mitochondrial contributions to health and disease.
    Keywords:  Bioenergetics; Metabolic specialization; Mitochondria; Mitophagy; Neuron plasticity
    DOI:  https://doi.org/10.1016/j.redox.2025.103859
  11. Int J Mol Sci. 2025 Aug 24. pii: 8216. [Epub ahead of print]26(17):
    A Perspective on the Role of Mitochondrial Biomolecular Condensates (mtBCs) in Neurodegenerative Diseases and Evolutionary Links to Bacterial BCs.
    Matteo Calcagnile, Pietro Alifano, Fabrizio Damiano, Paola Pontieri, Luigi Del Giudice.
      Biomolecular condensates (BCs), formed through liquid-liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies.
    Keywords:  bacteria; biomolecular condensates; disordered protein; liquid–liquid phase separation; mitochondria; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms26178216
  12. Cell Rep. 2025 Sep 05. pii: S2211-1247(25)01001-0. [Epub ahead of print]44(9): 116230
    ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
    Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi.
      Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.
    Keywords:  ADSL; CP: Metabolism; ERK; mitochondria; purine metabolism; rare genetic disease
    DOI:  https://doi.org/10.1016/j.celrep.2025.116230
  13. Nat Aging. 2025 Sep 10.
    Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
    Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.
      Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.
    DOI:  https://doi.org/10.1038/s43587-025-00942-x
  14. Nat Aging. 2025 Sep 09.
    Emerging strategies, applications and challenges of targeting NAD+ in the clinic.
    Jianying Zhang, He-Ling Wang, Sofie Lautrup, Hilde Loge Nilsen, Jonas T Treebak, Leiv Otto Watne, Geir Selbæk, Lindsay E Wu, Torbjørn Omland, Eija Pirinen, Tin Cho Cheung, Jun Wang, Mathias Ziegler, Ole-Bjørn Tysnes, Rubén Zapata-Pérez, Santina Bruzzone, Carles Canto, Michela Deleidi, Georges E Janssens, Riekelt H Houtkooper, Morten Scheibye-Knudsen, Masaya Koshizaka, Koutaro Yokote, Eric Verdin, Vilhelm A Bohr, Charalampos Tzoulis, David A Sinclair, Evandro Fei Fang.
      Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.
    DOI:  https://doi.org/10.1038/s43587-025-00947-6
  15. Infect Disord Drug Targets. 2025 Aug 19.
    Bacteria-Mitochondria Cross-talk: How Microbes Regulate Mitochondrial Dynamics and Bioenergetics of Host Cells.
    Tasbir Amin, Md Asaduzzaman Shishir, Mohammad Mamun Alam, Mohammad Badrul Anam, Nayeema Bulbul, Jinath Sultana Jime, Md Fakruddin.
      Mitochondria are the cellular powerhouses and are considered to be central to energy metabolism, dynamics, and homeostasis. There is growing evidence that the gut microbiome regulates mitochondrial biogenesis, dynamics (fission, fusion, mitoph-agy), and bioenergetics, and that it does so by connecting bacterial metabolites and signaling molecules. This review discusses the molecular mechanisms that underlie the interplay between bacteria and mitochondria, with a particular focus on the modulation of mitochondrial activities by microbial products, including bile acids, immunological mediators, and short-chain fatty acids (SCFAs). The evolutionary relationship between bacteria and mitochondria is explored, along with the implications of microbial dysbio-sis on mitochondrial dysfunction, which is linked to a variety of inflammatory, meta-bolic, and neurodegenerative disorders. Additionally, we emphasised the therapeutic potential of focusing on the microbiota to treat illnesses associated with the mitochon-dria and to restore mitochondrial health. A better understanding of the complex rela-tionship between bacteria and mitochondria can open up new avenues for disease man-agement and novel treatment possibilities.
    Keywords:  Mitochondria; bacteria-mitochondria cross-talk; bioenergetics; dysbiosis.; gut microbi-ota; microbial metabolites; microbiome; mitochondrial biogenesis; mitochondrial dynamics; short-chain fatty acids (SCFAs)
    DOI:  https://doi.org/10.2174/0118715265362556250717063603
  16. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Sep 07. pii: S1388-1981(25)00095-2. [Epub ahead of print] 159687
    Age-related changes in cardiolipin profile and functional consequences of altered fatty acid supply.
    Philipp W Weiß, Philip P Kaltenborn, Christiane Frahm, Ulrike Schulze-Späte, Estelle Heyne, Marten Szibor, Sandor Nietzsche, Ralf A Claus, Markus H Gräler.
      Cardiolipins (CLs) are primarily expressed in the inner mitochondrial membrane where they play essential roles in membrane architecture and mitochondrial functions. CLs have a unique structure characterized by four acyl chains with different stoichiometries such as chain length and degree of saturation. CL composition changes with disease and age, but it is largely unknown how dynamic changes affect mitochondrial function. Here, we compared CL profiles in different mouse tissues across different age groups using liquid chromatography and triple quadrupole mass spectrometry. A key finding was that CLs in the brain differ significantly from those in peripheral organs, with a tendency towards longer-chain variants. We hypothesized that these differences may be influenced by the availability of fatty acids (FA), which in the brain could be affected by the blood-brain barrier. In support of this notion, we found that FA concentrations varied in the different compartments. In addition, we found that CL profiles changed during aging. In cultivated macrophages supplemented with different FAs, we tested how altered CL profiles may affect both, mitochondrial morphology and function such as cristae density, and mitochondrial membrane potential and respiration, respectively. Finally, we validated our in vitro results in vivo by altering the CL profile in mice by using palmitic acid and oleic acid enriched diets. Our study highlights a dynamic adaptation of CL profiles in response to FA availability and aging and emphasizes its functional importance for mitochondrial function. Furthermore, FA supplementation may be a promising therapeutic strategy to address disease- and age-related mitochondrial malfunctions.
    Keywords:  Aging; Dietary fat; Lipid saturation; Mass spectrometry; Mitochondria; Phospholipid
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159687
  17. Nat Metab. 2025 Sep 10.
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1038/s42255-025-01363-1
  18. Neurobiol Dis. 2025 Sep 04. pii: S0969-9961(25)00301-8. [Epub ahead of print]215 107084
    The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
    L Daniel Estrella, Xiaoke Xu, Collin White, Jane E Manganaro, Lexi Sheldon, Trey Farmer, Kelly L Stauch.
      Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (ParkinW402A, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while ParkinW402A surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, ParkinW402A did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of ParkinW402A led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing ParkinW402A. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.
    Keywords:  Alzheimer's disease; Mitophagy; Parkin; ParkinW402A; Phosphorylated Tau; Synapse; Synaptic mitochondria; Tauopathy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107084
  19. Autophagy. 2025 Sep 13.
    Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
    Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.
    Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2025.2561073
  20. RSC Med Chem. 2025 Aug 01.
    Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
    Pradeep Kodam, Vaishali Kumar, Paramita Pattanayak, Praharsh Vitta, Tanmay Chatterjee, Shuvadeep Maity.
      Mitochondrial dysfunction is one of the primary cellular conditions involved in developing Huntington's disease (HD) pathophysiology. The accumulation of mutant huntingtin protein with abnormal PolyQ repeats resulted in the death of striatal neurons with enhanced mitochondrial fragmentation. In search of neuroprotective molecules against HD conditions, we synthesized a set of isoxazole-based small molecules to screen their suitability as beneficial chemicals improving mitochondrial health. Systematic characterization of one of these isoxazole derivatives, C-5, demonstrated improved mitochondrial health with reduced apoptosis via rebalancing fission-fusion dynamics in HD condition. Gene and protein expression analysis confirmed that C-5 treatment enhanced the expression of mitochondrial fusion regulators (MFN1/2) via transcriptional upregulation of PGC-1α, a transcriptional co-activator controlling mitochondrial biogenesis. Collectively, this novel fusion agonist can potentially become a new therapeutic alternative for treating PolyQ-mediated mitochondrial dysfunction, a hallmark of HD pathology.
    DOI:  https://doi.org/10.1039/d5md00345h
  21. J Mol Biol. 2025 Sep 06. pii: S0022-2836(25)00499-1. [Epub ahead of print] 169433
    Phosphomimetic experiments do not support a causal role for TFAM phosphorylation in mtDNA elimination in sperm.
    Natalya Kozhukhar, Yidong Bai, Mikhail F Alexeyev.
      In sexually reproducing eukaryotes-particularly mammals-mitochondrial DNA (mtDNA) is typically inherited from a single parent, making uniparental mtDNA inheritance a fundamental feature of eukaryotic biology. Recently, it has been suggested that spermatozoa contain no mtDNA because the matrix targeting sequence (MTS) of the mitochondrial transcription factor A (TFAM) becomes phosphorylated, which prevents the mitochondrial import of this protein essential for mtDNA replication. In this study, we used a combination of the GeneSwap technique and phosphomimetic mutations to investigate the impact of TFAM MTS phosphorylation on mtDNA maintenance in cultured cells. TFAM variants carrying phosphomimetic substitutions-S31D, S34D (TFAM-DD), and the double mutants S31D, P32D/S34D, F35D (TFAM-4D)-supported mtDNA maintenance in 143B cells, with their MTSs at least partially processed. This occurred despite the overall negative charge of the MTS in the TFAM-4D variant. Moreover, blocking the MTS processing by a combination of an overall negative charge and a mutation in the arginine residue critical for MTS cleavage did not prevent mtDNA maintenance. These observations led us to conclude that TFAM MTS phosphorylation alone is unlikely to explain mtDNA loss in human sperm during maturation.
    Keywords:  TFAM; maternal mtDNA inheritance; mitochondrial import; mtDNA loss; mtDNA maintenance; phosphorylation
    DOI:  https://doi.org/10.1016/j.jmb.2025.169433
  22. Int J Mol Sci. 2025 Sep 02. pii: 8537. [Epub ahead of print]26(17):
    Mitochondria-Associated Pathways in Cancer and Precancerous Conditions: Mechanistic Insights.
    Ling Li, Dan Pan, Ruixue Ai, Yu Zhou.
      Mitochondria perform critical roles in cellular functions, particularly in metabolism and cell death regulation. Mutations in nuclear and mitochondrial genes can cause mitochondrial dysfunction, leading to classical mitochondrial diseases. Emerging evidence suggests that mitochondrial adaptations in cancer support the high energy demands of proliferating cells and contribute to tumor progression through anti-apoptotic mechanisms, dysregulated mitochondrial quality control (mtQC), and altered mitochondrial DNA (mtDNA) copy numbers. Interestingly, several mitochondrial pathways involved in cancer progression resemble those implicated in mitochondrial diseases. From this perspective, although cancer is not a classical mitochondrial disease, its progression involves mitochondria-associated pathways similar to those in mitochondrial disorders, suggesting that cancer may be considered a mitochondria-related disease in a broader sense. Understanding these shared mechanisms could provide new insights into precision treatment strategies. Furthermore, mitochondrial dysfunction is increasingly recognized in precancerous conditions, suggesting its potential as a target for early intervention. Oral potentially malignant disorders (OPMDs) serve as a valuable model for studying these mitochondria-associated mechanisms, offering a promising avenue for both therapeutic advancements and preventive approaches.
    Keywords:  cancer; gene mutation; mitochondria disease; mitochondrial dysfunction; precancerous condition
    DOI:  https://doi.org/10.3390/ijms26178537
  23. Mech Ageing Dev. 2025 Sep 08. pii: S0047-6374(25)00088-0. [Epub ahead of print]228 112112
    Defective mitochondrial quality control in the aging of skeletal muscle.
    Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Francesco Landi, Anna Picca.
      Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation-contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.
    Keywords:  Autophagy; Damage associated molecular patterns; Mitochondrial DNA; Mitochondrial dynamics; Mitophagy; Myocyte; Proteasome
    DOI:  https://doi.org/10.1016/j.mad.2025.112112
  24. Int J Mol Sci. 2025 Aug 26. pii: 8266. [Epub ahead of print]26(17):
    Ligand-Enzyme Interaction Modeling of Missense Variants Implicated in Mitochondrial HMG-CoA Synthase Deficiency.
    María Arnedo, David Ros-Pardo, Beatriz Puisac, Cristina Lucia-Campos, Marta Gil-Salvador, Ana Latorre-Pellicer, Íñigo Marcos-Alcalde, Juan Pié, Paulino Gómez-Puertas.
      Human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase, mHS) synthase is a key enzyme in ketogenesis and is located mainly in the liver, but also in the colon, skeletal muscle, heart, pancreas, and testes. It is an inner mitochondrial membrane-associated protein. Mutations in the HMGCS2 gene, which encodes this enzyme, lead to "mHS deficiency," a rare, autosomal recessive, inherited metabolic disorder. To date, about 100 patients with this disorder have been described. The disorder usually appears during the first year of life, often after a period of starvation or an intercurrent illness. A total of 77 different DNA mutations has been described that are considered responsible for mHS deficiency, although the mechanisms leading to loss of function are not fully understood. To study how the different missense variants affect the enzymatic activity of the protein on an atomic scale, we used molecular dynamics computational simulation techniques for variants whose activity could be measured "in vitro." The study included a total of 46 molecular dynamics trajectories of enzyme-substrate/product interaction simulations, each 500 ns long (23 microseconds total). Currently, the atomic and biophysical effects of the mHS variants on their catalyzed reactions have not been studied in detail experimentally. To our knowledge, molecular dynamics simulations are one of the most promising tools for understanding the molecular basis of the phenotypic consequences of these variants. In the present work, molecular dynamics simulations reliably reproduce most experimental enzyme activity measurements, supporting their future application to the study of new mHS mutations.
    Keywords:  HMG-CoA synthase; mHS STAG2; mHS deficiency; molecular modeling; variant rationalization
    DOI:  https://doi.org/10.3390/ijms26178266
  25. Biochim Biophys Acta Bioenerg. 2025 Sep 04. pii: S0005-2728(25)00037-4. [Epub ahead of print] 149571
    Mechanism of Na+ ions contribution to the generation and maintenance of a high inner membrane potential in mitochondria.
    Victor V Lemeshko.
      A recent revision of the chemiosmotic theory was reported by Hernansanz-Agustín and coauthors as a discovery that a Na+ gradient across the mitochondrial inner membrane equates with the H+ gradient and contributes up to half of the inner membrane potential, without an explanation of the possible underlying mechanism. Based on the experimental data of these and other authors, and performed biophysical estimations, I propose a mechanism by which both the reported fast-acting Na+/H+ exchanger, associated with the complex I of the respiratory chain, and Na+ electrodiffusion in the intracristae space and the matrix allow maintenance of a high membrane potential.
    Keywords:  Chemiosmotic theory; Energy coupling; Inner membrane potential; Mitochondria; Na(+)/H(+) antiport
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149571
  26. Parkinsonism Relat Disord. 2025 Sep 03. pii: S1353-8020(25)00766-7. [Epub ahead of print]140 108025
    Acute refractory chorea as a novel phenotype of NARS2 gene mutation-related mitochondrial disorder.
    Nitish Kamble, Gautham Arunachal, Shravan Harish, Vana Bhaskara Rao, Vikram V Holla, Pramod Kumar Pal.
      
    Keywords:  Aminoacyl-tRNA synthetases; COXPD24; Chorea; Mitochondrial disorder; NARS2 gene
    DOI:  https://doi.org/10.1016/j.parkreldis.2025.108025
  27. Asian J Psychiatr. 2025 Sep 05. pii: S1876-2018(25)00337-5. [Epub ahead of print]112 104694
    Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.
    Xue Xia, Kaiqing Li, Baiyi Jiang, Wei Zou, Long Wang.
      Major depressive disorder (MDD) is a severe mental illness with complex pathophysiology. Growing evidence highlights mitochondrial dysfunction as a key player in MDD, influencing neuroinflammation, synaptic plasticity, and energy metabolism. This review summarizes recent advances in understanding how mitochondrial defects-including mtDNA mutations, impaired mitophagy, disrupted dynamics, altered biogenesis, and metabolic dysregulation-contribute to depressive pathogenesis. We also evaluate mitochondria-targeted therapeutic strategies, encompassing both pharmacological agents (e.g., antioxidants, CoQ10, NAD+ precursors, SSRIs, and natural compounds) and non-pharmacological interventions (e.g., exercise, ketogenic diet, photobiomodulation, and electroacupuncture). Importantly, we emphasize the interplay between mitochondrial processes and the need to balance anabolic and catabolic functions. While preclinical results are promising, further clinical translation is essential. This review underscores mitochondrial health as a central theme in MDD research and therapy development.
    Keywords:  Major depressive disorder; Mitochondria-targeted therapy; Mitochondrial DNA; Mitochondrial dysfunction; Neuroplasticity
    DOI:  https://doi.org/10.1016/j.ajp.2025.104694
  28. FEBS J. 2025 Sep 12.
    Activator of apoptosis harakiri (HRK) localisation at mitochondria alters mitochondrial morphology independently of other BCL-2 proteins.
    Louise E King, Lukas Faber, Ana J García-Sáez.
      The activator of apoptosis harakiri (HRK) is a pro-apoptotic BCL-2 homology 3 (BH3)-only protein of the apoptosis regulator Bcl-2 (BCL-2) family that is mainly expressed in neuronal and haematopoietic tissues. How specific HRK protein domains contribute to its pro-apoptotic function, and what other non-apoptotic roles HRK performs within cells, remain poorly understood. Here, we evaluated the apoptosis sensitivity, and mitochondrial shape and function of HCT116 human colorectal cells lacking all BH3-only proteins as well as all relevant BCL-2 proteins. By reconstituting individual BH3-only proteins on this genetic background, we observed that HRK induces apoptosis in a manner dependent on its BH3 domain, and the presence of the apoptosis regulator BAX and BCL-2 homologous antagonist/killer (BAK), but independent of its transmembrane domain. Intriguingly, HRK also causes mitochondrial aggregation without altering cristae structure or respiration. Although the BH3 domain is not required for mitochondrial reorganisation, we found that the transmembrane domain requires additional upstream amino acids for HRK mitochondrial localisation and reorganisation. These observations uncover a previously unknown role of HRK in modulating mitochondrial morphology that is independent of its BH3 domain and pro-death function.
    Keywords:  BH3; Harakiri; apoptosis; mitochondria; transmembrane
    DOI:  https://doi.org/10.1111/febs.70255
  29. Curr Biol. 2025 Sep 08. pii: S0960-9822(25)01029-2. [Epub ahead of print]35(17): 4309
    Mitochondria mechanosensing: The powerhouse fueling cellular force signaling.
    Jorge Oliver-De La Cruz, Pere Roca-Cusachs.
      
    DOI:  https://doi.org/10.1016/j.cub.2025.07.084
  30. Nature. 2025 Sep 10.
    ABCA7 variants impact phosphatidylcholine and mitochondria in neurons.
    Djuna von Maydell, Shannon E Wright, Ping-Chieh Pao, Colin Staab, Oisín King, Andrea Spitaleri, Julia Maeve Bonner, Liwang Liu, Chung Jong Yu, Ching-Chi Chiu, Daniel Leible, Aine Ni Scannail, Mingpei Li, Carles A Boix, Hansruedi Mathys, Guillaume Leclerc, Gloria Suella Menchaca, Gwyneth Welch, Agnese Graziosi, Noelle Leary, George Samaan, Manolis Kellis, Li-Huei Tsai.
      Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer's disease1,2, yet how they impact cellular states to drive disease remains unclear. Here, using single-nucleus RNA-sequencing analysis of human brain samples, we identified widespread gene expression changes across multiple neural cell types associated with rare ABCA7 loss-of-function variants. Excitatory neurons, which expressed the highest levels of ABCA7, showed disrupted lipid metabolism, mitochondrial function, DNA repair and synaptic signalling pathways. Similar transcriptional disruptions occurred in neurons carrying the common Alzheimer's-associated variant ABCA7 p.Ala1527Gly3, predicted by molecular dynamics simulations to alter the ABCA7 structure. Induced pluripotent stem (iPS)-cell-derived neurons with ABCA7 loss-of-function variants recapitulated these transcriptional changes, displaying impaired mitochondrial function, increased oxidative stress and disrupted phosphatidylcholine metabolism. Supplementation with CDP-choline increased phosphatidylcholine synthesis, reversed these abnormalities and normalized amyloid-β secretion and neuronal hyperexcitability-key Alzheimer's features that are exacerbated by ABCA7 dysfunction. Our results implicate disrupted phosphatidylcholine metabolism in ABCA7-related Alzheimer's risk and highlight a possible therapeutic approach.
    DOI:  https://doi.org/10.1038/s41586-025-09520-y
  31. Free Radic Biol Med. 2025 Sep 05. pii: S0891-5849(25)00964-5. [Epub ahead of print]240 663-673
    Protective role of Bre1 in mitochondrial function and energy metabolism in Drosophila models of Parkinson's disease.
    Zaiwa Wei, Liangxian Li, Xueting Fan, Yafang Tang, Chi Wei, Yonglian Zeng.
       BACKGROUND: The second most common cause of autosomal recessive early-onset Parkinson's disease (PD) can be attributed to mutations in the PINK1 gene, malfunction of the mitochondria is the key pathological mechanism. Bre1 encodes an E3 ubiquitin ligase, with the discovery of Bre1's role in repairing mitochondrial damage, further investigation into its implications for PD is warranted.
    METHODS: We used the PINK1B9 drosophila melanogaster as the PD model. The effects of Bre1 on PD phenotypes were evaluated based on the morphology of the wings and dorsal region, as well as flight ability. Immunostaining of dopaminergic neurons was used to examine neurodegeneration. Transcriptomes were used to detect the pathway directly involved. Mitochondrial structure and function were observed using electron microscopy, ATP detection, and an oxygen consumption assay. The detection of SOD activity and ROS were used to explicit the effects of Bre1 on oxidative stress. To identify the effects of Bre1 on glycolysis and tricarboxylic acid (TCA) cycle, we performed Western Blot and RT-PCR.
    RESULTS: We discovered that Bre1 overexpression significantly improved the phenotype of PD flies and protected their dopaminergic neurons from degeneration. More significantly, we observed that the overexpression of Bre1 markedly enhanced the respiratory capacity of mitochondrial Complex I and Complex II, elevated ATP levels, reduced ROS levels, and improved mitochondrial structural integrity. The Western Blot results demonstrate a significant increase in the critical glycolysis enzymes, Pfk and Pyk proteins. Moreover, qRT-PCR results showed a remarkably upregulation in the transcriptional level of OGDH, a critical rate-limiting enzyme in the TCA cycle. Therefore, our study suggests that Bre1 improves the phenotypes of PD model flies by attenuating mitochondrial damage and enhancing energy metabolism, offering a potential drug target for ameliorating the symptoms of PINK1 mutant autosomal recessive PD patients.
    Keywords:  Bre1; Energy metabolism; Mitochondria; PINK1; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.009
  32. Metabolomics. 2025 Sep 09. 21(5): 134
    MetabOCT: a clinical trial looking for a metabolomic signature predicting the onset of Leber's hereditary optic neuropathy in healthy MtDNA mutations carriers.
    Christophe Orssaud, Pascal Reynier.
       INTRODUCTION: The definition of Leber's hereditary optic neuropathy (LHON) does not take into account a preclinical phase during which the thickness of retinal nerve fiber layer (RNFL) is increased, prior to optic nerve atrophy, reducing the chances of visual recovery.
    OBJECTIVES: Search for a metabolomic signature characterizing this preclinical phase and identify biomarkers predicting the risk of LHON onset.
    METHODS AND RESULTS: The blood and tear metabolomic profiles of 90 asymptomatic LHON mutation carriers followed for one year will be explored as a function of RNFL thickness and compared to those of a healthy control.
    CONCLUSION: Identifying pre-clinical biomarkers would open a window for clinical trials.
    Keywords:  Clinical trial; Disease onset and progression; Leber hereditary optic neuropathy (LHON); Metabolomics; Retinal nerve fiber layer (RNFL)
    DOI:  https://doi.org/10.1007/s11306-025-02328-x
  33. Clin Genet. 2025 Sep 10.
    LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
    Undiagnosed Diseases Network
      LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.
    Keywords:  CODAS; LONP1; congenital diaphragmatic hernia; mitochondrial encephalopathy; neurodevelopmental disorder
    DOI:  https://doi.org/10.1111/cge.70057
  34. Exp Clin Transplant. 2025 Aug;23(8): 569-570
    Carriers of m.3243A>G Who Receive Transplant Must be Closely Monitored for Possible Mitochondrial Toxicity of Required Immunosuppressants.
    Josef Finsterer.
      
    DOI:  https://doi.org/10.6002/ect.2025.0099
  35. Mol Biol Rep. 2025 Sep 12. 52(1): 900
    Comprehensive review on alcohol-induced protein modifications in hepatic mitochondrial membranes and their functional implications.
    Kuruvalli Gouthami, P C Nagajyothi, Deepika Shekhawat, Ayantika Santra, Subhasish Maity, Venkata Prasad Surtineni, Selvam Arjunan, Vaddi Damodara Reddy, Jaesool Shim.
      Chronic alcohol consumption induces significant structural and functional impairments in hepatic mitochondria, primarily mediated through increased production of reactive oxygen and nitrogen species (ROS/RNS), leading to oxidative and nitrosative damage. The mitochondrial electron transport chain (ETC), especially complexes I, II, IV, and V, is a major target of such damage, resulting in diminished catalytic activities as demonstrated by decreased NADH dehydrogenase and cytochrome c oxidase activities in ethanol-fed rat models. Notably, succinate dehydrogenase (complex II) remains largely unaffected, consistent with prior studies. Peroxynitrite-mediated nitration of critical subunits further compromises ETC function, impairing oxidative phosphorylation and ATP synthesis. Ethanol-induced mitochondrial dysfunction also involves altered mitochondrial protein synthesis due to inhibited translation of mitochondrial-encoded polypeptides, disruption of nuclear-mitochondrial cross-talk, and increased proteolytic degradation of respiratory chain proteins. Additionally, ethanol exposure reduces cytochrome content, especially cytochrome a a3, exacerbating impaired electron transfer and respiratory capacity. Membrane transport processes are disrupted, as evidenced by altered Na⁺/K⁺-ATPase activity and compromised membrane fluidity, further impacting cellular homeostasis. Oxidative modifications to mitochondrial protein thiols, elevated protein carbonylation, and increased protein acetylation, particularly mediated by Sirt3 dysregulation, contribute to mitochondrial dysfunction. These post-translational modifications (PTMs) alter enzyme activity, protein stability, and mitochondrial signalling pathways. Cumulatively, these biochemical and molecular alterations compromise mitochondrial membrane polarization, β-oxidation, and ATP production, contributing to alcoholic liver disease pathogenesis. Our review elucidates multiple mechanistic facets of alcohol-induced mitochondrial injury, emphasizing the critical role of oxidative/nitrosative stress and PTMs in mitochondrial and hepatic cellular dysfunction.
    Keywords:  ALD; Cytochrome c; Electron transport chain; NADH dehydrogenase; Β-oxidation
    DOI:  https://doi.org/10.1007/s11033-025-10985-3
  36. Front Cell Dev Biol. 2025 ;13 1643141
    The potential of mitochondrial transfer as the modifying therapy for osteoarthritis.
    Yuanpei He, Xinge Wang, Boya Xu, Shichao Chen, Hongcai Li, Bei Chang, Chao Hu, Xiaorong Lan, Shiting Li, Guangwen Li.
      Mitochondrial transfer is defined the process through which specific cell types release their mitochondria and subsequently transfer them to unrelated cell types in response to various physiological or pathological stimuli. This process enhances cellular function and alters disease states. Recent research has begun to explore the potential of intercellular mitochondrial transfer as a therapeutic strategy for human diseases. Mitochondrial dysfunction represents a significant pathological alteration in osteoarthritis, and studies indicate that mitochondrial transfer may serve as an effective modulatory treatment approach for osteoarthritis. Mitochondrial transfer, as an innovative subcellular therapeutic technique, presents the advantages of diverse acquisition methods and multiple transmission pathways. This paper aims to summarize the current understanding of the mechanisms of mitochondrial transfer in relation to osteoarthritis, emphasizing the existing research on mitochondrial transfer in osteoarthritis and its potential as a disease-modifying therapy.
    Keywords:  artificial mitochondrial transfer; disease-modifying; mitochondrial transfer; osteoarthritis; therapymitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fcell.2025.1643141
  37. Nat Genet. 2025 Sep 09.
    The Solve-RD Solvathons as a pan-European interdisciplinary collaboration to diagnose patients with rare disease.
    Solve-RD DITF-EPICARE
      Despite advances in genomic diagnostics, the majority of individuals with rare diseases remain without a confirmed genetic diagnosis. The rapid emergence of advanced omics technologies, such as long-read genome sequencing, optical genome mapping and multiomic profiling, has improved diagnostic yield but also substantially increased analytical and interpretational complexity. Addressing this complexity requires systematic multidisciplinary collaboration, as recently demonstrated by targeted diagnostic workshops. Here, we highlight the experience of the Solve-RD consortium, a pan-European initiative, in implementing four structured workshops, termed 'Solvathons', as a regular and effective component of its operational workflow. We provide actionable insights, best practices and lessons learned for successful data integration, expert training and scalable collaborative diagnostics within large research consortia.
    DOI:  https://doi.org/10.1038/s41588-025-02290-3
  38. Nature. 2025 Sep 10.
    Structure and mechanism of the mitochondrial calcium transporter NCLX.
    Minrui Fan, Chen-Wei Tsai, Jinru Zhang, Jianxiu Zhang, Aswini R Krishnan, Tsung-Yun Liu, Yu-Lun Huang, Deniz Aydin, Siyuan Du, Briana L Sobecks, Madison X Rodriguez, Andrew H Reiter, Carolyn R Bertozzi, Ron O Dror, Ming-Feng Tsai, Liang Feng.
      As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes1-3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction4-9. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H+/Ca2+ exchanger, rather than as a Na+/Ca2+ exchanger as widely believed1. These findings provide critical insights into mitochondrial Ca2+ homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca2+.
    DOI:  https://doi.org/10.1038/s41586-025-09491-0
  39. iScience. 2025 Sep 19. 28(9): 113311
    An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.
    Dimitri Budinger, Sharmin Alhaque, Ramón González-Méndez, Chris Dadswell, Katy Barwick, Arianna Ferrini, Charlotte Roth, Conor J McCann, Karin Tuschl, Fatma Al Jasmi, Maha S Zaki, Julien H Park, Russell C Dale, Shekeeb Mohammad, John Christodoulou, Dale Moulding, Michael R Duchen, Serena Barral, Manju A Kurian.
      Manganese (Mn) is an essential trace metal required for normal biological function, yet it also poses neurotoxic risks when dysregulated. Maintaining proper intracellular and extracellular Mn levels is critical, as Mn imbalance has been implicated in a spectrum of human diseases-including inherited Mn transport disorders, acquired manganism, and more prevalent neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Despite these associations, the cellular mechanisms driving Mn-induced neuropathology remain poorly understood. To investigate this, we developed an induced pluripotent stem cell (iPSC)-derived midbrain neuronal model using patient lines with mutations in SLC39A14, SLC39A8, and SLC30A10. Through integrated transcriptomic and functional analyses, we found that Mn dyshomeostasis disrupts essential neuronal pathways, including mitochondrial bioenergetics, calcium signaling, endocytosis, glycosylation, and stress responses-leading to early neurodegeneration. This humanized model advances our understanding of Mn's impact on neuronal health and disease and highlights potential molecular targets for future therapeutic interventions in Mn-related neurological disorders.
    Keywords:  Cell biology; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.113311
  40. Eur J Clin Invest. 2025 Sep 11. e70114
    OXPHOS complex deficiency in congenital myopathy: A systematic review.
    Megan J du Preez, Maryke Schoonen, Monray E Williams, Michelle Bisschoff, Francois H van der Westhuizen.
       BACKGROUND: Congenital myopathies are inherited neuromuscular disorders characterized by early-onset muscle weakness and distinct histopathological features. Although mitochondrial involvement in congenital myopathy is well recognized in its pathophysiology, oxidative phosphorylation (OXPHOS) complex dysfunction, which is associated with primary mitochondrial diseases (MD), is not. This systematic review aimed to evaluate the prevalence and characteristics of reported OXPHOS complex dysfunction in genetically confirmed congenital myopathy cases.
    METHODS: A systematic literature search was conducted in PubMed, Scopus and Web of Science. The search strategy was developed according to PRISMA guidelines. Two independent reviewers screened the studies for inclusion. Eligible studies reported genetically confirmed congenital myopathy cases or disease models and included diagnostic OXPHOS complex analyses via enzyme kinetic assays and/or protein/RNA expression.
    RESULTS: Of 5841 studies screened, 23 publications (2009-2025) met the inclusion criteria, comprising 45 congenital myopathy cases. OXPHOS complex dysfunction was reported in 78% of these cases, including all human cases where OXPHOS enzymology was performed. Nine congenital myopathy-associated genes were involved in the cases, with RYR1 being the most frequent. No definitive genotype-phenotype relationship was established between specific genes and affected complexes.
    CONCLUSIONS: OXPHOS complex dysfunction in congenital myopathy appears to be more prevalent than previously recognized, challenging the traditional view that associates such dysfunction exclusively with MD. This emerging evidence suggests that mitochondrial involvement in congenital myopathy is not incidental but may represent a meaningful aspect of its pathophysiology. The potential dysregulation of OXPHOS in congenital myopathy has implications for refining diagnostic frameworks for both congenital myopathy and MD.
    Keywords:  congenital myopathy; good health and well‐being; mitochondrial disease; mitochondrial dysfunction; neuromuscular diseases diagnosis; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/eci.70114
  41. Pediatr Ann. 2025 Sep;54(9): e330-e335
    Incorporating Rare Disease Growth Monitoring Into Routine Practice to Improve Early Recognition and Diagnosis of Genetic Conditions.
    Natasha Shur, Seth Berger, Andrew Dauber, Carrie Daymont.
      Routine growth monitoring includes plotting children on World Health Organization or Centers for Disease Control and Prevention charts that have primarily been developed on typical, healthy populations. However, it is advisable to plot children with known genetic conditions on specialized growth curves (SGCs) when they are available. In this review, we highlight the most common genetic conditions for which SGCs are available, clinical reasons to use SGCs based on specific rare diseases, and how these SGCs can be found. In addition, we raise awareness of the limitations of SGCs and future directions to improve rare disease growth curve accessibility and ease of use into general pediatric practice.
    DOI:  https://doi.org/10.3928/19382359-20250707-05
  42. J Int Med Res. 2025 Sep;53(9): 3000605251375537
    Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 deficiency with severe hyperglycemia in a child: A rare case report.
    Chang Dong, Tiantian Lu, Yazhou Jiang, Zihao Yan, Suyue Zhu.
      Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) deficiency is an exceptionally rare autosomal recessive metabolic disorder that impairs ketogenesis. It is typically characterized by hypoketotic hypoglycemia during periods of fasting or metabolic stress. Notably, severe hyperglycemia as an initial presenting symptom has not been previously reported. We report the case of a 6-month-old girl who suddenly developed coma after 1 day of fasting due to repeated vomiting during pneumonia. At presentation, she had hyperglycemia (25.8 mmol/L), ketonuria (1+), glucosuria (3+), metabolic acidosis (pH 6.90), elevated serum alanine transaminase and aspartate aminotransferase levels, increased blood ammonia levels, and liver enlargement on ultrasound. However, fasting insulin, glucagon, and glycated hemoglobin levels were all within the normal range. Whole-exome sequencing identified compound heterozygous mutations in the HMGCS2 gene-c.1175C>T (p.S392L) inherited from the father and c.719A>T (p.A240V) inherited from the mother-thereby confirming the diagnosis of HMGCS2 deficiency. This case highlights severe hyperglycemia as an atypical clinical feature of HMGCS2 deficiency. Increased awareness of such rare manifestations may assist in improving early diagnosis and treatment of this condition.
    Keywords:  Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2; hyperglycemia; ketogenesis; metabolic disorder; mutations
    DOI:  https://doi.org/10.1177/03000605251375537
  43. J Clin Med. 2025 Aug 30. pii: 6145. [Epub ahead of print]14(17):
    Next-Gen Neuroprotection in Glaucoma: Synergistic Molecules for Targeted Therapy.
    Alessio Martucci, Massimo Cesareo, Maria Dolores Pinazo-Durán, Francesco Aiello, Giulio Pocobelli, Raffaele Mancino, Carlo Nucci.
       BACKGROUND: Glaucoma is a progressive optic neuropathy marked by retinal ganglion cells (RGCs), apoptosis, vascular insufficiency, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. While intraocular pressure (IOP) reduction remains the primary intervention, many patients continue to lose vision despite adequate pressure control. Emerging neuroprotective agents-citicoline, coenzyme Q10 (CoQ10), pyruvate, nicotinamide, pyrroloquinoline quinone (PQQ), homotaurine, berberine, and gamma-aminobutyric acid (GABA)-target complementary pathogenic pathways in experimental and clinical settings.
    METHODS: This literature review synthesizes current evidence on glaucoma neuroprotection, specifically drawing on the most relevant and recent studies identified via PubMed.
    RESULTS: Citicoline enhances phospholipid synthesis, stabilizes mitochondrial membranes, modulates neurotransmitters, and improves electrophysiological and visual field outcomes. CoQ10 preserves mitochondrial bioenergetics, scavenges reactive oxygen species, and mitigates glutamate-induced excitotoxicity. Pyruvate supports energy metabolism, scavenges reactive oxygen species, and restores metabolic transporter expression. Nicotinamide and its precursor nicotinamide riboside boost NAD+ levels, protect against early mitochondrial dysfunction, and enhance photopic negative response amplitudes. PQQ reduces systemic inflammation and enhances mitochondrial metabolites, while homotaurine modulates GABAergic signaling and inhibits β-amyloid aggregation. Berberine attenuates excitotoxicity, inflammation, and apoptosis via the P2X7 and GABA-PKC-α pathways. Preclinical models demonstrate synergy when agents are combined to address multiple targets. Clinical trials of fixed-dose combinations-such as citicoline + CoQ10 ± vitamin B3, citicoline + homotaurine ± vitamin E or PQQ, and nicotinamide + pyruvate-show additive improvements in RGCs' electrophysiology, visual function, contrast sensitivity, and quality of life without altering IOP.
    CONCLUSIONS: A multi-targeted approach is suitable for glaucoma's complex neurobiology and may slow progression more effectively than monotherapies. Ongoing randomized controlled trials are essential to establish optimal compound ratios, dosages, long-term safety, and structural outcomes. However, current evidence remains limited by small sample sizes, heterogeneous study designs, and a lack of long-term real-world data. Integrating combination neuroprotection into standard care holds promise for preserving vision and reducing the global burden of irreversible glaucoma-related blindness.
    Keywords:  berberine; citicoline; coenzyme Q10; gamma-aminobutyric acid; glaucoma; homotaurine; neuroprotection; nicotinamide; pyrroloquinoline quinone; pyruvate
    DOI:  https://doi.org/10.3390/jcm14176145
  44. Int J Mol Sci. 2025 Sep 06. pii: 8690. [Epub ahead of print]26(17):
    Mitochondrial Gene Regulation and Pain Susceptibility: A Multi-Omics Causal Inference Study.
    Chien-Cheng Liu.
      The causal contributions of specific mitochondrial genes to common pain phenotypes remain unclear. We employed a multi-omics Mendelian randomization (SMR) approach, integrating QTL data (expression, methylation, protein) for mitochondrial genes with GWAS summary statistics for seven pain phenotypes. We identified 18 candidate genes with robust SMR associations across omics layers. However, strong colocalization evidence (PP.H4 > 0.7) was largely absent, pointing towards complex genetic architectures. A notable exception was a strong signal for a shared causal variant found at the methylation level for the MCL1 gene in hip pain (PP.H4 = 0.962), nominating it as a high-confidence candidate. Additionally, genetically predicted higher protein levels of Glycine amidinotransferase (GATM) showed consistent protective associations with neck or shoulder, back, and knee pain. This study provides novel evidence for mitochondrial gene regulation in pain, highlighting the GATM pathway as protective and identifying MCL1 methylation as a potential causal mechanism in hip pain.
    Keywords:  Mendelian randomization; gene expression; methylation; mitochondria; neuralgia; neuritis; protein
    DOI:  https://doi.org/10.3390/ijms26178690
  45. Cell Signal. 2025 Sep 08. pii: S0898-6568(25)00536-4. [Epub ahead of print]136 112121
    Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
    Chao Hu, Tianhong Su, Ying Zhang, Jing Yang, Xun Su, Zhikang Zhang, Xin Wang, Weiwei Zou, Dan Liang, Yajing Liu, Dongmei Ji, Yunxia Cao.
      Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G > A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing OPA1-mediated fusion and enhancing DRP1-dependent fission, resulting in decreased expression of ND1, ND5, NDUFB8, SDHB and COX2, impaired mitochondrial bioenergetic function, and cell proliferation. Additionally, the m.3635G > A mutation promoted intrinsic apoptosis, altered autophagic flux, evidenced by elevating levels in apoptotic proteins PARP1, caspase-3, and 9, reduced levels of autophagy protein LC3-II, and increased levels of substrate P62. Moreover, the m.3635G > A mutation inhibited PINK1-Parkin-dependent mitophagy. Based on sex-specific differences in hormone metabolism, we proposed that estrogen plays a protective role in women and showed that estrogen receptor α and β were downregulated in LHON. We demonstrated that estradiol improved cell viability by reducing apoptosis, inducing mitochondrial biogenesis through the PGC1α-NRF1/2-TFAM axis, and vigorously promoting PINK1-Parkin-dependent mitophagy in LHON iPSCs and iPSC-derived RPE cells. Our findings have highlighted the critical role of the m.3635G > A mutation in the pathogenetic process of LHON, and our observations support the hypothesis that estrogen is helpful in the preventive treatment of LHON.
    Keywords:  Autophagy; Induced pluripotent stem cell; Leber's hereditary optic neuropathy (LHON); Mitochondrial disease; Mitophagy; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112121
  46. Free Radic Biol Med. 2025 Sep 09. pii: S0891-5849(25)00968-2. [Epub ahead of print]
    CRABS-ROC, A Respirometry Protocol For Overcoming Substrate Limitations, Reveals Excess Brain Mitochondrial Complex I Capacity.
    Naibo Zhang, Brian A Roelofs, Evan A Bordt, Boris Piskoun, Courtney L Robertson, Brian M Polster.
      Mitochondrial bioenergetic competency in cells is frequently assessed by the Mito Stress Test protocol, which includes uncoupler addition for evaluating respiratory capacity. The uncoupled oxygen consumption rate (OCR) is usually defined as maximal respiration, with little consideration of whether the measured rate is restricted by substrate supply. In this study, we show that the uncoupled OCR is substrate-limited in rat primary cortical neurons and isolated mouse forebrain synaptosomes. We use a different respirometry protocol we name CRABS-ROC (Complex Respirometry Assay Bypassing Substrate-Restricted Oxygen Consumption) that enables evaluation of individual electron transport chain (ETC) complex capacities using saturating levels of substrates to bypass this restriction. Optimization of the cytochrome c concentration was critical for ETC complex capacity assessment. Applying CRABS-ROC to primary cortical neurons reveals >2-fold excess Complex I capacity beyond the uncoupled OCR of cells metabolizing glucose and pyruvate. Furthermore, we demonstrate that CRABS-ROC can expose a Complex I deficit in isolated harlequin mutant brain mitochondria that display wild-type levels of Complex I-substrate-linked respiration despite having about half the normal level of Complex I. Thus, CRABS-ROC should be broadly useful for studies on mitochondrial function because it can both reveal excess ETC capacity and unmask ETC alterations that may be missed by the most widely used methods.
    Keywords:  AIF; PDH; Respiration; Seahorse; electron transport chain; harlequin; pyruvate
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.011
  47. Commun Biol. 2025 Sep 09. 8(1): 1341
    Mitochondria delay action potential propagation.
    Ann M Castelfranco, Pepe Alcami.
      The internal resistance of axons to ionic current flow determines action potential conduction velocity. Although mitochondria support axonal function, axons have been modeled as organelle-free cables, and mitochondrial impact on conduction velocity, specifically by increasing internal resistance, remains understudied. We combine computational modeling and electron microscopy of forebrain premotor axons controlling birdsong production. Modeling shows that when the propagating action potential in an unmyelinated axon encounters a mitochondrion, conduction velocity decreases, delaying the action potential by tenths of microseconds to microseconds, an effect that is stronger in small axons. Axonal mitochondria thereby induce conduction inhomogeneities, accumulating total delays of tenths of milliseconds to ~ a millisecond over 3 millimeters-long axons, in the range of the temporal precision of these neurons. Thus, by partially occupying the axoplasm, mitochondria constrain information processing in vertebrate small-diameter axons. Our model should permit future investigations on the impact of mitochondrial axonal plasticity on action potential temporal coding.
    DOI:  https://doi.org/10.1038/s42003-025-08583-x
  48. Int J Mol Sci. 2025 Sep 06. pii: 8693. [Epub ahead of print]26(17):
    Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.
    Agnieszka Dominiak, Elżbieta Gawinek, Agnieszka Anna Banaszek, Anna Wilkaniec.
      Mitochondrial quality control (MQC) mechanisms, including proteostasis, mitophagy, mitochondrial dynamics, and biogenesis, are essential for maintaining mitochondrial function and overall cellular health. Dysregulation of these systems is a common feature of both neurodegenerative diseases and cancer, but the outcomes differ. Neurons depend strongly on healthy mitochondria and are easily damaged when MQC fails, resulting in organellar dysfunction and oxidative stress. By contrast, cancer cells often adapt by using MQC pathways to sustain survival and resist cell death. The mitochondrial unfolded protein response (mtUPR) and mitophagy are central to these processes, yet their roles are context-dependent. In neurodegeneration, activation of these pathways may help neurons survive, yet persistent stimulation can shift towards harmful effects. In cancer, these same pathways enhance metabolic flexibility, promote resistance to treatment, and support tumor progression. Although therapeutic strategies targeting MQC are being explored, their translation to the clinic is difficult, partly due to opposite effects in different diseases. The observed inverse epidemiological link between cancer and neurodegeneration may also reflect the distinct regulation of MQC pathways. A clearer understanding of these mechanisms is needed to identify new treatment strategies for disorders that are clinically distinct but share common mitochondrial defects.
    Keywords:  cancer; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms26178693
  49. Int J Mol Sci. 2025 Aug 31. pii: 8475. [Epub ahead of print]26(17):
    Mitochondrial Transport Proteins in Cardiovascular Diseases: Metabolic Gatekeepers, Pathogenic Mediators and Therapeutic Targets.
    Yue Pei, Sitong Wan, Jingyi Qi, Xueyao Xi, Yinhua Zhu, Peng An, Junjie Luo, Yongting Luo.
      Mitochondria, as the metabolic hubs of cells, play a pivotal role in maintaining cardiovascular homeostasis through dynamic regulation of energy metabolism, redox balance, and calcium signaling. Cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, cardiomyopathies, and myocardial infarction, remain the leading cause of global mortality, with mitochondrial dysfunction emerging as a unifying pathological mechanism across these conditions. Emerging evidence suggests that impaired mitochondrial transport systems-critical gatekeepers of metabolite flux, ion exchange, and organelle communication-drive disease progression by disrupting bioenergetic efficiency and exacerbating oxidative stress. This review synthesizes current knowledge on mitochondrial transport proteins, such as the voltage-dependent anion channels, transient receptor potential channels, mitochondrial calcium uniporter, and adenine nucleotide translocator, focusing on their structural-functional relationships and dysregulation in CVD pathogenesis. We highlight how aberrant activity of these transporters contributes to hallmark features of cardiac pathology, including metabolic inflexibility, mitochondrial permeability transition pore destabilization, and programmed cell death. Furthermore, we critically evaluate preclinical advances in targeting mitochondrial transport systems through pharmacological modulation, gene editing, and nanoparticle-based delivery strategies. By elucidating the mechanistic interplay between transport protein dysfunction and cardiac metabolic reprogramming, we address a critical knowledge gap in cardiovascular biology and provide a roadmap for developing precision therapies. Our insights underscore the translational potential of mitochondrial transport machinery as both diagnostic biomarkers and therapeutic targets, offering new avenues to combat the growing burden of CVDs in aging populations.
    Keywords:  cardiovascular diseases (CVDs); metabolic reprogramming; mitochondrial dysfunction; mitochondrial transport proteins; therapeutic targets
    DOI:  https://doi.org/10.3390/ijms26178475
  50. Am J Physiol Cell Physiol. 2025 Sep 12.
    Muscle Memory of Exercise Optimizes Mitochondrial Metabolism to Support Skeletal Muscle Growth.
    Clay J Weidenhamer, Yi-Heng Huang, Subhashis Natua, Auinash Kalsotra, Diego Hernandez-Saavedra.
      Exercise protects against age-related declines in skeletal muscle mass and function while improving overall health. Exercise can also prime long-term muscle health to enhance adaptations upon exercise retraining, a phenomenon termed muscle memory that remains largely understudied. To assess how prior endurance training elicits a lasting metabolic memory in skeletal muscle, we utilized C57BL/6 mice fed either a control (CD) or obesogenic diet (HFD) that underwent 4-week training, detraining, and retraining periods. Our results show that exercise retraining attenuated weight gain and potentiated muscle growth, even with reduced voluntary running volumes. Training increased fiber size (fCSA), which disappeared with detraining and was recovered with retraining regardless of diet, pointing to a glycolytic-to-oxidative fiber shift. Transcriptomic analysis (bulk RNA-seq) of the retrained muscle revealed a robust enhancement of mitochondrial oxidative phosphorylation (OxPhos) and mitoribosomal genes, paralleled by increases in OxPhos protein complex IV levels, higher long-chain fatty acid oxidative capacity (ACADL), and sustained citrate synthase activity 1 week after retraining, reinforcing the optimization of mitochondrial metabolism. While transcriptomic evidence revealed a major overlap between HFD- and CD-fed mice, discrepancies in protein abundance emerged, which point to an intricate regulation of mitochondrial programming that supports the muscle memory of growth. Our study identifies common and selective mechanisms by which the muscle memory of exercise overrides dietary challenges and promotes fiber hypertrophy, offering insight into potential mechanisms to leverage to promote healthy aging.
    Keywords:  Exercise; Hypertrophy; Mitochondria; Muscle Memory; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpcell.00451.2025
  51. Chem Sci. 2025 Jul 16.
    A mitochondria targeted nitroreductase-sensitive self-immolative spacer as an efficient shuttle for uncharged amine-based molecules.
    Laurane Michel, Vincent Steinmetz, Sophia Godel-Pastre, Philippe Durand, Arnaud Chevalier.
      Mitochondria have emerged as critical therapeutic targets in a wide range of diseases. The detailed examination of this organelle, as well as the search for methods to efficiently address it, therefore, represent significant challenges. In this article, we present a simple and robust method for the functionalization of uncharged amine-based molecules to enable their intracellular transport and selective accumulation in mitochondria. To this end, we have synthesized a self-immolative spacer that is both sensitive to mitochondrial nitroreductase and incorporates a triphenylphosphonium vectorising moiety. To demonstrate the efficacy of this mitochondrial shuttling technology, we have designed, synthesized, and employed a fluorogenic probe that unambiguously validates the concept. An initial extension of this technology for therapeutic purposes is proposed through the intramitochondrial delivery of native doxorubicin, showing promising potential for overcoming drug resistance mechanisms.
    DOI:  https://doi.org/10.1039/d5sc03665h
  52. Eur J Heart Fail. 2025 Sep 08.
    Ferric derisomaltose augments intrinsic skeletal muscle electron transport chain activity in heart failure: A FERRIC-HF II molecular substudy.
    Mohamad F Barakat, Nelson Amaral, Daniel Brayson, George Amin-Youssef, Huda Abu-Own, Salma Ayis, Francesco Papalia, Fadi Jouhra, Adam Nabeebaccus, Mark Monaghan, Gerry Carr-White, Alison Sleigh, Geoffrey Charles-Edwards, Ajay M Shah, Graham J Kemp, Andrew J Murray, Darlington O Okonko.
       AIMS: Skeletal muscle energetic augmentation might be a mechanism via which intravenous iron improves symptoms in heart failure, but no direct measurement of intrinsic mitochondrial function has been performed to support this notion. This molecular substudy of the FERRIC-HF II trial tested the hypothesis that ferric derisomaltose (FDI) would improve electron transport chain activity, given its high dependence on iron-sulfur clusters which facilitate electron transfer during oxidative phosphorylation.
    METHODS AND RESULTS: Vastus lateralis skeletal muscle biopsies were taken before and 2 weeks after randomization. Mitochondrial complex I, II, and I&II respiration were quantified with respirometry of permeabilized fresh skeletal muscle biopsies. Net respiratory capacities, reflecting respiration that is truly available for adenosine triphosphate generation, were calculated by subtracting non-phosphorylating LEAK respiration. Complex I-V and myoglobin protein levels, and skeletal muscle fibre type composition were assayed. Patients randomised to FDI (n = 21) or placebo (n = 19) were similar (age 66 ± 13 years, 73% men, left ventricular ejection fraction 37 ± 8%, 48% New York Heart Association class III, 50% diabetic). After 2 weeks, total complex I-linked respiration (0.33 [interquartile range 0.24-0.37] vs. 0.19 [0.06-0.27] nmol/min/mg, p = 0.03) and net complex I-linked respiration (0.21 [0.16-0.24] vs. 0.11 [0.04-0.16] nmol/min/mg, p = 0.01) were higher in patients allocated to FDI. There was no intergroup difference in other respiratory states, in mitochondrial abundance as reflected by complex I-V protein levels, and in skeletal muscle myoglobin and oxidative fibre type content.
    CONCLUSIONS: Iron repletion induces an early, selective, and potentially direct enhancement of mitochondrial complex I-dependent respiration in the skeletal muscle of heart failure patients. This could be harnessed to optimize repletion protocols to maximize patient benefits.
    Keywords:  Energetics; Heart failure; Iron; Mitochondria; Muscle; Respirometry
    DOI:  https://doi.org/10.1002/ejhf.70028
  53. Redox Biol. 2025 Aug 30. pii: S2213-2317(25)00363-5. [Epub ahead of print]86 103850
    Mitochondrial lipidome's fatty acid profile and peroxidation index are programmed tissue-specific traits.
    Natàlia Mota-Martorell, Anna Fernàndez-Bernal, Joaquim Sol, Marta Santacreu-Vilaseca, Alba Juanes-Casado, Manuel Portero-Otín, Mariona Jové, Reinald Pamplona.
      Mitochondria are dynamic systems adapted to the different cellular demands. In this context, it is hypothesized that lipids, and particularly fatty acids, are also affected by these adaptations and supported at transcriptional level. By analyzing seven mammalian organs from rats, covering the three germ layers and belonging to the four basic types of tissue, we evaluated the differences in the lipidome's fatty acid profiles, calculated fatty acid-derived parameters including susceptibility to lipid peroxidation, and estimated enzymatic activity. Then, we analyzed gene expression datasets of rat tissues to identify specific signatures supporting fatty acid profiles and extended the analysis to human datasets to evaluate shared and differential traits. Our findings demonstrate that a) mitochondrial lipotype is determined by the basic type of tissue instead of the germ layer origin; b) mitochondrial fatty acid profiles define the tissue; c) myristic acid (FA14:0) and docosapentaenoic acid n-6 (22:5n-6) act as biomarkers for global definition of the tissue mitotype; d) brain and adipose tissue mitochondria are especially resistant to lipid peroxidation; e) mitochondrial fatty acid signatures are supported at transcriptional level; and f) tissue-specific transcriptomic patterns of elongase and desaturase expression in rats are largely conserved in humans (e.g., Elovl4, Elovl7, Scd, and Fads6), although species-specific differences are observed for certain transcripts, such as Elovl2, Elovl3, and Elovl5. Our findings suggest that mitochondria share general inter-tissue features but also exhibit tissue-specific specializations in their lipid phenotype. We infer that the mitochondrial fatty acid composition and its derived peroxidation index may be programmed, tissue-specific traits.
    Keywords:  Desaturases; Double bond index; Elongases; Fatty acids; Mitochondria; Peroxidation index
    DOI:  https://doi.org/10.1016/j.redox.2025.103850
  54. Am J Med Genet A. 2025 Sep 13. e64259
    Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review.
    Arzu Selamioglu, Mazlum Akif Altun, Kimberly Bliven, Gökçen Ünverengil, Dilek Güneş, Meryem Karaca, Mehmet Cihan Balcı, Asuman Gedikbaşı, Fatmahan Atalar, Gülden Gökçay.
      Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure. This report presents a case of a 32-year-old female manifesting with HCMP and myopathy beyond the neonatal period. The patient's neuromotor development was initially normal, but from 1.5 years of age, she exhibited fatigue and muscle weakness, particularly after walking. Muscle biopsy revealed normal muscle fiber size with a predominance of type 1 fibers. The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy. The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated. Genetic analysis identified a homozygous splicing variant in the SLC25A3 gene [NM_005888.4:c.158-9A>G (IVS2-9A>G)], consistent with mitochondrial PiC deficiency. At the age of 32 years, the patient remained stable with HCMP and persistently high lactate levels. This case supports the expansion of the clinical spectrum of mitochondrial PiC deficiency by presenting a patient with a later-onset phenotype compared to previously reported cases.
    Keywords:  SLC25A3; hypertrophic cardiomyopathy; mitochondrial phosphate carrier deficiency; muscular hypotonia
    DOI:  https://doi.org/10.1002/ajmg.a.64259
  55. Biosci Biotechnol Biochem. 2025 Sep 09. pii: zbaf119. [Epub ahead of print]
    IL-1β restrains its own apoptosis-promoting activity via NF-κB (RelA) Ser276/p62-mediated elimination of damaged mitochondria in Chondrocytes.
    Junzheng Hu, Weituo Zhang, Zhe Zhao.
      Interleukin-1β (IL-1β) is a central proinflammatory cytokine implicated in osteoarthritis (OA), but its precise role in chondrocyte apoptosis remains to be fully elucidated. In this study, we demonstrate that IL-1β triggers mitophagy in chondrocytes by promoting Parkin translocation and p62 recruitment to damaged mitochondria, thereby reducing mitochondrial dysfunction and apoptosis. Loss of p62 resulted in impaired mitophagy, excessive mitochondrial superoxide accumulation, and increased cell death. Mechanistically, IL-1β enhanced NF-κB (RelA) phosphorylation at Ser276 and Ser536, accompanied by elevated MSK1 expression. Inhibition of MSK1 selectively suppressed Ser276 phosphorylation without affecting Ser536, leading to reduced p62 expression and disrupted mitophagy. These findings reveal a previously unrecognized intrinsic regulatory mechanism by which IL-1β limits its own apoptosis-promoting effect through activation of the NF-κB (RelA) Ser276-p62-mitophagy axis. This pathway facilitates the clearance of damaged mitochondria and preserves chondrocyte viability, offering potential therapeutic insight into inflammation-associated cartilage degeneration in OA.
    Keywords:  Chondrocytes; IL-1β; Mitophagy; NF-κB; p62
    DOI:  https://doi.org/10.1093/bbb/zbaf119
  56. FASEB J. 2025 Sep 15. 39(17): e70986
    Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.
    Miki Shavit, Marie Vancová, Jan Jedlicka, Tomáš Bílý, Mushrek Mahrouk, Jan Cendelin, Kateřina Grygarova, Kristýna Popelková, Zdeněk Tůma, Gabriela Pribanova, Jitka Kuncová, Jan Nevoral.
      Mitochondria in the egg are suggested to be crucial for the onset of new life. However, there is ambiguous knowledge about the necessity for fertilization and early embryonic development. Therefore, we created a conditional Tfam knockout (TfamloxP/loxP; Zp3-Cre) to produce Tfamnull oocytes for investigation of the mitochondrial abundance in oocytes and early embryos. This created mtDNA-depleted eggs, although the abundance of mitochondria did not change. Despite decreased mitochondrial membrane potential, Tfamnull oocytes matured and were fertilized, which led to embryo formation. These Tfamnull eggs were developed into mtDNA-deficient blastocysts. Both TFAM and mtDNA appear to be dispensable for the success of embryo implantation. Tfam expression and mtDNA replication rescue the mtDNA-deficient embryo after implantation, enabling passage through a post-implantation bottleneck, and allowing survivor embryos to develop into healthy individuals. Our findings highlight the uncoupled relationship between mtDNA replication and mitochondrial abundance in the growing oocyte and show the importance of the oocyte bulk mtDNA for successful mitochondrial activation in post-implantation embryos.
    Keywords:  embryo; fertilization; mitochondrial; mitochondrion; oocyte; transcription factor A
    DOI:  https://doi.org/10.1096/fj.202501179R
  57. Neuropsychiatr Dis Treat. 2025 ;21 1945-1953
    Updates on Parkinson's Disease.
    Hong Bai, Wenhui Ma, Lei Zhu, Yaling Lu, Jiaojiao Fan, Mengjia Chen, Cong Huang.
      Parkinson's disease (PD) represents a progressive neurodegenerative disorder with escalating global burden, with mechanistic studies revealing α-synuclein propagation through gut-brain axis, mitochondrial defects, and neuroinflammatory cascades driven by genetic-environmental interplay. Recent advancements in diagnostic paradigms have successfully combined α-synuclein seed amplification assays with multimodal neuroimaging techniques, achieving an impressive diagnostic accuracy of 92% during the prodromal stages of disease. Phase II trials highlight disease-modifying potential of α-synuclein-targeting immunotherapies (40% reduction in motor decline) and LRRK2 kinase inhibitors showing blood-brain barrier penetration. Neuromodulation advances feature closed-loop deep brain stimulation systems with 63% superior symptom control versus conventional approaches. Current challenges center on biomarker validation across ethnic cohorts (30% variability in α-synuclein thresholds) and non-motor symptom management. Emerging solutions leverage single-cell spatial transcriptomics identifying dopaminergic neuron vulnerability signatures, coupled with wearable-enabled digital phenotyping achieving 89% prediction accuracy for motor fluctuations. This synthesis underscores the critical transition from symptomatic care to precision-targeted interventions of PD pathogenesis.
    Keywords:  Parkinson’s disease; biomarkers; deep brain stimulation; disease-modifying therapies; gene-environment interaction; mitochondrial dysfunction; precision medicine; α-synuclein propagation
    DOI:  https://doi.org/10.2147/NDT.S540718
  58. Nature. 2025 Sep;645(8080): 283
    Synthetic data can benefit medical research - but risks must be recognized.
      
    Keywords:  Computer science; Machine learning; Technology
    DOI:  https://doi.org/10.1038/d41586-025-02869-0
  59. JCI Insight. 2025 Sep 09. pii: e187758. [Epub ahead of print]10(17):
    Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.
    Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig.
      Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic disorders. Metabolic flux analyses confirmed robust BCAT inhibition, with reduction of labeling of proximal and distal BCAA-derived metabolites in MMA hepatocytes. In vivo experiments verified the BCAT inhibition, but total levels of distal BCAA catabolite disease markers and clinical symptoms were not normalized, indicating contributions of substrates other than BCAA to these distal metabolite pools. Our study demonstrates the importance of understanding the underlying pathology of metabolic disorders for identification of therapeutic targets and the use of multiple, complementary models to evaluate them.
    Keywords:  Amino acid metabolism; Genetics; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.187758
  60. Mol Cells. 2025 Sep 04. pii: S1016-8478(25)00098-6. [Epub ahead of print] 100274
    Current Therapeutic Strategies in Parkinson's Disease: Future Perspectives.
    Tae Young Kim, Byoung Dae Lee.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of misfolded α-synuclein. Current treatments, including dopaminergic medications and deep brain stimulation (DBS), provide symptomatic relief but do not halt disease progression. Recent advances in molecular research have enabled the development of disease-modifying strategies targeting key pathogenic mechanisms, such as α-synuclein aggregation, mitochondrial dysfunction, and genetic mutations including LRRK2 and GBA1. In parallel, pluripotent stem cell (PSC)-derived dopaminergic neurons have emerged as a scalable and ethically viable source for cell replacement therapy. Early-phase clinical trials have demonstrated the safety and functional integration of these grafts. Ongoing research is now focused on enhancing graft purity, immune compatibility, and anatomical precision, including homotopic transplantation and circuit-level reconstruction. Together, these emerging strategies offer the potential to shift PD treatment paradigms by combining symptomatic control with long-term neural restoration. This review summarizes current therapeutic approaches and highlights recent advances in disease-modifying and regenerative interventions for PD.
    Keywords:  Cell replacement therapy; Dopaminergic neurons; Parkinson's disease; Pluripotent stem cell; neurodegeneration
    DOI:  https://doi.org/10.1016/j.mocell.2025.100274
  61. Mol Genet Metab Rep. 2025 Dec;45 101249
    Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female.
    Stephen G Kaler, William Fyke, Angela Lignelli-Dipple, Valentina Emmanuele, Eun Bi Lee, Hyein Kathy Lee, Adiel Munk, Jose Andres Morales Corado, Alejandro Iglesias, Priyanka Mehrotra.
      NDUFV1 encodes NADH: ubiquinone oxidoreductase core subunit V1, a key component of mitochondrial Complex 1. Biallelic pathogenic variants in this gene produce a broad and variable phenotypic spectrum in affected individuals, including ophthalmoplegia, developmental delays, brain imaging abnormalities, and recurrent episodes of emesis and lactic acidemia. We report female siblings compound heterozygous for two missense variants (Arg40Gln, Val245Met) in NDUFV1 with unusual presentations of this condition. The 6-year-old proband showed normal growth and neurodevelopment until recently when weight loss and recurrent vomiting were noticed and brain imaging abnormalities consistent with Complex 1 deficiency were documented. She developed lactic acidemia without a clear precipitating factor and that, incongruously, was associated with profound alkalosis with blood pH as high as 7.83. We describe management of her acute illness during a hospital admission with aggressive sodium bicarbonate and sodium acetate replacement, and eventual recognition that anxiety-related hyperventilation contributed substantially to her transient profound alkalosis. We review the complex interplay of lactic acidemia due to mitochondrial Complex 1 deficiency, metabolic acidosis from acute loss of bicarbonate, respiratory alkalosis from hyperventilation and hypocapnia, and other concomitant medical issues, as well as her distinctive neuroradiological findings. Her 14-year-old sister was diagnosed retrospectively despite an earlier initial presentation, and manifests greater neurocognitive effects, similar neuroradiological signs, but no history of acute metabolic decompensation. These cases expand the phenotypic spectrum of this rare inherited illness, provide new information about its presentation and intrafamilial variability, and offer insight relevant to management of life-threatening metabolic crises associated with this disorder.
    Keywords:  Alkalosis; Lactic acidosis; Metabolic crisis; Mitochondria
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101249
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