bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–02–09
fifty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
  2. Gene therapy prevents hepatic mitochondrial dysfunction in murine deoxyguanosine kinase deficiency.
  3. Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.
  4. Protocol for assessing the clogging of the mitochondrial translocase of the outer membrane by precursor proteins in human cells.
  5. iPSC models of mitochondrial diseases.
  6. Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
  7. Novel pathogenic mtDNA variants in Chinese children with neurological mitochondrial disorders.
  8. Activating AMPK improves pathological phenotypes due to mtDNA depletion.
  9. An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
  10. Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
  11. Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings.
  12. The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.
  13. Leber Hereditary Optic Neuropathy: Support, Genetic Prediction and Accurate Genetic Counselling Enhance Family Planning Choices.
  14. Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.
  15. Creating Optimal Western Blot Conditions for OPA1 Isoforms in Skeletal Muscle Cells and Tissue.
  16. MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity.
  17. Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.
  18. Imaging and Quantifying Mitochondrial Morphology in C. elegans During Aging.
  19. The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
  20. Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss.
  21. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
  22. The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology.
  23. Prenatal Counseling and Diagnosis of COX20 Gene-Related Mitochondrial Complex IV Deficiency: A Case Report and Literature Review.
  24. The Lily Foundation: supporting patients, raising awareness and funding research into mitochondrial diseases.
  25. DNA repair pathways in the mitochondria.
  26. Endocrine dysfunction in primary mitochondrial diseases.
  27. Development and validation of a sensitive sandwich ELISA against human PINK1.
  28. Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.
  29. Diurnal variation in skeletal muscle mitochondrial function dictates time-of-day-dependent exercise capacity.
  30. Photodistributed pigmentation revealing mitochondrial disease.
  31. Imaging flow cytometry-based cellular screening elucidates pathophysiology in individuals with Variants of Uncertain Significance.
  32. Ensuring patient access to gene therapies for rare diseases: Navigating reimbursement and coverage challenges.
  33. Ontology-based expansion of virtual gene panels to improve diagnostic efficiency for rare genetic diseases.
  34. Harmine promotes axon regeneration through enhancing glucose metabolism.
  35. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  36. Translational activators align mRNAs at the small mitoribosomal subunit for translation initiation.
  37. RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.
  38. The additional diagnostic yield of long-read sequencing in undiagnosed rare diseases.
  39. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  40. Rhodoquinone carries electrons in the mammalian electron transport chain.
  41. MitoEdit: a pipeline for optimizing mtDNA base editing and predicting bystander effects.
  42. Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia.
  43. Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production.
  44. Asymmetric partitioning of persistent paternal mitochondria during cell divisions safeguards embryo development and mitochondrial inheritance.
  45. A new player in the mammalian electron transport chain.
  46. Arginine: at the crossroads of nitrogen metabolism.
  47. Harnessing an MMP-Independent NIR Probe Unveiling the Different Mitochondrial Cristae Changes during Mitophagy and Ferroptosis under STED Microscopy.
  48. A Case of Leber's Hereditary Optic Neuropathy With Reversible Symmetric Lesions in the Substantia Nigra.
  49. Mitochondria as you've never seen them - January's best science images.
  50. Time for lipid cell biology.
  51. Phospho-seq: integrated, multi-modal profiling of intracellular protein dynamics in single cells.
  52. Reaction-free mitochondrial membrane potential independent luminogens with aggregation-induced emission characteristics for live neuron imaging.
  53. A window into intracellular events in myositis through subcellular proteomics.
  54. Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.
  55. Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target.
  1. bioRxiv. 2025 Jan 25. pii: 2025.01.22.634397. [Epub ahead of print]
    VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
    Xiaomeng Yin, Ruoxi Wang, Andrea Thackeray, Eric H Baehrecke, Mark J Alkema.
      Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. VPS13D encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. VPS13D mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create VPS13D related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in VPS13D 's orthologue vps-13D in C. elegans . Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a vps-13D deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPR mt ). The cellular and behavioral changes caused by VPS13D mutations in C. elegans advance the development of animal models that are needed to study SCAR4 pathogenesis.
    DOI:  https://doi.org/10.1101/2025.01.22.634397
  2. Mol Ther Methods Clin Dev. 2025 Mar 13. 33(1): 101397
    Gene therapy prevents hepatic mitochondrial dysfunction in murine deoxyguanosine kinase deficiency.
    Nandaki Keshavan, Miriam Greenwood, Helen Prunty, Juan Antinao Diaz, Riccardo Privolizzi, John Counsell, Anna Karlsson, Neil Sebire, Simon Waddington, Rajvinder Karda, Shamima Rahman.
      Primary mitochondrial disorders are a cause of neonatal liver failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localizing enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome, leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9-hDGUOK intravenously to newborn Dguok knock-out mice and showed that liver dysfunction was prevented in a dose-dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were observed. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III, and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.
    Keywords:  AAV9; DGUOK deficiency; deoxyguanosine kinase deficiency; gene therapy; mitochondrial DNA depletion syndrome; primary mitochondrial disease
    DOI:  https://doi.org/10.1016/j.omtm.2024.101397
  3. J Biol Chem. 2025 Feb 03. pii: S0021-9258(25)00100-0. [Epub ahead of print] 108253
    Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.
    Raelynn Brassard, Elena Arutyunova, Emmanuella Takyi, L Michel Espinoza-Fonseca, Howard Young, Nicolas Touret, M Joanne Lemieux.
      Parkinson's disease (PD) is a devastating neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Familial and sporadic forms of the disease have been linked to mitochondrial dysfunction. Pathology has been identified with mutations in the PARK6 gene encoding PTEN-induced kinase 1 (PINK1), a quality control protein in the mitochondria. Disease-associated mutations at the transmembrane region of PINK1 protein were predicted to disrupt the cleavage of the transmembrane region by the PARL protease at the inner mitochondrial membrane. Here, using microscopy, kinetic analysis and molecular dynamic simulations, we analyzed 3 PD associated TM mutations; PINK1-C92F, PINK1-R98W and PINK1-I111S, and found that mitochondrial localization and cleavage by the PARL protease were not significantly impaired. However, clearance of hydrolyzed PINK1-R98W appears to be compromised due to altered positioning of the protein in the outer mitochondrial membrane, preventing association with TOM complexes and slowing cleavage by PARL. This single amino acid change slows degradation of proteolyzed PINK1, increasing its accumulation at the outer mitochondrial membrane and resulting in increased mitophagy and decreased mitochondrial content among these cells.
    Keywords:  MD Simulation; PARL; Parkinson’s Disease; Proteostasis; Rhomboid Protease
    DOI:  https://doi.org/10.1016/j.jbc.2025.108253
  4. STAR Protoc. 2025 Jan 31. pii: S2666-1667(25)00023-1. [Epub ahead of print]6(1): 103617
    Protocol for assessing the clogging of the mitochondrial translocase of the outer membrane by precursor proteins in human cells.
    John Kim, Hilla Weidberg.
      Protein import into the mitochondria is required for organellar function. Inefficient import can result in the stalling of mitochondrial precursors inside the translocase of the outer membrane (TOM) and blockage of the mitochondrial entry gate. Here, we present a protocol to assess the clogging of TOM by mitochondrial precursors in human cell lines. We describe how the localization of mitochondrial precursors can be determined by cellular fractionation. We then show how co-immunoprecipitation can be used to test the stalling of precursors inside TOM. For complete details on the use and execution of this protocol, please refer to Kim et al.1.
    Keywords:  cell biology; cell culture; cell separation/fractionation; molecular biology; protein biochemistry; protein expression and purification
    DOI:  https://doi.org/10.1016/j.xpro.2025.103617
  5. Neurobiol Dis. 2025 Jan 30. pii: S0969-9961(25)00038-5. [Epub ahead of print] 106822
    iPSC models of mitochondrial diseases.
    Sonja Heiduschka, Alessandro Prigione.
      Mitochondrial diseases are historically difficult to study. They cause multi-systemic defects with prevalent impairment of hard-to-access tissues such as the brain and the heart. Furthermore, they suffer from a paucity of conventional model systems, especially because of the challenges associated with mitochondrial DNA (mtDNA) engineering. Consequently, most mitochondrial diseases are currently untreatable. Human induced pluripotent stem cells (iPSCs) represent a promising approach for developing human model systems and assessing therapeutic avenues in a patient- and tissue-specific context. iPSCs are being increasingly used to investigate mitochondrial diseases, either for dissecting mutation-specific defects within two-dimensional (2D) or three-dimensional (3D) progenies or for unveiling the impact of potential treatment options. Here, we review how iPSC-derived 2D cells and 3D organoid models have been applied to the study of mitochondrial diseases caused by either nuclear or mtDNA defects. We anticipate that the field of iPSC-driven modeling of mitochondrial diseases will continue to grow, likely leading to the development of innovative platforms for treatment discovery and toxicity that could benefit the patient community suffering from these debilitating disorders with highly unmet medical needs.
    Keywords:  Brain organoids; Disease modeling; Drug discovery; Mitochondrial diseases; Pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.nbd.2025.106822
  6. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251316350
    Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
    Noelle Alexa Novales, Hadar Meyer, Yeynit Asraf, Maya Schuldiner, Catherine F Clarke.
      Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.
    Keywords:  ER-mitochondrial encounter structure; artificial tether; coenzyme Q; mitochondria
    DOI:  https://doi.org/10.1177/25152564251316350
  7. Ann Clin Transl Neurol. 2025 Feb 06.
    Novel pathogenic mtDNA variants in Chinese children with neurological mitochondrial disorders.
    Zhimei Liu, Kexin Pan, Mingzhao Wang, Yijun Jin, Wenxin Yang, Keer Chen, Chaolong Xu, Xin Duan, Ying Zou, Changhong Ren, Lifang Dai, Suzhou Zhao, Ya Wang, Lijun Shen, Fang Fang, Hezhi Fang.
       OBJECTIVE: Pathogenic variations in the mitochondrial genome are tightly linked to neurological mitochondrial disorders in children. However, the mutation spectrum of mitochondrial DNA (mtDNA) in the Chinese population remains incomplete. Therefore, the primary objective of our study was to comprehensively characterize pathogenic mtDNA variants in Chinese children with mitochondrial disorders at clinical, molecular, and functional levels.
    METHODS: Between February 2019 and September 2023, we analyzed pathogenic mtDNA variants in a cohort of over 600 Chinese children suspected of having mitochondrial disorders. Whole-exome sequencing (WES) and whole-mtDNA sequencing were performed on the cohort.
    RESULTS: We identified 54 pathogenic or likely pathogenic mtDNA variants in 227 Chinese children with neurological mitochondrial disorders. Among the eight novel heteroplasmic variants detected in seven patients, in silico analyses suggested likely pathogenic features. Functional analyses using either primary fibroblasts or cybrid cells carrying different mutant loads of mtDNA variants showed impaired mitochondrial respiration, ATP generation, and mitochondrial membrane potential in five of the eight novel variants, including m.4275G>A, m.10407G>A, m.5828G>A, m.3457G>A, and m.13112T>C. The m.8427T>C variant was identified as a rare polymorphism because, despite being located at MT-ATP8, it does not affect both the assembly and activity of mitochondrial complex V in cells carrying homoplasmic m.8427T>C variation. Transcriptome profiling further confirmed the pathogenic contributions of these five variants by altering mitochondrial pathways.
    CONCLUSION: In summary, we revisited the mtDNA mutation spectrum in Chinese children with mitochondrial disorders, and identified five novel pathogenic mtDNA variants with functional verification that are related to neurological mitochondrial disorders in children.
    DOI:  https://doi.org/10.1002/acn3.52315
  8. FEBS J. 2025 Feb 07.
    Activating AMPK improves pathological phenotypes due to mtDNA depletion.
    Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij.
      AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.
    Keywords:  AMPK; AMP‐activated protein kinase; mitochondrial DNA depletion; polymerase ɣ
    DOI:  https://doi.org/10.1111/febs.70006
  9. Nat Cell Biol. 2025 Jan 31.
    An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
    Michaela Oborská-Oplová, Alexander Gregor Geiger, Erich Michel, Purnima Klingauf-Nerurkar, Sven Dennerlein, Yury S Bykov, Simona Amodeo, André Schneider, Maya Schuldiner, Peter Rehling, Vikram Govind Panse.
      The correct sorting of nascent ribosomal proteins from the cytoplasm to the nucleus or to mitochondria for ribosome production poses a logistical challenge for cellular targeting pathways. Here we report the discovery of a conserved mitochondrial avoidance segment (MAS) within the cytosolic ribosomal protein uS5 that resolves an evolutionary lethal conflict between the nuclear and mitochondrial targeting machinery. MAS removal mistargets uS5 to the mitochondrial matrix and disrupts the assembly of the cytosolic ribosome. The resulting lethality can be rescued by impairing mitochondrial import. We show that MAS triages nuclear targeting by disabling a cryptic mitochondrial targeting activity within uS5 and thereby prevents fatal capture by mitochondria. Our findings identify MAS as an essential acquisition by the primordial eukaryote that reinforced organelle targeting fidelity while developing an endosymbiotic relationship with its mitochondrial progenitor.
    DOI:  https://doi.org/10.1038/s41556-024-01588-4
  10. Signal Transduct Target Ther. 2025 Feb 07. 10(1): 36
    Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
    Fabian den Brave, Swadha Mishra, Thomas Becker.
      
    DOI:  https://doi.org/10.1038/s41392-025-02130-0
  11. Mitochondrion. 2025 Jan 31. pii: S1567-7249(25)00004-2. [Epub ahead of print] 102007
    Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings.
    Jaakko Oikarainen, Reetta Hinttala, Naemeh Nayebzadeh, Salla M Kangas, Katariina Mankinen, Elisa Rahikkala, Hannaleena Kokkonen, Päivi Vieira, Maria Suo-Palosaari, Johanna Uusimaa.
      Leigh syndrome is the most common phenotype of mitochondrial disorders in children. This study demonstrates clinical, neuroradiological, and molecular genetic findings in siblings with Leigh syndrome and isolated complex I assembly defect associated with intronic c.16 + 5G > A variant in the NDUFS7 gene. Whole exome sequencing was carried out to identify the causative variant. The gene and protein expression of NDUFS7 were studied using patient-derived fibroblasts. Assembly of mitochondrial respiratory chain enzymes was analyzed using Blue Native PAGE. This study shows that the NDUFS7 c.16 + 5G > A variant (rs375282422) has a causative role in Leigh syndrome. Evolution of neuroimaging findings related to this gene variant are demonstrated.
    Keywords:  Intronic variant; Leigh syndrome; Mitochondrial; NDUFS7; Neuroimaging; Rare variant
    DOI:  https://doi.org/10.1016/j.mito.2025.102007
  12. Microbiol Res. 2025 Jan 31. pii: S0944-5013(25)00036-9. [Epub ahead of print]293 128080
    The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.
    Chenhui Zhao, Ke Liu, Yifan Wu, Shuaijie Yan, Jiajia He, Chuanhai Fu.
      Mitochondria are organelles involved in energy metabolism and biosynthesis. As the metabolites released from mitochondria are raw materials used for lipid synthesis, mitochondria also play important roles in lipid metabolism. Here we report that Slc1, a 1-acylglycerol-3-phosphate O-acyltransferase in the fission yeast Schizosaccharomyces pombe, is required to maintain tubular mitochondrial morphology and normal mitochondrial functions. The absence of Slc1 causes mitochondrial fragmentation, increases mitochondrial fission frequency, reduces mitochondrial respiration, and slows down nitrogen starvation-induced mitophagy. In addition, the absence of Slc1 significantly increases the protein level of Ptl2, which is the triacylglycerol lipase localized on lipid droplets. The phenotypes caused by the absence of Slc1 depend on its acyltransferase enzymatic activity. Therefore, our study uncovers new roles of a lipid synthesis enzyme Slc1 in regulating mitochondria and lipid droplets.
    Keywords:  1-acylglycerol-3-phosphate O-acyltransferase; Lipid droplet; Mitochondria; Mitophagy; Schizosaccharomyces pombe
    DOI:  https://doi.org/10.1016/j.micres.2025.128080
  13. Clin Exp Ophthalmol. 2025 Feb 02.
    Leber Hereditary Optic Neuropathy: Support, Genetic Prediction and Accurate Genetic Counselling Enhance Family Planning Choices.
    Lisa S Kearns, Sandra E Staffieri, David A Mackey.
      With the increased availability of genetic testing and the addition of mitochondrial genetic variants on disease panels, accurate genetic counselling for individuals and families affected by, or at risk of, Leber hereditary optic neuropathy (LHON) is becoming increasingly relevant. Challenges in providing genetic counselling for LHON include its mitochondrial inheritance pattern, different haplogroups, incomplete penetrance and that it predominantly affects males. Accurate genetic counselling aims to avoid incorrect disease-risk assessment and delays in either diagnosis or implementation of psychosocial support. Families are also empowered to make autonomous health decisions regarding potential trigger factors for LHON vision loss and informed reproductive choices. Using clinical vignettes, this review demonstrates that an increased awareness of LHON amongst eye care, general and genetic health professionals can address challenges and misconceptions.
    Keywords:  Leber hereditary optic neuropathy; counselling; genetics; mitochondrial disease
    DOI:  https://doi.org/10.1111/ceo.14493
  14. EMBO Rep. 2025 Jan 31.
    Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.
    Akshaya Seshadri, Anjana Badrinarayanan.
      Mitochondrial DNA (mtDNA) replication is essential for mitochondrial function. This is carried out by a dedicated DNA polymerase gamma, with 5'-3' polymerase and 3'-5' proofreading/ exonuclease activity. Perturbations to either property can have pathological consequences. Predominant sources for replication stress are DNA lesions, such as those induced by oxidative damage. How mtDNA lesions affect the polymerase activity and mtDNA stability in vivo is not fully understood. To address this, we induce mtDNA-specific damage in S. cerevisiae. We observe that mtDNA damage results in significant mtDNA loss. This loss occurs independent of cell cycle progression or cell division, suggesting an active mechanism for damaged mtDNA clearance. We implicate the 3'-5' exonuclease activity of the mtDNA polymerase in this clearance, with rates of loss being affected by cellular dNTP levels. Overall, our findings reveal context-dependent, selective regulation of two critical but opposing functions of polymerase gamma to ensure mitochondrial genome integrity.
    Keywords:  DNA Replication; Mip1; PolG; Proofreading; mtDNA Damage
    DOI:  https://doi.org/10.1038/s44319-025-00380-1
  15. Curr Protoc. 2025 Feb;5(2): e70004
    Creating Optimal Western Blot Conditions for OPA1 Isoforms in Skeletal Muscle Cells and Tissue.
    Margaret Mungai, Amber Crabtree, Han Le, Johnathan Moore, Desiree Nguyen, Benjamin Rodriguez, Chanel Harris, Dominique C Stephens, Heather K Beasley, Edgar Garza-Lopez, Kit Neikirk, Bryanna Shao, Ashton Oliver, Genesis Wilson, Serif Bacevac, Larry Vang, Zer Vue, Neng Vue, Andrea G Marshall, Kyrin Turner, Elma Zaganjor, Jianqiang Shao, Sandra Murray, Jennifer A Gaddy, Celestine Wanjalla, Jamaine Davis, Steven M Damo, Lori D Banks, Antentor Hinton.
      OPA1 is a dynamin-related GTPase that modulates mitochondrial dynamics and cristae integrity. Humans carry eight different isoforms of OPA1 and mice carry five, all of which are expressed as short- or long-form isoforms. These isoforms contribute to OPA1's ability to control mitochondrial energetics and DNA maintenance. However, western blot isolation of all long and short isoforms of OPA1 can be difficult. To address this issue, we developed an optimized western blot protocol based on improving running time to isolate five different isoforms of OPA1 in mouse cells and tissues. This protocol can be applied to study changes in mitochondrial structure and function. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Western Blot Protocol for Isolating OPA1 Isoforms in Mouse Primary Skeletal Muscle Cells.
    Keywords:  isoforms; mitochondria; muscle tissue; optic atrophy‐1 (OPA1); western blot
    DOI:  https://doi.org/10.1002/cpz1.70004
  16. Sci Rep. 2025 Feb 06. 15(1): 4540
    MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity.
    Katy E Pannoni, Quentin S Fischer, Renesa Tarannum, Mikel L Cawley, Mayd M Alsalman, Nicole Acosta, Chisom Ezigbo, Daniela V Gil, Logan A Campbell, Shannon Farris.
      Neuronal mitochondria are diverse across cell types and subcellular compartments in order to meet unique energy demands. While mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria to support normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) is proposed to couple neuronal activity to mitochondrial ATP production, which would allow neurons to rapidly adapt to changing energy demands. MCU is uniquely enriched in hippocampal CA2 distal dendrites compared to proximal dendrites, however, the functional significance of this layer-specific enrichment is not clear. Synapses onto CA2 distal dendrites readily express plasticity, unlike the plasticity-resistant synapses onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU deletion impairs plasticity at distal dendrite synapses. However, mitochondria were more fragmented and spine head area was diminished throughout the dendritic layers of MCU cKO mice versus control mice. Fragmented mitochondria might have functional changes, such as altered ATP production, that could explain the structural and functional deficits at cKO synapses. Differences in MCU expression across cell types and circuits might be a general mechanism to tune mitochondrial function to meet distinct synaptic demands.
    Keywords:  Dendrites; Hippocampal CA2; Mitochondria; Mitochondrial calcium uniporter; Spines; Synaptic plasticity
    DOI:  https://doi.org/10.1038/s41598-025-85958-4
  17. bioRxiv. 2025 Jan 23. pii: 2025.01.22.634344. [Epub ahead of print]
    Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.
    Avijit Mallick, Yunguang Du, Theresa Ramalho, Rui Li, Levi Ali, Sookyung Kim, Lihua Julie Zhu, Cole M Haynes.
      The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans . Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1 -deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1 . We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1 . Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1 , in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans , S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5 -knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.
    DOI:  https://doi.org/10.1101/2025.01.22.634344
  18. J Vis Exp. 2025 Jan 17.
    Imaging and Quantifying Mitochondrial Morphology in C. elegans During Aging.
    Juri Kim, Maxim Averbukh, Athena Alcala, Rebecca Aviles Barahona, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Naibedya Dutta.
      Mitochondria, important cellular organelles found in most eukaryotic cells, are major sites of energy production through aerobic respiration. Beyond this well-known role as the 'cellular powerhouse,' mitochondria are also involved in many other essential cellular processes, including the regulation of cellular metabolism, proliferation, immune signaling, and hormonal signaling. Deterioration in mitochondrial function during aging or under mitochondrial stress is often characterized by distinct changes in mitochondrial morphology and volume. The nematode C. elegans is an ideal model for studying these changes due to its transparent body and short lifespan, which facilitate live microscopy throughout its lifetime. However, even within the C. elegans field, numerous transgenic constructs and methods for mitochondrial imaging are available, each with its own limitations. Here, single-copy, matrix-localized GFP constructs are presented as a robust and reliable method for imaging mitochondrial morphology in C. elegans. This study specifically focuses on experimentally controllable factors to minimize errors and reduce variability between replicates and across studies when performing mitochondrial imaging during the aging process. Additionally, mitoMAPR is recommended as a robust method to quantify changes in mitochondrial morphology across tissue types during aging.
    DOI:  https://doi.org/10.3791/67610
  19. Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00036-X. [Epub ahead of print]85(3): 638-651.e9
    The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
    Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen.
      Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.
    Keywords:  DNAJC; OGDH; TCAIM; charperon; metabolism; mitochondria; protein degradation; protein interaction; single-particle cryo-EM; α-ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.006
  20. Brain. 2025 Feb 06. pii: awaf051. [Epub ahead of print]
    Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss.
    Axel Chemla, Giuseppe Arena, Ginevra Sacripanti, Kyriaki Barmpa, Alise Zagare, Pierre Garcia, Vyron Gorgogietas, Paul Antony, Jochen Ohnmacht, Alexandre Baron, Jaqueline Jung, Frida Lind-Holm Mogensen, Alessandro Michelucci, Anne-Marie Marzesco, Manuel Buttini, Thorsten Schmidt, Anne Grünewald, Jens C Schwamborn, Rejko Krüger, Cláudia Saraiva.
      The complex and heterogeneous nature of Parkinson's disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients. Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD. Experimental work performed in induced pluripotent stem cells (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. This was accompanied by increased α-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation - located in the calcium-binding domain of the GTPase - disrupted calcium homeostasis. This resulted in the calcium-dependent activation of calpain proteases and the subsequent cleavage of α-synuclein. Knock-in mice expressing p.R285Q Miro1 (the orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated α-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra, accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.
    Keywords:  calcium homeostasis; knock-in mice; neurodegeneration; p.R272Q Miro1; patient-specific iPSC-derived models; α-synuclein
    DOI:  https://doi.org/10.1093/brain/awaf051
  21. Science. 2025 Feb 06. eadf2034
    Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
    Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.
      Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
    DOI:  https://doi.org/10.1126/science.adf2034
  22. Mitochondrion. 2025 Feb 03. pii: S1567-7249(25)00005-4. [Epub ahead of print] 102008
    The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology.
    Irene M G M Hemel, Carlijn Steen, Simon L I J Denil, Gökhan Ertaylan, Martina Kutmon, Michiel Adriaens, Mike Gerards.
      Mitochondrial dynamics is crucial for cellular homeostasis. However, not all proteins involved are known. Using a protein-protein interaction (PPI) approach, we identified ITPRIPL2 for involvement in mitochondrial dynamics. ITPRIPL2 co-localizes with intermediate filament protein vimentin, supported by protein simulations. ITPRIPL2 knockdown reveals mitochondrial elongation, disrupts vimentin processing, intermediate filament formation, and alters vimentin-related pathways. Interestingly, vimentin knockdown also leads to mitochondrial elongation. These findings highlight ITPRIPL2 as vimentin-associated protein essential for intermediate filament structure and suggest a role for intermediate filaments in mitochondrial morphology. Our study demonstrates that PPI analysis is a powerful approach for identifying novel mitochondrial dynamics proteins.
    Keywords:  Intermediate filaments; Mitochondria; Mitochondrial dynamics; Network analysis; Protein-protein interactions
    DOI:  https://doi.org/10.1016/j.mito.2025.102008
  23. Int J Womens Health. 2025 ;17 179-183
    Prenatal Counseling and Diagnosis of COX20 Gene-Related Mitochondrial Complex IV Deficiency: A Case Report and Literature Review.
    Junyou Su, Lingdong Zeng, Hongfei Chen, Junru Tong, Yan Chen, Lingling Huang, Li Deng, Yan Huang.
       Background: COX20-related mitochondrial complex IV deficiency is a rare autosomal recessive metabolic disorder that arises from biallelic loss-of-function mutations. Given the lack of specific treatments, affected children are at a heightened risk of disability. Consequently, prenatal counseling and prenatal diagnosis should be conducted to reduce the birth rate of children with such mitochondrial diseases. We report a case of COX20 gene associated mitochondrial complex IV deficiency in a child, and describe the prenatal counseling and prenatal diagnosis of the mother in subsequent pregnancies to provide reference for prenatal counseling and prenatal diagnosis of this disease.
    Case Presentation: In this study, we presented a case of a pediatric patient who displayed symptoms such as gait instability, ataxia, cognitive impairment, dysarthria, muscle weakness, and absent reflexes. Through the application of whole-exome sequencing (WES), compound heterozygous COX20 mutations (c.41A>G and c.259C>T) were detected, leading to the confirmation of a diagnosis of mitochondrial complex IV deficiency. A thorough review of the existing literature revealed seven additional cases carrying the same mutations. Moreover, this report delineated the process of prenatal counseling and diagnostic testing that was undertaken for the subsequent pregnancy of the patient's mother.
    Conclusion: The presence of ataxia, cognitive impairment, and peripheral neuropathy in children should prompt consideration of COX20-related mitochondrial disease. Utilizing WES is beneficial for identifying COX20 mutations, and offering prenatal counseling and diagnostic testing to mothers of affected children can reduce the birth rate of children with such mitochondrial diseases.
    Keywords:  COX20; complex IV deficiency; prenatal counseling; prenatal diagnosis
    DOI:  https://doi.org/10.2147/IJWH.S505352
  24. FEBS Lett. 2025 Feb 06.
    The Lily Foundation: supporting patients, raising awareness and funding research into mitochondrial diseases.
    Liz Curtis, Maria E O'Hanlon, Katie Waller, Duncan E Wright.
      Primary mitochondrial diseases ('mito') are a group of genetically and phenotypically diverse disorders caused by defects in mitochondrial structure or function. Although they are individually rare, they collectively have an incidence of around 1 : 4300. Mitochondrial diseases can arise from mutations in either mitochondrial or nuclear genes, complicating genetic diagnosis. The Lily Foundation was founded by Liz Curtis in the UK in 2007 in order to raise awareness of mitochondrial diseases and to fund research into diagnosis and treatment. In this first of a new series on patient advocacy, FEBS Letters interviews Founder and CEO Liz Curtis MBE, Head of Patient Programmes Katie Waller and Research Manager Dr. Maria O'Hanlon on the aims, achievements and activities of the Lily Foundation.
    DOI:  https://doi.org/10.1002/1873-3468.15107
  25. DNA Repair (Amst). 2025 Feb 01. pii: S1568-7864(25)00010-2. [Epub ahead of print]146 103814
    DNA repair pathways in the mitochondria.
    Dillon E King, William C Copeland.
      Mitochondria contain their own small, circular genome that is present in high copy number. The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain. Mutations in the mitochondrial genome are associated with a wide range of mitochondrial diseases and the maintenance and replication of mtDNA is crucial to cellular health. Despite the importance of maintaining mtDNA genomic integrity, fewer DNA repair pathways exist in the mitochondria than in the nucleus. However, mitochondria have numerous pathways that allow for the removal and degradation of DNA damage that may prevent accumulation of mutations. Here, we briefly review the DNA repair pathways present in the mitochondria, sources of mtDNA mutations, and discuss the passive role that mtDNA mutagenesis may play in cancer progression.
    Keywords:  DNA repair; Mitochondria; MtDNA; Mutagenesis
    DOI:  https://doi.org/10.1016/j.dnarep.2025.103814
  26. Endocr Rev. 2025 Feb 01. pii: bnaf002. [Epub ahead of print]
    Endocrine dysfunction in primary mitochondrial diseases.
    Rachel Varughese, Shamima Rahman.
      Primary mitochondrial disorders (PMD) are genetic disorders affecting the structure or function of the mitochondrion. Mitochondrial functions are diverse, including energy production, ion homeostasis, reactive oxygen species regulation, antioxidant defence, and biosynthetic responsibilities, notably including steroidogenesis. Mitochondria provide the energy to drive intracellular production and extracellular secretion of all hormones. The understanding of the endocrine consequences of PMD is key to timely identification of both endocrine complications in PMD patients, and PMD presenting primarily with endocrine disease. This is a narrative review on the endocrine manifestations of PMD, underlying disease mechanisms and current and emerging approaches to diagnosing and treating these complex disorders. Diabetes is the most frequent endocrine manifestation of PMD, but growth hormone deficiency, adrenal insufficiency, hypogonadism and parathyroid dysfunction may occur. Despite the intricate involvement of the thyroid gland in metabolic regulation, there is little evidence for a causal relationship between thyroid dysfunction and PMD. In conclusion, endocrine dysfunction is observed in PMD with varying incidence depending on the specific mitochondrial disorder and the endocrine organ in question. Diagnosis of PMD in a patient with endocrine presenting features requires a high level of clinical suspicion, particularly when apparently unrelated co-morbidities co-exist. Similarly, endocrine pathology may be subtle in patients with known PMD and thorough consideration must be given to ensure timely diagnosis and treatment. The scope for novel therapeutics for this group of devastating conditions is enormous, however, several challenges remain to be overcome before hopes of curative treatments can be brought into clinical practice.
    DOI:  https://doi.org/10.1210/endrev/bnaf002
  27. Autophagy. 2025 Feb 06. 1-16
    Development and validation of a sensitive sandwich ELISA against human PINK1.
    Zahra Baninameh, Jens O Watzlawik, Bernardo A Bustillos, Gabriella Fiorino, Tingxiang Yan, Szymon L Lewicki, Haonan Zhang, Dennis W Dickson, Joanna Siuda, Zbigniew K Wszolek, Wolfdieter Springer, Fabienne C Fiesel.
      The ubiquitin kinase and ligase PINK1 and PRKN together label damaged mitochondria for their elimination in lysosomes by selective autophagy (mitophagy). This cytoprotective quality control pathway is genetically linked to familial Parkinson disease but is also altered during aging and in other neurodegenerative disorders. However, the molecular mechanisms of these mitophagy changes remain uncertain. In healthy mitochondria, PINK1 protein is continuously imported, cleaved, and degraded, but swiftly accumulates on damaged mitochondria, where it triggers the activation of the mitophagy pathway by phosphorylating its substrates ubiquitin and PRKN. Levels of PINK1 protein can therefore be used as a proxy for mitochondrial damage and mitophagy initiation. However, validated methodologies to sensitively detect and quantify PINK1 protein are currently not available. Here, we describe the development and thorough validation of a novel immunoassay to measure human PINK1 on the Meso Scale Discovery platform. The final assay showed excellent linearity, parallelism, and sensitivity. Even in the absence of mitochondrial stress (i.e. at basal conditions), when PINK1 protein is usually not detectable by immunoblotting, significant differences were obtained when comparing samples from patient fibroblasts or differentiated neurons with and without PINK1 expression. Of note, PINK1 protein levels were found increased in human postmortem brain with normal aging, but not in brains with Alzheimer disease, suggesting that indeed different molecular mechanisms are at play. In summary, we have developed a novel sensitive PINK1 immunoassay that will complement other efforts to decipher the roles and biomarker potential of the PINK1-PRKN mitophagy pathway in the physiological and pathological context. Abbreviations: AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; iPSC: induced pluripotent stem cell; KO: knockout; LLOQ: lower limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-Ub: serine-65 phosphorylated ubiquitin; Ub: ubiquitin; ULOQ: upper limit of quantification; WT: wild-type.
    Keywords:  Autophagy; P-S65-Ub; PINK1; Parkin; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2025.2457915
  28. NPJ Metab Health Dis. 2025 ;3(1): 4
    Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.
    Fivos Borbolis, Christina Ploumi, Konstantinos Palikaras.
      Calcium signaling plays a pivotal role in diverse cellular processes through precise spatiotemporal regulation and interaction with effector proteins across distinct subcellular compartments. Mitochondria, in particular, act as central hubs for calcium buffering, orchestrating energy production, redox balance and apoptotic signaling, among others. While controlled mitochondrial calcium uptake supports ATP synthesis and metabolic regulation, excessive accumulation can trigger oxidative stress, mitochondrial membrane permeabilization, and cell death. Emerging findings underscore the intricate interplay between calcium homeostasis and mitophagy, a selective type of autophagy for mitochondria elimination. Although the literature is still emerging, this review delves into the bidirectional relationship between calcium signaling and mitophagy pathways, providing compelling mechanistic insights. Furthermore, we discuss how disruptions in calcium homeostasis impair mitophagy, contributing to mitochondrial dysfunction and the pathogenesis of common neurodegenerative diseases.
    Keywords:  Metabolic disorders; Mitochondria
    DOI:  https://doi.org/10.1038/s44324-025-00049-2
  29. FASEB J. 2025 Feb 15. 39(3): e70365
    Diurnal variation in skeletal muscle mitochondrial function dictates time-of-day-dependent exercise capacity.
    Subhash Khatri, Souparno Das, Anshit Singh, Shabbir Ahmad, Mohit Kashiv, Sunil Laxman, Ullas Kolthur-Seetharam.
      Exercise impinges on almost all physiological processes at an organismal level and is a potent intervention to treat various diseases. Exercise performance is well established to display diurnal rhythm, peaking during the late active phase. However, the underlying molecular/metabolic factors and mitochondrial energetics that possibly dictate time-of-day exercise capacity remain unknown. Here, we have unraveled the importance of diurnal variation in mitochondrial functions as a determinant of skeletal muscle exercise performance. Our results show that exercise-induced muscle metabolome and mitochondrial energetics are distinct at ZT3 and ZT15. Importantly, we have elucidated key diurnal differences in mitochondrial functions that are well correlated with disparate time-of-day-dependent exercise capacity. Providing causal mechanistic evidence, we illustrate that loss of Sirtuin4 (SIRT4), a well-known mitochondrial regulator, abrogates mitochondrial diurnal variation and consequently abolishes time-of-day-dependent muscle output. Therefore, our findings unequivocally demonstrate the pivotal role of baseline skeletal muscle mitochondrial functions in dictating diurnal exercise capacity.
    Keywords:  Sirtuin4 (SIRT4); chronobiology; circadian exercise physiology; exercise metabolism; mitochondrial metabolism; skeletal muscle energetics; time‐of‐day exercise capacity
    DOI:  https://doi.org/10.1096/fj.202402930R
  30. Eur J Dermatol. 2024 Dec 01. 34(6): 672-674
    Photodistributed pigmentation revealing mitochondrial disease.
    Coline Pineau, Henri Adamski, Sylvie Nivot-Adamiak, Valérie Desquiret-Dumas, Patrizia Amati Bonneau, Lise Boussemart, Laurent Pasquier, Catherine Droitcourt.
      
    DOI:  https://doi.org/10.1684/ejd.2024.4803
  31. Genome Med. 2025 Feb 07. 17(1): 12
    Imaging flow cytometry-based cellular screening elucidates pathophysiology in individuals with Variants of Uncertain Significance.
    Irena Josephina Johanna Muffels, Hans R Waterham, Giuseppina D'Alessandro, Guido Zagnoli-Vieira, Michael Sacher, Dirk J Lefeber, Celine Van der Vinne, Chaim M Roifman, Koen L I Gassen, Holger Rehmann, Desiree Y Van Haaften-Visser, Edward S S Nieuwenhuis, Stephen P Jackson, Sabine A Fuchs, Femke Wijk, Peter van Hasselt.
       BACKGROUND: Deciphering variants of uncertain significance (VUS) represents a major diagnostic challenge, partially due to the lack of easy-to-use and versatile cellular readouts that aid the interpretation of pathogenicity and pathophysiology. To address this challenge, we propose a high-throughput screening of cellular functionality through an imaging flow cytometry (IFC)-based platform.
    METHODS: Six assays to evaluate autophagic-, lysosomal-, Golgi- health, mitochondrial function, ER stress, and NF-κβ activity were developed in fibroblasts. Assay sensitivity was verified with compounds (N = 5) and positive control patients (N = 6). Eight healthy controls and 20 individuals with VUS were screened.
    RESULTS: All molecular compounds and positive controls showed significant changes on their cognate assays, confirming assay sensitivity. Simultaneous screening of positive control patients on all six assays revealed distinct phenotypic profiles. In addition, individuals with VUS(es) in well-known disease genes showed distinct - but similar-phenotypic profiles compared to patients with pathogenic variants in the same gene.. For all individuals with VUSes in Genes of Uncertain Significance (GUS), we found one or more of six assays were significantly altered. Broadening the screening to an untargeted approach led to the identification of two clusters that allowed for the recognition of altered cell cycle dynamics and DNA damage repair defects. Experimental follow-up of the 'DNA damage repair defect cluster' led to the discovery of highly specific defects in top2cc release from double-strand DNA breaks in one of these individuals, harboring a VUS in the RAD54L2 gene.
    CONCLUSIONS: Our high-throughput IFC-based platform simplifies the process of identifying VUS pathogenicity through six assays and allows for the recognition of useful pathophysiological markers that structure follow-up experiments, thereby representing a novel valuable tool for precise functional diagnostics in genomics.
    Keywords:  DNA damage repair defect; Functional genomics; Genetic diseases; High-throughput screening; Imaging flow cytometry; Metabolic disorders; Precision genomic diagnostics; Variant of uncertain significance
    DOI:  https://doi.org/10.1186/s13073-025-01433-9
  32. Mol Ther Methods Clin Dev. 2025 Mar 13. 33(1): 101403
    Ensuring patient access to gene therapies for rare diseases: Navigating reimbursement and coverage challenges.
    Diane Berry, Carolyn Hickey, Lisa Kahlman, James Long, Christina Markus, Caitlin K McCombs.
      The rapid transformation in rare disease treatment, driven by advances in genetic medicine and diagnostics, underscores the urgent need for access to these innovative therapies. With over 10,000 identified rare diseases globally, 80% of which are genetic, the current therapeutic landscape indicates that only 5% of these conditions have FDA-approved treatments. This article examines the critical logistical challenges in commercializing and paying for gene therapies for rare diseases. It highlights the importance of considering innovative payment models, addressing patient portability issues, and aligning payer coverage policies with FDA-approved indications. It emphasizes the need to account for the broader value of gene therapies, incorporate input from disease-specific clinical experts in payer coverage decisions, and reduce administrative barriers to coverage. By adopting a multifaceted approach, we can foster a more supportive environment for the sustainable delivery of gene therapies, significantly improving the lives of patients with rare genetic disorders while rewarding and driving continued innovation.
    DOI:  https://doi.org/10.1016/j.omtm.2024.101403
  33. BMC Med Inform Decis Mak. 2025 Feb 05. 25(Suppl 1): 59
    Ontology-based expansion of virtual gene panels to improve diagnostic efficiency for rare genetic diseases.
    Jaemoon Shin, Toyofumi Fujiwara, Hirotomo Saitsu, Atsuko Yamaguchi.
       BACKGROUND: Virtual Gene Panels (VGP) comprising disease-associated causal genes are utilized in the diagnosis of rare genetic diseases to evaluate candidate genes identified by whole-genome and whole-exome sequencing. VGPs generated by the PanelApp software were utilized in a UK 100,000 Genome Project pilot study to filter candidate genes, thus enhancing diagnostic efficiency for rare diseases. However, PanelApp also filtered out disease-causing genes in nearly 50% of the cases.
    METHODS: Here, we propose various methods for optimized approach to design VGPs that significantly improve the diagnostic efficiency by leveraging the hierarchical structure of the Mondo disease ontology, without excluding disease-causing genes. We also performed computational experiments on an evaluation dataset comprising 74 patients to determine the optimal VGP design method.
    RESULTS: Our results demonstrate that the proposed method can significantly enhance rare disease diagnosis efficiency by automatically identifying candidate genes. The proposed method successfully designed VGPs that improve diagnosis efficiency without excluding disease-causing genes.
    CONCLUSION: We have developed novel methods for VGP design that leverage the hierarchical structure of the Mondo disease ontology to improve rare genetic disease diagnosis efficiency. This approach identifies candidate genes without excluding disease-causing genes, and thereby improves diagnostic efficiency.
    Keywords:  Genetic testing; Ontology; Rare disease; Virtual gene panel
    DOI:  https://doi.org/10.1186/s12911-025-02910-2
  34. J Biol Chem. 2025 Feb 02. pii: S0021-9258(25)00101-2. [Epub ahead of print] 108254
    Harmine promotes axon regeneration through enhancing glucose metabolism.
    Ruixuan Liu, Bing Zhou.
      Axon regeneration requires a substantial mitochondrial energy supply. However, injured mature neurons often fail to regenerate due to their inability to meet these elevated energy demands. Our findings indicate that harmine compensates for the energy deficit following axonal injury by enhancing the coupling between glucose metabolism and mitochondrial homeostasis, thereby promoting axon regeneration. Notably, harmine facilitates mitochondrial biogenesis and enhances mitophagy, ensuring efficient mitochondrial turnover and energy supply. Thus, harmine plays a crucial role in enhancing glucose metabolism to maintain mitochondrial function, demonstrating significant potential in treating mature neuronal axon injuries and sciatic nerve injuries.
    Keywords:  axon regeneration; energy supply; glucose metabolism; harmine; metabolic coupling; mitochondrial function; neuron
    DOI:  https://doi.org/10.1016/j.jbc.2025.108254
  35. bioRxiv. 2025 Jan 23. pii: 2025.01.20.633997. [Epub ahead of print]
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Nidhi Raghuram, Thomas Knight, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    Significance Statement: Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.
    DOI:  https://doi.org/10.1101/2025.01.20.633997
  36. bioRxiv. 2025 Jan 26. pii: 2025.01.26.634913. [Epub ahead of print]
    Translational activators align mRNAs at the small mitoribosomal subunit for translation initiation.
    Joseph B Bridgers, Andreas Carlström, Dawafuti Sherpa, Mary T Couvillion, Urška Rovšnik, Jingjing Gao, Bowen Wan, Sichen Shao, Martin Ott, L Stirling Churchman.
      Mitochondrial gene expression is essential for oxidative phosphorylation. Mitochondrial-encoded mRNAs are translated by dedicated mitochondrial ribosomes (mitoribosomes), whose regulation remains elusive. In the baker's yeast Saccharomyces cerevisiae , nuclear-encoded mitochondrial translational activators (TAs) facilitate transcript-specific translation by a yet unknown mechanism. Here, we investigated the function of TAs containing RNA-binding pentatricopeptide repeats (PPRs) using selective mitoribosome profiling and cryo-EM structural analysis. These analyses revealed that TAs exhibit strong selectivity for mitoribosomes initiating on their target transcripts. Moreover, TA-mitoribosome footprints indicated that TAs recruit mitoribosomes proximal to the start codon. Two cryo-EM structures of mRNA-TA complexes bound to post-initiation/pre-elongation-stalled mitoribosomes revealed the general mechanism of TA action. Specifically, the TAs bind to structural elements in the 5' UTR of the client mRNA as well as to the mRNA channel exit to align the mRNA in the small subunit during initiation. Our findings provide a mechanistic basis for understanding how mitochondria achieve transcript-specific translation initiation without relying on general sequence elements to position mitoribosomes at start codons.
    DOI:  https://doi.org/10.1101/2025.01.26.634913
  37. Mol Cell. 2025 Feb 04. pii: S1097-2765(25)00079-6. [Epub ahead of print]
    RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.
    Sujin Kim, Stephanie Tan, Jayoung Ku, Tria Asri Widowati, Doyeong Ku, Keonyong Lee, Kwontae You, Yoosik Kim.
      
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.029
  38. Genome Res. 2025 Feb 03.
    The additional diagnostic yield of long-read sequencing in undiagnosed rare diseases.
    Giulia F Del Gobbo, Kym M Boycott.
      Long-read sequencing (LRS) is a promising technology positioned to study the significant proportion of rare diseases (RDs) that remain undiagnosed as it addresses many of the limitations of short-read sequencing, detecting and clarifying additional disease-associated variants that may be missed by the current standard diagnostic workflow for RDs. Some key areas where additional diagnostic yields may be realized include: (1) detection and resolution of structural variants (SVs); (2) detection and characterization of tandem repeat expansions; (3) coverage of regions of high sequence similarity; (4) variant phasing; (5) the use of de novo genome assemblies for reference-based or graph genome variant detection; and (6) epigenetic and transcriptomic evaluations. Examples from over 50 studies support that the main areas of added diagnostic yield currently lie in SV detection and characterization, repeat expansion assessment, and phasing (with or without DNA methylation information). Several emerging studies applying LRS in cohorts of undiagnosed RDs also demonstrate that LRS can boost diagnostic yields following negative standard-of-care clinical testing and provide an added yield of 7%-17% following negative short-read genome sequencing. With this evidence of improved diagnostic yield, we discuss the incorporation of LRS into the diagnostic care pathway for undiagnosed RDs, including current challenges and considerations, with the ultimate goal of ending the diagnostic odyssey for countless individuals with RDs.
    DOI:  https://doi.org/10.1101/gr.279970.124
  39. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  40. Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]
    Rhodoquinone carries electrons in the mammalian electron transport chain.
    Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.
      Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
    Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone
    DOI:  https://doi.org/10.1016/j.cell.2024.12.007
  41. bioRxiv. 2025 Jan 25. pii: 2025.01.22.634390. [Epub ahead of print]
    MitoEdit: a pipeline for optimizing mtDNA base editing and predicting bystander effects.
    Devansh Shah, Kelly McCastlain, Ti-Cheng Chang, Gang Wu, Mondira Kundu.
       Motivation: Human mitochondrial DNA (mtDNA) mutations are causally implicated in maternally inherited mitochondrial respiratory disorders; however, the role of somatic mtDNA mutations in both late-onset chronic diseases and cancer remains less clear. Although recent advances in mtDNA base editing technology have the potential to model and characterize many of these mutations, current editing approaches are complicated by the potential for multiple unintentional edits (bystanders) that are only identifiable through empirical 'trial and error', thereby sacrificing valuable time and effort towards suboptimal construct development.
    Results: We developed MitoEdit, a novel tool that incorporates empirical base editor patterns to facilitate identification of optimal target windows and potential bystander edits. MitoEdit allows users to input DNA sequences in a text-based format, specifying the target base position and its desired modification. The program generates a list of candidate target windows with a predicted number of bystander edits and their functional impact, along with flanking nucleotide sequences designed to bind TALE (transcription activator-like effectors) array proteins. In silico evaluations indicate that MitoEdit can predict the majority of bystander edits, thereby reducing the number of constructs that need to be tested empirically. To the best of our knowledge, MitoEdit is the first tool to automate prediction of base edits.
    Availability and implementation: MitoEdit is freely available at Kundu Lab GitHub ( https://github.com/Kundu-Lab/mitoedit ).
    Contact: Corresponding email: Gang.Wu@stjude.org ; Mondira.Kundu@stjude.org.
    Supplementary information: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1101/2025.01.22.634390
  42. Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00036-1. [Epub ahead of print]44(2): 115265
    Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia.
    Zeng Zhang, Quan Guo, Zhihan Yang, Yukai Sun, Shuaiming Jiang, Yangli He, Jiahe Li, Jiachao Zhang.
      Sarcopenia significantly diminishes quality of life and increases mortality risk in older adults. While the connection between the gut microbiome and muscle health is recognized, the underlying mechanisms are poorly understood. In this study, shotgun metagenomics revealed that Bifidobacterium adolescentis is notably depleted in individuals with sarcopenia, correlating with reduced muscle mass and function. This finding was validated in aged mice. Metabolomics analysis identified nicotinic acid as a key metabolite produced by B. adolescentis, linked to improvements in muscle mass and functionality in individuals with sarcopenia. Mechanistically, nicotinic acid restores nicotinamide adenine dinucleotide (NAD+) levels in muscle, inhibits the FoxO3/Atrogin-1/Murf-1 axis, and promotes satellite cell proliferation, reducing muscle atrophy. Additionally, NAD+ activation enhances the silent-information-regulator 1 (SIRT1)/peroxisome-proliferator-activated-receptor-γ-coactivator 1-alpha (PGC-1α) axis, stimulating mitochondrial biogenesis and promoting oxidative metabolism in slow-twitch fibers, ultimately improving muscle function. Our findings suggest that B. adolescentis-derived nicotinic acid could be a promising therapeutic strategy for individuals with sarcopenia.
    Keywords:  Bifidobacterium adolescentis; CP: Metabolism; CP: Microbiology; NAD+; gut microbiome; mitochondria biogenesis; multi-omics; nicotinic acid; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.115265
  43. Cell Mol Life Sci. 2025 Feb 07. 82(1): 72
    Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production.
    Nafisa R Komilova, Plamena R Angelova, Elisa Cali, Annarita Scardamaglia, Ulugbek Z Mirkhodjaev, Henry Houlden, Noemi Esteras, Andrey Y Abramov.
      Charcot Marie Tooth (CMT) or hereditary motor and sensory neuropathy is a heterogeneous neurological disorder leading to nerve damage and muscle weakness. Although multiple mutations associated with CMT were identified, the cellular and molecular mechanisms of this pathology are still unclear, although most of the subtype of this disease involve mitochondrial dysfunction and oxidative stress in the mechanism of pathology. Using patients' fibroblasts of autosomal recessive, predominantly demyelinating form of CMT-CMT4B3 subtype, we studied the effect of these mutations on mitochondrial metabolism and redox balance. We have found that CMT4B3-associated mutations decrease mitochondrial membrane potential and mitochondrial NADH redox index suggesting an increase rate of mitochondrial respiration in these cells. However, mitochondrial dysfunction had no profound effect on the overall levels of ATP and on the energy capacity of these cells. Although the rate of reactive oxygen species production in mitochondria and cytosol in fibroblasts with CMT4B3 pathology was not significantly higher than in control, the level of GSH was significantly lower. Lower level of glutathione was most likely induced by the lower level of NADPH production, which was used for a GSH cycling, however, expression levels and activity of the major NADPH producing enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH) was not altered. Low level of GSH renders the fibroblast with CMT4B3 pathology more sensitive to oxidative stress and further treatment of cells with hydroperoxide increases CMT patients' fibroblast death rates compared to control. Thus, CMT4B3 pathology makes cells vulnerable to oxidative stress due to the lack of major endogenous antioxidant GSH.
    Keywords:  ATP; CMT (Charcot Marie Tooth disease); Glutathione; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s00018-025-05612-0
  44. Dev Cell. 2025 Jan 30. pii: S1534-5807(25)00033-4. [Epub ahead of print]
    Asymmetric partitioning of persistent paternal mitochondria during cell divisions safeguards embryo development and mitochondrial inheritance.
    Songyun Wang, Ding Xue.
      Most eukaryotes inherit only maternal mitochondria. The reasons for paternal mitochondrial elimination and the impacts of persistent paternal mitochondria on animals remain elusive. We show that undegraded paternal mitochondria in autophagy-deficient C. elegans embryos are gradually excluded from germ blastomeres through asymmetric partitioning during cell divisions. The embryonic cortical flow drives anterior-directed movements of paternal mitochondria and contributes to their asymmetric apportioning between two daughter blastomeres. By contrast, autophagosome-enclosed paternal mitochondria cluster around and segregate with centrosomes during mitosis and are rapidly degraded through lysosomes concentrated near centrosomes. Failure to exclude persistent paternal mitochondria from the germ blastomere at first cleavage causes their enrichment in the descendant endomesodermal (EMS) blastomere, leading to elevated reactive oxygen species levels, elongated EMS lineage durations, and increased embryonic lethality, which antioxidant treatments can suppress. Thus, regulated paternal mitochondrial distribution away from germ blastomeres is a fail-safe mechanism, protecting embryo development and maternal mitochondrial inheritance.
    Keywords:  C. elegans; PME; ROS; asymmetric partitioning of mitochondria; autophagy; cortical flow; embryo development; germline blastomere; mitochondrial inheritance; paternal mitochondrial elimination; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.devcel.2025.01.013
  45. Cell Metab. 2025 Feb 04. pii: S1550-4131(24)00494-7. [Epub ahead of print]37(2): 310-312
    A new player in the mammalian electron transport chain.
    Judy Hirst.
      In an evolutionary twist to mammalian bioenergetics, Spinelli and coworkers reveal the presence of rhodoquinones in mammalian mitochondria, expanding the established premise that the mammalian respiratory chain relies uniquely on ubiquinones for catalysis.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.012
  46. EMBO J. 2025 Feb 07.
    Arginine: at the crossroads of nitrogen metabolism.
    Tak Shun Fung, Keun Woo Ryu, Craig B Thompson.
      L-arginine is the most nitrogen-rich amino acid, acting as a key precursor for the synthesis of nitrogen-containing metabolites and an essential intermediate in the clearance of excess nitrogen. Arginine's side chain possesses a guanidino group which has unique biochemical properties, and plays a primary role in nitrogen excretion (urea), cellular signaling (nitric oxide) and energy buffering (phosphocreatine). The post-translational modification of protein-incorporated arginine by guanidino-group methylation also contributes to epigenetic gene control. Most human cells do not synthesize sufficient arginine to meet demand and are dependent on exogenous arginine. Thus, dietary arginine plays an important role in maintaining health, particularly upon physiologic stress. How cells adapt to changes in extracellular arginine availability is unclear, mostly because nearly all tissue culture media are supplemented with supraphysiologic levels of arginine. Evidence is emerging that arginine-deficiency can influence disease progression. Here, we review new insights into the importance of arginine as a metabolite, emphasizing the central role of mitochondria in arginine synthesis/catabolism and the recent discovery that arginine can act as a signaling molecule regulating gene expression and organelle dynamics.
    Keywords:  Arginine Deficiency; Arginine Metabolism; Metabolite Signaling; Mitochondria; Protein Synthesis
    DOI:  https://doi.org/10.1038/s44318-025-00379-3
  47. Anal Chem. 2025 Feb 02.
    Harnessing an MMP-Independent NIR Probe Unveiling the Different Mitochondrial Cristae Changes during Mitophagy and Ferroptosis under STED Microscopy.
    Yangang Su, Wendong Jin, Jie Niu, Xingyu Lyu, Qiuhua Hao, Qing Lyu, Nan Sheng, Zhiqiang Liu, Xiaoqiang Yu.
      Mitochondrial cristae remain dynamic structures in order to adapt various physiopathologic processes (e.g., mitophagy and ferroptosis); thus, visualizing and tracking different changes of cristae are crucial for a deeper understanding of these processes. Fluorescent probes that can realize long-term visualization of mitochondrial cristae under stimulated emission depletion (STED) microscopy are powerful tools for their in-depth research. However, there are few reports on such probes, and their constructions remain challenging. Here, we reported a robust squaraine probe (CSN) for visualizing and tracking the changes of mitochondrial cristae in various physiological and pathological processes using STED microscopy. The lipophilic unit of CSN enabled it to firmly immobilize in mitochondria via a hydrophobic interaction, which let the labeling ability of CSN independent of mitochondrial membrane potential (MMP). Using CSN, the mitochondrial cristae were clearly observed at a resolution of 52 nm under STED microscopy. Furthermore, CSN was successfully applied to track the destruction processes of mitochondrial cristae during autophagy and ferroptosis. Interestingly, we found that during mitophagy, mitochondria first underwent swelling and cristae rupture, and then partial vacuolization, and finally complete vacuolization, whereas during ferroptosis, mitochondria first underwent a gradual reduction in the number of cristae, and then partial fracture, and finally vacuolization. This work revealed the difference in mitochondrial cristae changes during mitophagy and ferroptosis, which provided insights into the two physiological and pathological processes. We believed that CSN could serve as a desirable tool to track cristae changes of intracellular activity processes.
    DOI:  https://doi.org/10.1021/acs.analchem.4c05544
  48. Cureus. 2025 Jan;17(1): e76883
    A Case of Leber's Hereditary Optic Neuropathy With Reversible Symmetric Lesions in the Substantia Nigra.
    Yasuyuki Takai, Akiko Yamagami, Mayumi Iwasa, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.
      A 34-year-old man with a history of alcoholism experienced progressive vision loss in both eyes over two months. His best corrected visual acuity was 0.1 OD and 0.2 OS, with visual field tests showing central scotoma bilaterally. Fundus examination revealed reddish optic discs with peripapillary telangiectasia in both eyes. Brain MRI showed bilateral high-intensity lesions in the substantia nigra on T2-weighted/Fluid-Attenuated Inversion Recovery (FLAIR) and diffusion-weighted images. Mitochondrial genetic analysis confirmed the m.11778G>A variant. After the patient stopped consuming alcohol and improved his nutrition, the substantia nigra lesions resolved 18 months after initial symptoms. The improvement of lesions following alcohol abstinence implies a possible link between nutritional status and substantia nigra abnormalities, suggesting concurrent alcohol encephalopathy. While substantia nigra lesions can complicate the diagnosis of Leber's hereditary optic neuropathy (LHON), careful assessment of alcohol consumption history and improvement following abstinence is essential for differential diagnosis.
    Keywords:  leber’s hereditary optic neuropathy; m.11778g>a variant; mitochondrial disease; substantia nigra; wernicke encephalopathy
    DOI:  https://doi.org/10.7759/cureus.76883
  49. Nature. 2025 Jan 31.
    Mitochondria as you've never seen them - January's best science images.
    Emma Stoye.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-025-00269-y
  50. Nat Cell Biol. 2025 Feb 05.
    Time for lipid cell biology.
    Xiao-Wei Chen, Anthony S Don, Maria Fedorova, Takeshi Harayama, Natalie Krahmer, Shigekazu Nagata, Priyanka Narayan, Dequina Nicholas, Sara M Nowinski, Yasunori Saheki, Clay F Semenkovich, Xiaoai Zhao, Yilong Zou.
      
    DOI:  https://doi.org/10.1038/s41556-025-01609-w
  51. Nat Commun. 2025 Feb 04. 16(1): 1346
    Phospho-seq: integrated, multi-modal profiling of intracellular protein dynamics in single cells.
    John D Blair, Austin Hartman, Fides Zenk, Philipp Wahle, Giovanna Brancati, Carol Dalgarno, Barbara Treutlein, Rahul Satija.
      Cell signaling plays a critical role in neurodevelopment, regulating cellular behavior and fate. While multimodal single-cell sequencing technologies are rapidly advancing, scalable and flexible profiling of cell signaling states alongside other molecular modalities remains challenging. Here we present Phospho-seq, an integrated approach that aims to quantify cytoplasmic and nuclear proteins, including those with post-translational modifications, and to connect their activity with cis-regulatory elements and transcriptional targets. We utilize a simplified benchtop antibody conjugation method to create large custom neuro-focused antibody panels for simultaneous protein and scATAC-seq profiling on whole cells, alongside both experimental and computational strategies to incorporate transcriptomic measurements. We apply our workflow to cell lines, induced pluripotent stem cells, and months-old retinal and brain organoids to demonstrate its broad applicability. We show that Phospho-seq can provide insights into cellular states and trajectories, shed light on gene regulatory relationships, and help explore the causes and effects of diverse cell signaling in neurodevelopment.
    DOI:  https://doi.org/10.1038/s41467-025-56590-7
  52. Chem Commun (Camb). 2025 Feb 06.
    Reaction-free mitochondrial membrane potential independent luminogens with aggregation-induced emission characteristics for live neuron imaging.
    Hojeong Park, Guangle Niu, Alex Y H Wong, Eric Y Yu, Ryan T K Kwok, Ben Zhong Tang.
      We developed novel photostable mitochondria targeting probes based on aggregation-induced emission (AIE) luminogens with a cyanostilbene core. The introduction of an alkyl chain onto the pyridinium moiety enhanced their interaction with the mitochondrial membrane. This design effectively prevents probe leakage following mitochondrial membrane depolarization while significantly reducing cytotoxicity.
    DOI:  https://doi.org/10.1039/d4cc06022a
  53. Inflamm Res. 2025 Jan 31. 74(1): 31
    A window into intracellular events in myositis through subcellular proteomics.
    Jennifer M Peterson, Valérie Leclair, Olumide E Oyebode, Dema M Herzallah, Andrea L Nestor-Kalinoski, Jose Morais, René P Zahedi, Mazen Alamr, John A Di Battista, Marie Hudson.
       OBJECTIVE AND DESIGN: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of inflammatory muscle disorders of unknown etiology. It is postulated that mitochondrial dysfunction and protein aggregation in skeletal muscle contribute to myofiber degeneration. However, molecular pathways that lead to protein aggregation in skeletal muscle are not well defined.
    SUBJECTS: Here we have isolated membrane-bound organelles (e.g., nuclei, mitochondria, sarcoplasmic/endoplasmic reticulum, Golgi apparatus, and plasma membrane) from muscle biopsies of normal (n = 3) and muscle disease patients (n = 11). Of the myopathy group, 10 patients displayed mitochondrial abnormalities (IIM (n = 9); mitochondrial myopathy (n = 1)), and one IIM patient did not show mitochondrial abnormalities (polymyositis).
    METHODS: Global proteomic analysis was performed using an Orbitrap Fusion mass spectrometer. Upon unsupervised clustering, normal and mitochondrial myopathy muscle samples clustered separately from IIM samples.
    RESULTS: We have confirmed previously known protein alterations in IIM and identified several new ones. For example, we found differential expression of (i) nuclear proteins that control cell division, transcription, RNA regulation, and stability, (ii) ER and Golgi proteins involved in protein folding, degradation, and protein trafficking in the cytosol, and (iii) mitochondrial proteins involved in energy production/metabolism and alterations in cytoskeletal and contractile machinery of the muscle.
    CONCLUSIONS: Our data demonstrates that molecular alterations are not limited to protein aggregations in the cytosol (inclusions) and occur in nuclear, mitochondrial, and membrane compartments of IIM skeletal muscle.
    Keywords:  Biopsy; Human; Muscle; Myositis; Proteomics
    DOI:  https://doi.org/10.1007/s00011-025-01996-8
  54. Aging Dis. 2025 Feb 01.
    Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.
    Runyu Liang, Qiang Tang, Jia Chen, Yongyin Huang, Luwen Zhu.
      Since the association between mitochondria and aging was first identified, significant efforts have been devoted to elucidating the role of mitochondrial DNA mutations in the aging process. Due to their age-dependent accumulation, intrinsically high mutation rates, and defective replication mechanisms, mtDNA mutations have often been regarded as pivotal drivers of aging. This has led to certain intuitive yet inherently limited conclusions. Aging, however, is a multifactorial process, and the role of mtDNA cannot be simply categorized in binary terms, as its influence emerges as a composite vector of numerous interconnected physiological processes. Adopting alternative perspectives may mitigate the discrepancies between theoretical expectations and empirical findings, offering new directions and insights for future research.
    DOI:  https://doi.org/10.14336/AD.2024.1469
  55. Nat Aging. 2025 Feb 05.
    Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target.
    Xinrong Zuo, Rui Zhao, Minming Wu, Yanyan Wang, Shisheng Wang, Kuo Tang, Yang Wang, Jie Chen, Xiaoxiang Yan, Yang Cao, Tao Li.
      Sarcopenia is a geriatric disorder characterized by a gradual loss of muscle mass and function. Despite its prevalence, the underlying mechanisms remain unclear, and there are currently no approved treatments. In this study, we conducted a comprehensive analysis of the molecular and metabolic signatures of skeletal muscle in patients with impaired muscle strength and sarcopenia using multi-omics approaches. Across discovery and replication cohorts, we found that disrupted branched-chain amino acid (BCAA) catabolism is a prominent pathway in sarcopenia, which leads to BCAA accumulation and decreased muscle health. Machine learning analysis further supported the causal role of BCAA catabolic dysfunction in sarcopenia. Using mouse models, we validated that defective BCAA catabolism impairs muscle mass and strength through dysregulated mTOR signaling, and enhancing BCAA catabolism by BT2 protects against sarcopenia in aged mice and in mice lacking Ppm1k, a positive regulator of BCAA catabolism in skeletal muscle. This study highlights improving BCAA catabolism as a potential treatment of sarcopenia.
    DOI:  https://doi.org/10.1038/s43587-024-00797-8
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