bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–02–23
72 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
  2. Endurance swimming exacerbates mitochondrial myopathy in mice with high mtDNA deletions.
  3. Bioinformatics Tools for NGS-Based Identification of Single Nucleotide Variants and Large-Scale Rearrangements in Mitochondrial DNA.
  4. Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans.
  5. Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA-cycling hypothesis and beyond.
  6. Compositionally unique mitochondria in filopodia support cellular migration.
  7. Leber's hereditary optic neuropathy - current status of idebenone and gene replacement therapies.
  8. VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
  9. Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
  10. Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment.
  11. Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
  12. A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
  13. Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.
  14. A molecular switch at the yeast mitoribosomal tunnel exit controls cytochrome b synthesis.
  15. Mitophagy at the oocyte-to-zygote transition promotes species immortality.
  16. Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.
  17. How are mitochondrial nucleoids trafficked?
  18. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) Phenotype Associated With Unique Compound Heterozygous POLG Variants: Case Presentation and Review of the Literature.
  19. AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
  20. Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
  21. Overfeeding induces adipose tissue release of distinct mitochondria.
  22. Bayesian classification of OXPHOS deficient skeletal myofibres.
  23. Polyamine Metabolism is Dysregulated in COXFA4 Related Mitochondrial Disease.
  24. RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
  25. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
  26. Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
  27. HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.
  28. Isolation of Intact Mitochondria From Drosophila melanogaster and Assessment of Mitochondrial Respiratory Capacity Using Seahorse Analyzer.
  29. Non-canonical ORFs-derived protein products in mitochondria: A multifaceted exploration of their functions in health and disease.
  30. Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
  31. Functional compartmentalization of hepatic mitochondrial subpopulations during MASH progression.
  32. SIRT3-Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease.
  33. Mitochondrial control of ciliary gene expression and structure in striatal neurons.
  34. MAJIQ-CLIN: A novel tool for the identification of Mendelian disease-causing variants from RNA-Seq data.
  35. Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.
  36. Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
  37. Identification of a novel truncated pathogenic variant in PUS1 gene in two siblings of consanguineous Tunisian family: intrafamilial phenotypic variability related to mtDNA copy number.
  38. GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
  39. Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells.
  40. CRISPuRe-seq: pooled screening of barcoded ribonucleoprotein reporters reveals regulation of RNA polymerase III transcription by the integrated stress response via mTOR.
  41. Imbalanced mitochondrial dynamics in human and mouse PD brains.
  42. Outlook of SNCA (α-synuclein) transgenic fly models in delineating the sequel of mitochondrial dysfunction in Parkinson's disease.
  43. Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
  44. An organism-level quantitative flux model of energy metabolism in mice.
  45. Rare genetic disorder treated in womb for the first time.
  46. Complex I superoxide anion production is necessary and sufficient for complex I inhibitor-induced dopaminergic neurodegeneration in Caenorhabditis elegans.
  47. Low-Magnitude High-Frequency Vibration Attenuates Sarcopenia by Modulating Mitochondrial Quality Control via Inhibiting miR-378.
  48. Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport.
  49. Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight.
  50. Expanding the Phenotypic Spectrum of SPG7 Rare Damaging Variants: Insights From a Hungarian Cohort.
  51. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy.
  52. Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database (P3-11.017).
  53. Developing splice-switching oligonucleotides for urea cycle disorder using an integrated diagnostic and therapeutic platform.
  54. Leber Hereditary Optic Neuropathy "Plus" with the m.14487 T>C Mutation as the Causality of Hemidystonia: A Case Report.
  55. TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
  56. Biggest-ever AI biology model writes DNA on demand.
  57. Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans.
  58. FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice.
  59. DHFR2 RNA directly regulates dihydrofolate reductase and its expression level impacts folate one carbon metabolism.
  60. Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria-Associated ER Membrane.
  61. MICU1 related myopathy - a rare report from India.
  62. Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.
  63. Structural dynamics of human fatty acid synthase in the condensing cycle.
  64. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
  65. The link between Mitochondria and Sarcopenia.
  66. What are the best AI tools for research? Nature's guide.
  67. Genetics and diagnostics of inherited retinal diseases in the era of whole genome sequencing.
  68. The integrated stress response in neurodegenerative diseases.
  69. Unveiling BCO2 function in macular pigment metabolism: Mitochondrial processing and expression in the primate retina.
  70. Omics and rare diseases: challenges, applications, and future perspectives.
  71. Gene therapies for neurogenetic disorders.
  72. Quantifying hope: an EU perspective of rare disease therapeutic space and market dynamics.
  1. Nature. 2025 Feb 19.
    Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
    Kate McArthur, Michael T Ryan.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00303-z
  2. Mitochondrion. 2025 Feb 14. pii: S1567-7249(25)00007-8. [Epub ahead of print]81 102010
    Endurance swimming exacerbates mitochondrial myopathy in mice with high mtDNA deletions.
    Sho Hanada, Kaori Ishikawa, Takanaga Shirai, Tohru Takemasa, Kazuto Nakada.
      Recent studies have reported that endurance exercise enhances mitochondrial function, facilitating discussions of its potential as a therapeutic strategy for mitochondrial diseases caused by the accumulation of mutant mitochondrial DNA (mtDNA). In this study, we assessed the effects of endurance exercise on muscle pathology in a mitochondrial disease mouse model (mito-miceΔ) that is characterized by severe clinical phenotypes owing to the predominant accumulation of mtDNA with a large-scale deletion (ΔmtDNA). Contrary to expectations that endurance exercise may enhance mitochondrial function, endurance exercise exacerbated muscle pathology in mito-miceΔ. Therefore, exercise interventions should be potentially avoided in patients with severe mitochondrial diseases.
    Keywords:  Endurance exercise; Mitochondrial diseases; Mitochondrial respiratory function; Mouse model; Muscle atrophy
    DOI:  https://doi.org/10.1016/j.mito.2025.102010
  3. BioTech (Basel). 2025 Feb 12. pii: 9. [Epub ahead of print]14(1):
    Bioinformatics Tools for NGS-Based Identification of Single Nucleotide Variants and Large-Scale Rearrangements in Mitochondrial DNA.
    Marco Barresi, Giulia Dal Santo, Rossella Izzo, Andrea Zauli, Eleonora Lamantea, Leonardo Caporali, Daniele Ghezzi, Andrea Legati.
      The unique features of mitochondrial DNA (mtDNA), including its circular and multicopy nature, the possible coexistence of wild-type and mutant molecules (i.e., heteroplasmy) and the presence of nuclear mitochondrial DNA segments (NUMTs), make the diagnosis of mtDNA diseases particularly challenging. The extensive deployment of next-generation sequencing (NGS) technologies has significantly advanced the diagnosis of mtDNA-related diseases. However, the vast amounts and diverse types of sequencing data complicate the interpretation of these variants. From sequence alignment to variant calling, NGS-based mtDNA sequencing requires specialized bioinformatics tools, adapted for the mitochondrial genome. This study presents the use of new bioinformatics approaches, optimized for short- and long-read sequencing data, to enhance the accuracy of mtDNA analysis in diagnostics. Two recent and emerging free bioinformatics tools, Mitopore and MitoSAlt, were evaluated on patients previously diagnosed with single nucleotide variants or large-scale deletions. Analyses were performed in Linux-based environments and web servers implemented in Python, Perl, Java, and R. The results indicated that each tool demonstrated high sensitivity and specific accuracy in identifying and quantifying various types of pathogenic variants. The study suggests that the integrated and parallel use of these tools offers a significant advantage over traditional methods in interpreting mtDNA genetic variants, reducing the computational demands, and provides an accurate diagnostic solution.
    Keywords:  NGS; bioinformatics; mitochondrial DNA; mtDNA
    DOI:  https://doi.org/10.3390/biotech14010009
  4. bioRxiv. 2025 Feb 05. pii: 2025.02.03.636310. [Epub ahead of print]
    Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans.
    Bharat Vivan Thapa, Mohit Das, James P Held, Maulik R Patel.
      Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPR mt ) activators in C. elegans , we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes a dually localized methionine tRNA synthetase (MetRS). Here, we characterize the UPR mt induction by Y105E8A.20, which we call mars-2 , and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show impaired mars-2 activity in the mitochondria triggers UPR mt . This strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.
    DOI:  https://doi.org/10.1101/2025.02.03.636310
  5. Protein Sci. 2025 Mar;34(3): e70047
    Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA-cycling hypothesis and beyond.
    Elena E Pohl, Mario Vazdar, Jürgen Kreiter.
      The mitochondrial ADP/ATP carrier (AAC, ANT), a member of the SLC25 family of solute carriers, plays a critical role in transporting purine nucleotides (ATP and ADP) as well as protons across the inner mitochondrial membrane. However, the precise mechanism and physiological significance of proton transport by ADP/ATP carrier remain unclear. Notably, the presence of uncouplers-such as long-chain fatty acids (FA) or artificial compounds like dinitrophenol (DNP)-is essential for this process. We explore two potential mechanisms that describe ADP/ATP carrier as either (i) a proton carrier that functions in the presence of FA or DNP, or (ii) an anion transporter (FA- or DNP). In the latter case, the proton is translocated by the neutral form of FA, which carries it from the matrix to the intermembrane space (FA-cycling hypothesis). Our recent results support this hypothesis. We describe a four-step mechanism for the "sliding" of the FA anion from the matrix to the mitochondrial intermembrane space and discuss a possible generalization of this mechanism to other SLC25 carriers.
    Keywords:  MD simulations; bilayer lipid membranes; membrane proteins; mitochondrial transporter; reconstituted protein; uncoupling protein
    DOI:  https://doi.org/10.1002/pro.70047
  6. Curr Biol. 2025 Feb 14. pii: S0960-9822(25)00125-3. [Epub ahead of print]
    Compositionally unique mitochondria in filopodia support cellular migration.
    Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen, Jonathan R Friedman.
      Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.
    Keywords:  MCU; MICOS; MYO19; calcium; cristae; filopodia; migration; mitochondria; organelle
    DOI:  https://doi.org/10.1016/j.cub.2025.01.062
  7. Med Genet. 2025 Apr;37(1): 57-63
    Leber's hereditary optic neuropathy - current status of idebenone and gene replacement therapies.
    Thomas Klopstock, Leopold H Zeng, Claudia Priglinger.
      Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease, and was the first to be linked to mitochondrial DNA (mtDNA) variations. Recently, autosomal recessive forms of LHON were described in addition to the classical mtDNA-associated forms. Clinically, LHON manifests with subacute and painless loss of central visual acuity, in most cases starting unilaterally, and involving the second eye a few weeks later. Almost all LHON cases are caused by pathogenic variants in genes that code for proteins relevant for function of Complex I of the respiratory chain. The Complex I dysfunction in LHON leads to decreased ATP synthesis and to increased production of reactive oxygen species which ultimately initiates dysfunction and apoptosis of retinal ganglion cells and their axons, the optic nerve. Idebenone, a synthetic CoQ derivative, is a potent intramitochondrial antioxidant and can shuttle electrons directly to complex III of the respiratory chain, thereby bypassing complex I deficiency. On the basis of several clinical trials, it has been approved as a treatment for LHON in 2015 (in the EU). In addition, direct intravitreal gene replacement therapy is being investigated, with several late-stage clinical trials already completed. In the future, gene editing of mtDNA variants may also become a therapeutic option.
    Keywords:  Complex I; LHON; gene therapy; idebenone; mtDNA
    DOI:  https://doi.org/10.1515/medgen-2024-2066
  8. G3 (Bethesda). 2025 Feb 17. pii: jkaf023. [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 (UPRmt). 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.
    Keywords:   Caenorhabditis elegans ; VPS13D ; vps-13D ; WormBase; mitochondrial homeostasis
    DOI:  https://doi.org/10.1093/g3journal/jkaf023
  9. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]
    Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
    Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.
      Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
    Keywords:  MPST; ergothioneine; exercise; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
  10. Brain Commun. 2025 ;7(1): fcae453
    Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment.
    Rauan Kaiyrzhanov, Kyle Thompson, Stephanie Efthymiou, Askhat Mukushev, Akbota Zharylkassyn, Chitra Prasad, Ehsan Ghayoor Karimiani, Javeria Raza Alvi, Dmitriy Niyazov, Ahmad Alahmad, Meisam Babaei, Homa Tajsharghi, Buthaina Albash, Ahmad Alaqeel, Majida Charif, Narges Hashemi, Morteza Heidari, Seyed Mehdi Kalantar, Guy Lenaers, Mohammad Yahya Vahidi Mehrjardi, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Seyed Hamidreza Mirabutalebi, Deanna Alexis Carere, Mojtaba Movahedinia, David Murphy, Robert McFarland, Mohamed S Abdel-Hamid, Rasha M Elhossini, Shahryar Alavi, Melanie Napier, Amaya Belanger-Quintana, Asuri N Prasad, Jessica Jakobczyk, Agathe Roubertie, Tony Rupar, Tipu Sultan, Mehran Beiraghi Toosi, Leonid Sazanov, Mariasavina Severino, Henry Houlden, Robert W Taylor, Reza Maroofian.
      Biallelic variants in NADH (nicotinamide adenine dinucleotide (NAD) + hydrogen (H))-ubiquinone oxidoreductase 1 alpha subcomplex 13 have been linked to mitochondrial complex I deficiency, nuclear type 28, based on three affected individuals from two families. With only two families reported, the clinical and molecular spectrum of NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13-related diseases remains unclear. We report 10 additional affected individuals from nine independent families, identifying four missense variants (including recurrent c.170G > A) and three ultra-rare or novel predicted loss-of-function biallelic variants. Updated clinical-radiological data from previously reported families and a literature review compiling clinical features of all reported patients with isolated complex I deficiency caused by 43 genes encoding complex I subunits and assembly factors are also provided. Our cohort (mean age 7.8 ± 5.4 years; range 2.5-18) predominantly presented a moderate-to-severe neurodevelopmental syndrome with oculomotor abnormalities (84%), spasticity/hypertonia (83%), hypotonia (69%), cerebellar ataxia (66%), movement disorders (58%) and epilepsy (46%). Neuroimaging revealed bilateral symmetric T2 hyperintense substantia nigra lesions (91.6%) and optic nerve atrophy (66.6%). Protein modeling suggests missense variants destabilize a critical junction between the hydrophilic and membrane arms of complex I. Fibroblasts from two patients showed reduced complex I activity and compensatory complex IV activity increase. This study characterizes NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13-related disease in 13 individuals, highlighting genotype-phenotype correlations.
    Keywords:  Leigh syndrome; NDUFA13; complex I deficiency; mitochondrial disorders; neurodevelopmental disorder
    DOI:  https://doi.org/10.1093/braincomms/fcae453
  11. Nature. 2025 Feb 19.
    Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
    Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.
      Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.
    DOI:  https://doi.org/10.1038/s41586-025-08590-2
  12. bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]
    A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
    Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.
      Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.
    DOI:  https://doi.org/10.1101/2025.02.03.635951
  13. bioRxiv. 2025 Jan 30. pii: 2025.01.30.635785. [Epub ahead of print]
    Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.
    Iryna Bohovych, Gabriella Menezes da Silva, Saieeda Fabia Ali, Emma J Bergmeyer, Edward M Germany, Adarsh Mayank, James A Wohlschlegel, Jason C Casler, Muhammad Arifur Rahman, Taras Y Nazarko, Maureen Tarsio, Takuya Shiota, Laura L Lackner, Steven M Claypool, Patricia M Kane, Antoni Barrientos, Oleh Khalimonchuk.
      The mitochondrial inner membrane is among the most protein-dense cellular membranes. Its functional integrity is maintained through a concerted action of several conserved mechanisms that are far from clear. Here, using the baker's yeast model, we functionally characterize Mdm38/LETM1, a disease-related protein implicated in mitochondrial translation and ion homeostasis, although the molecular basis of these connections remains elusive. Our findings reveal a novel role for Mdm38 in maintaining protein homeostasis within the inner membrane. Specifically, we demonstrate that Mdm38 is required for mitochondrial iron homeostasis and for signaling iron bioavailability from mitochondria to vacuoles. These processes are linked to the m- AAA quality control protease, whose unrestrained activity disrupts the assembly and stability of respiratory chain complexes in Mdm38-deficient cells. Our study highlights the central role of Mdm38 in mitochondrial biology and reveals how it couples proteostatic mechanisms to ion homeostasis across subcellular compartments.
    DOI:  https://doi.org/10.1101/2025.01.30.635785
  14. bioRxiv. 2025 Jan 31. pii: 2025.01.30.635641. [Epub ahead of print]
    A molecular switch at the yeast mitoribosomal tunnel exit controls cytochrome b synthesis.
    Andreas Carlstrom, Joseph B Bridgers, Mary Couvillion, Abeer Prakash Singh, Ignasi Forne, Axel Imhof, L Stirling Churchman, Martin Ott.
      Mitochondrial gene expression needs to be balanced with cytosolic translation to produce oxidative phosphorylation complexes. In yeast, translational feedback loops involving lowly expressed proteins called translational activators help to achieve this balance. Synthesis of cytochrome b (Cytb or COB), a core subunit of complex III in the respiratory chain, is controlled by three translational activators and the assembly factor Cbp3-Cbp6. However, the molecular interface between the COB translational feedback loop and complex III assembly is yet unknown. Here, using protein-proximity mapping combined with selective mitoribosome profiling, we reveal the components and dynamics of the molecular switch controlling COB translation. Specifically, we demonstrate that Mrx4, a previously uncharacterized ligand of the mitoribosomal polypeptide tunnel exit, interacts with either the assembly factor Cbp3-Cbp6 or with the translational activator Cbs2. These reciprocal interactions determine whether the translational activator complex with bound COB mRNA can interact with the mRNA channel exit on the small ribosomal subunit for translation initiation. Organization of the feedback loop at the tunnel exit therefore orchestrates mitochondrial translation with respiratory chain biogenesis.
    DOI:  https://doi.org/10.1101/2025.01.30.635641
  15. bioRxiv. 2025 Feb 03. pii: 2025.02.01.636045. [Epub ahead of print]
    Mitophagy at the oocyte-to-zygote transition promotes species immortality.
    Siddharthan Balachandar Thendral, Sasha Bacot, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.
      The quality of inherited mitochondria determines embryonic viability 1 , metabolic health during adulthood and future generation endurance. The oocyte is the source of all zygotic mitochondria 2 , and mitochondrial health is under strict developmental regulation during early oogenesis 3-5 . Yet, fully developed oocytes exhibit the presence of deleterious mitochondrial DNA (mtDNA) 6,7 and mitochondrial dysfunction from high levels of endogenous reactive oxygen species 8 and exogenous toxicants 9 . How fully developed oocytes prevent transmission of damaged mitochondria to the zygotes is unknown. Here we discover that the onset of oocyte-to-zygote transition (OZT) developmentally triggers a robust and rapid mitophagy event that we term mitophagy at OZT (MOZT). We show that MOZT requires mitochondrial fragmentation, activation of the macroautophagy system and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Oocytes upregulate expression of FUNDC1 in response to diverse mitochondrial insults, including mtDNA mutations and damage, uncoupling stress, and mitochondrial dysfunction, thereby promoting selection against damaged mitochondria. Loss of MOZT leads to increased inheritance of deleterious mtDNA and impaired bioenergetic health in the progeny, resulting in diminished embryonic viability and the extinction of descendent populations. Our findings reveal FUNDC1-mediated MOZT as a mechanism that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity. These results may explain how mature oocytes from many species harboring mutant mtDNA give rise to healthy embryos with reduced deleterious mtDNA.
    DOI:  https://doi.org/10.1101/2025.02.01.636045
  16. Free Radic Biol Med. 2025 Feb 13. pii: S0891-5849(25)00087-5. [Epub ahead of print]
    Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.
    Juan Wang, Rongjuan Zhao, Jing Ma, Jiangbo Qin, Huiqiu Zhang, Junhong Guo, Xueli Chang, Wei Zhang.
      Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.
    Keywords:  FDXR; ataxia; ferroptosis; idebenone; mitochondrial diseases
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.012
  17. Trends Cell Biol. 2025 Feb 20. pii: S0962-8924(24)00272-1. [Epub ahead of print]
    How are mitochondrial nucleoids trafficked?
    Josefa Macuada, Isidora Molina-Riquelme, Verónica Eisner.
      Mitochondria harbor their own DNA (mtDNA), which codifies essential proteins of the oxidative phosphorylation (OXPHOS) system and locally feeds them to their surrounding inner mitochondrial membrane (IMM), according to the 'sphere of influence' theory. mtDNA is compacted into nucleoids, which are tethered to the IMM and distributed throughout the mitochondrial network. Some nucleoid subpopulations present distinct intramitochondrial positioning during fission and their correct positioning is associated with mtDNA segregation and selective degradation. This opinion article focuses on different mechanisms that could control nucleoid positioning through intramitochondrial trafficking, either by cristae reshaping or by intercompartment-driven mechanisms involving the mitochondrial membranes and extramitochondrial elements. Understanding nucleoid trafficking promises insights into mitochondrial dysfunction in pathologies with mtDNA distribution and segregation issues.
    Keywords:  cristae reshaping; mitochondrial nucleoid; mtDNA inheritance; nucleoid dynamics; sphere of influence
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.007
  18. Pediatr Dev Pathol. 2025 Feb 21. 10935266251321317
    Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) Phenotype Associated With Unique Compound Heterozygous POLG Variants: Case Presentation and Review of the Literature.
    Laura S Finn, Amy Goldstein, Holly L Hedrick.
      We report a teenage patient with a delayed diagnosis of compound heterozygous POLG pathogenic variants [(POLG c. 1943 C>G, p.P648R) and (POLG c. 679 C>T, p.R227W)] who presented with fatigue and neuropathy, as well as long standing malnutrition and cachexia, erroneously attributed to an eating disorder. She experienced multiple bowel perforations and pathologic examination revealed jejunal diverticula and features of visceral neuromyopathy. In addition to ganglion cell mega-mitochondrial inclusions, there were multiple foci of interrupted muscularis mucosae, an alteration not previously recognized in the intestines of patients with primary mitochondrial disorders. We provide a detailed account of the gastrointestinal pathologic findings in this patient and compare with prior cases of Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) phenotypes.
    Keywords:  MNGIE; POLG; diverticula; mtDNA depletion; muscularis mucosae; pseudo-obstruction
    DOI:  https://doi.org/10.1177/10935266251321317
  19. Nat Commun. 2025 Feb 20. 16(1): 1804
    AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
    Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang.
      Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases ROS generation, and simultaneously hinders antioxidant defense. Expression of NADH dehydrogenase NDI1 restores mitochondrial functions partially and protects neurons in AIF3-splicing mice. Our findings unveil an underrated role of AIF as a mammalian mitochondrial complex-I alternative NAD(P)H dehydrogenase and provide insights into pathologic AIF-variants in mitochondrial disorders and brain development.
    DOI:  https://doi.org/10.1038/s41467-025-57081-5
  20. bioRxiv. 2025 Feb 01. pii: 2025.01.31.635929. [Epub ahead of print]
    Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
    Janell Lm Smith, Kamaryn Tanner, Jack Devine, Anna S Monzel, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to metabolic perturbations, we develop an ISR GDF15 index quantifying the GDF15 arm of the ISR activation in human cells. Validation of ISR GDF15 index across 44 postmortem human tissues illustrates how this index can be applied to investigate tissue-specific and age-related ISR activation.
    DOI:  https://doi.org/10.1101/2025.01.31.635929
  21. Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00089-0. [Epub ahead of print]44(2): 115318
    Overfeeding induces adipose tissue release of distinct mitochondria.
    Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante.
      Overfeeding animals beyond what they eat ad libitum causes rapid adipose tissue expansion, leading to an unusual form of obesity characterized by low immune cell accumulation in fat and sustained anorexia. To investigate how overfeeding affects adipose tissue, we studied the protein secretome of fat from equally obese overfed and ad libitum-fed mice. Fat from overfed animals secretes lower amounts of immune regulatory proteins. Unexpectedly, fat from overfed mice releases larger amounts of mitochondrial proteins. Microscopy identified mitochondria in the conditioned medium of cultured fat that were found not within extracellular vesicles but rather as free extracellular organelles. The protein profile of released mitochondria was distinct from the mitochondrial protein profile of the whole fat, suggesting that the metabolic stress of overfeeding leads to the release of a mitochondrial subset favoring de novo lipogenesis. These findings add to growing evidence that cells alter their energy profiles through the release of mitochondria.
    Keywords:  CP: Metabolism; adipose tissue; mitochondria; obesity; overfeeding
    DOI:  https://doi.org/10.1016/j.celrep.2025.115318
  22. PLoS Comput Biol. 2025 Feb;21(2): e1012770
    Bayesian classification of OXPHOS deficient skeletal myofibres.
    Jordan Childs, Tiago Bernardino Gomes, Amy E Vincent, Andrew Golightly, Conor Lawless.
      Mitochondria are organelles in most human cells which release the energy required for cells to function. Oxidative phosphorylation (OXPHOS) is a key biochemical process within mitochondria required for energy production and requires a range of proteins and protein complexes. Mitochondria contain multiple copies of their own genome (mtDNA), which codes for some of the proteins and ribonucleic acids required for mitochondrial function and assembly. Pathology arises from genetic defects in mtDNA and can reduce cellular abundance of OXPHOS proteins, affecting mitochondrial function. Due to the continuous turn-over of mtDNA, pathology is random and neighbouring cells can possess different OXPHOS protein abundance. Estimating the proportion of cells where OXPHOS protein abundance is too low to maintain normal function is critical to understanding disease severity and predicting disease progression. Currently, one method to classify single cells as being OXPHOS deficient is prevalent in the literature. The method compares a patient's OXPHOS protein abundance to that of a small number of healthy control subjects. If the patient's cell displays an abundance which differs from the abundance of the controls then it is deemed deficient. However, due to the natural variation between subjects and the low number of control subjects typically available, this method is inflexible and often results in a large proportion of patient cells being misclassified. These misclassifications have significant consequences for the clinical interpretation of these data. We propose a single-cell classification method using a Bayesian hierarchical mixture model, which allows for inter-subject OXPHOS protein abundance variation. The model accurately classifies an example dataset of OXPHOS protein abundances in skeletal muscle fibres (myofibres). When comparing the proposed and existing model classifications to manual classifications performed by experts, the proposed model results in estimates of the proportion of deficient myofibres that are consistent with expert manual classifications.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012770
  23. HGG Adv. 2025 Feb 17. pii: S2666-2477(25)00021-1. [Epub ahead of print] 100418
    Polyamine Metabolism is Dysregulated in COXFA4 Related Mitochondrial Disease.
    Jonathan Marquez, Stephen Viviano, Erika Beckman, Jenny Thies, Joshua Friedland-Little, Christina T Lam, Engin Deniz, Emily Shelkowitz.
      Most of the chemical energy that organisms rely on to support cellular function is generated through oxidative phosphorylation, a metabolic pathway in which electron donors, NADH and FADH, are oxidized through a series of successive steps to generate adenosine triphosphate. These redox reactions are orchestrated by a series of five protein complexes that sit within the mitochondrial membrane. Deficiency of cytochrome c oxidase, the fourth of these complexes, is a recognized cause of mitochondrial disease. COXFA4, encodes one of the protein subunits of cytochrome c oxidase and variants in COXFA4 have recently been reported in individuals with a range of symptoms. These can include feeding difficulties, poor growth, cardiomyopathy, Leigh or Leigh-like disease, and neurodevelopmental delay. Though these symptoms vary widely between individuals. Yet, a mechanistic understanding of the connection between COXFA4 loss and these varied disease manifestations is lacking. Using animal modeling in Xenopus, we explored the ramifications of coxfa4 loss of function on the early developing heart. We then conducted a hypothesis naive analysis of cellular gene expression in the context of COXFA4 deletion and discovered a downstream deficiency in the ornithine decarboxylase pathway. Small molecule-based modulation of the ornithine decarboxylase pathway in our model modified the extent of disease including improvement of cardiac function. Our findings point to a mechanism by which COXFA4 dysfunction leads to tissue specific disease.
    DOI:  https://doi.org/10.1016/j.xhgg.2025.100418
  24. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]
    RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
    Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.
      Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.
    Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
  25. Sci Adv. 2025 Feb 21. 11(8): eadu3011
    Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
    Tatsuya Morishima, Md Fakruddin, Yohei Kanamori, Takeshi Masuda, Akiko Ogawa, Yuxin Wang, Vivien A C Schoonenberg, Falk Butter, Yuichiro Arima, Takaaki Akaike, Toshiro Moroishi, Kazuhito Tomizawa, Toshio Suda, Fan-Yan Wei, Hitoshi Takizawa.
      Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.
    DOI:  https://doi.org/10.1126/sciadv.adu3011
  26. Cell Death Dis. 2025 Feb 14. 16(1): 99
    Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
    Irene Pertici, Donato D'Angelo, Denis Vecellio Reane, Massimo Reconditi, Ilaria Morotti, Elena Putignano, Debora Napoli, Giorgia Rastelli, Gaia Gherardi, Agnese De Mario, Rosario Rizzuto, Simona Boncompagni, Laura Baroncelli, Marco Linari, Marco Caremani, Anna Raffaello.
      Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT-/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT-/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.
    DOI:  https://doi.org/10.1038/s41419-025-07381-x
  27. Cell. 2025 Feb 12. pii: S0092-8674(25)00098-4. [Epub ahead of print]
    HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.
    Skyler Y Blume, Ankur Garg, Yolanda Martí-Mateos, Ayush D Midha, Brandon T L Chew, Baiwei Lin, Cecile Yu, Ryan Dick, Patrick S Lee, Eva Situ, Richa Sarwaikar, Eric Green, Vyas Ramanan, Gijsbert Grotenbreg, Maarten Hoek, Christopher Sinz, Isha H Jain.
      We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.
    Keywords:  Leigh syndrome; hemoglobin; hyperoxia; hypoxia; mitochondrial disease; oxygen; red blood cells; therapy
    DOI:  https://doi.org/10.1016/j.cell.2025.01.029
  28. Bio Protoc. 2025 Feb 05. 15(3): e5180
    Isolation of Intact Mitochondria From Drosophila melanogaster and Assessment of Mitochondrial Respiratory Capacity Using Seahorse Analyzer.
    Christopher M Groen, Anthony J Windebank.
      Analysis of mitochondrial function has broad applicability in many research specialties. Neurodegenerative disorders such as chemotherapy-induced peripheral neuropathy (CIPN) often exhibit damaged mitochondria or reduced mitochondrial respiratory capacity. Isolation of intact mitochondria for protein analysis or respiration measurements has been previously reported in numerous model organisms. Here, we describe an adaptation of previous protocols to isolate intact functional mitochondria from Drosophila melanogaster for use in a model of CIPN. Whole Drosophila are ground in isolation buffer, and mitochondria are purified using differential centrifugation through a sucrose and mannitol solution. The intact mitochondria are plated as a monolayer for measurements of mitochondrial oxygen consumption rates and response to inhibitor compounds on an Agilent Seahorse analyzer. This experimental protocol is quick and yields a purified population of intact mitochondria that may be used for functional assays for several hours after isolation. The isolated mitochondria may be used for respiration measurements, which reflect their health, and stored for protein or genetic analysis. Mitochondrial populations from multiple strains or treatment groups can be easily compared simultaneously. The rapid biochemical assessment of mitochondria, in combination with the utility of Drosophila as an in vivo genetic model system, offers great potential for researchers to probe the impact of genetics and pharmacologic interventions on mitochondrial respiratory capacity. Key features • This protocol describes rapid isolation of intact, functional mitochondria that may be used for respiration measurements or other biochemical analyses. • Mitochondria isolated from Drosophila are assessed in an Agilent Seahorse analyzer utilizing multiple substrates and electron transport chain inhibitors to fully characterize mitochondrial respiratory capacity. • This protocol is optimized to use Drosophila for easy in vivo genetic and pharmacologic manipulation, and assessment of the impact on mitochondrial function.
    Keywords:  Differential centrifugation; Drosophila; Mitochondria; Oxygen consumption; Respiration; Seahorse
    DOI:  https://doi.org/10.21769/BioProtoc.5180
  29. Protein Sci. 2025 Mar;34(3): e70053
    Non-canonical ORFs-derived protein products in mitochondria: A multifaceted exploration of their functions in health and disease.
    Ikram Ajala, Benoît Vanderperre.
      Traditionally, eukaryotic mRNAs were perceived as inherently monocistronic. However, recent insights from ribosome profiling (Ribo-seq) and proteomics studies challenge this paradigm. These investigations reveal that, beyond the currently annotated reference proteins (RefProts), there exist additional proteins known as alternative proteins (AltProts) and small open reading frames derived microproteins encoded in regions of mRNAs previously considered untranslated or in non-coding transcripts. This experimental evidence broadens the spectrum of functional proteins within cells, tissues, and organs, potentially offering crucial insights into biological processes. Notably, a significant proportion of these newly identified AltProts and microproteins demonstrates localization in mitochondria, contributing to the functions of mitochondrial complexes. This review delves into the overlooked realm of the alternative proteome within mitochondria, exploring the role of nuclear or mitochondrial-genome-encoded AltProts and microproteins in physiological and pathological cellular processes.
    Keywords:  alternative open reading frames (AltORFs); alternative proteins (AltProts); mitochondria; proteome; small ORF (sORF)
    DOI:  https://doi.org/10.1002/pro.70053
  30. bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]
    Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
    Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.
      Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
    DOI:  https://doi.org/10.1101/2025.01.28.635306
  31. Commun Biol. 2025 Feb 18. 8(1): 258
    Functional compartmentalization of hepatic mitochondrial subpopulations during MASH progression.
    Noble Kumar Talari, Ushodaya Mattam, Afra P Rahman, Brook K Hemmelgarn, Michael A Wyder, Pamela B Sylvestre, Kenneth D Greis, Karthickeyan Chella Krishnan.
      The role of peridroplet mitochondria (PDM) in diseased liver, such as during the progression of metabolic dysfunction-associated steatohepatitis (MASH), remains unknown. We isolated hepatic cytoplasmic mitochondria (CM) and PDM from a mouse model of diet-induced MASLD/MASH to characterize their functions from simple steatosis to advanced MASH, using chow-fed mice as controls. Our findings show an inverse relationship between hepatic CM and PDM levels from healthy to steatosis to advanced MASH. Proteomics analysis revealed these two mitochondrial populations are compositionally and functionally distinct. We found that hepatic PDM are more bioenergetically active than CM, with higher pyruvate oxidation capacity in both healthy and diseased liver. Higher respiration capacity of PDM was associated with elevated OXPHOS protein complexes and increased TCA cycle flux. In contrast, CM showed higher fatty acid oxidation capacity with MASH progression. Transmission electron microscopy revealed larger and elongated mitochondria during healthy and early steatosis, which appeared small and fragmented during MASH progression. These changes coincided with higher MFN2 protein levels in hepatic PDM and higher DRP1 protein levels in hepatic CM. These findings highlight the distinct roles of hepatic CM and PDM in MASLD progression towards MASH.
    DOI:  https://doi.org/10.1038/s42003-025-07713-9
  32. Adv Sci (Weinh). 2025 Feb 20. e2411235
    SIRT3-Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease.
    Ye Xi, Kai Tao, Xiaomin Wen, Dayun Feng, Zifan Mai, Hui Ding, Honghui Mao, Mingming Wang, Qian Yang, Jie Xiang, Jie Zhang, Shengxi Wu.
      Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin-related protein 1 (DRP1) causes mitochondrial dysfunction in dopaminergic (DA) neurons. However, the mechanism of DRP1 activation and its role in PD progression remain unclear. In this study, Mass spectrometry analysis is performed and identified a significant increased DRP1 acetylation at lysine residue 711 (K711) in the mitochondria under oxidative stress. Enhanced DRP1K711 acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1K711 acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)-3 in deacetylating DRP1K711, thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1K711 acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1K711 acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3-mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment.
    Keywords:  DRP1K711; Parkinson's disease; SIRT3; acetylation; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1002/advs.202411235
  33. J Physiol. 2025 Feb 18.
    Mitochondrial control of ciliary gene expression and structure in striatal neurons.
    Dogukan H Ulgen, Alessandro Chioino, Olivia Zanoletti, Albert Quintana, Elisenda Sanz, Carmen Sandi.
      Mitochondria play essential metabolic roles and are increasingly understood to interact with other organelles, influencing cellular function and disease. Primary cilia, as sensory and signalling organelles, are crucial for neuronal communication and function. Emerging evidence suggests that mitochondria and primary cilia may interact to regulate cellular processes, as recently shown in brain cells such as astrocytes. Here, we investigated whether mitochondria also regulate primary cilia in neurons, focusing on molecular pathways linking both organelles and structural components within cilia. We employed a cross-species, molecular pathway-focused approach to explore connections between mitochondrial and ciliary pathways in neurons, revealing strong associations suggesting coordinated functionality. Furthermore, we found that viral-induced downregulation of the mitochondrial fusion gene mitofusin 2 (Mfn2) in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the nucleus accumbens (NAc) altered ciliary gene expression, with Crocc - the gene encoding rootletin - showing the most pronounced downregulation. This reduction in Crocc expression was linked to decreased levels of rootletin protein, a key structural component of the ciliary rootlet. Notably, viral-mediated overexpression of rootletin restored ciliary complexity and elongation, without compromising neuronal adaptation to Mfn2 downregulation. Our findings provide novel evidence of a functional mitochondria-cilia interaction in neurons, specifically in striatal D1-MSNs. These results reveal a previously unrecognized role of mitochondrial dynamics in regulating ciliary structure in neurons, with potential implications for neuropsychiatric and neurodegenerative disease mechanisms. KEY POINTS: Mitochondria are cell structures known for producing energy but are also emerging as regulators of other cellular components, including primary cilia, antenna-like structures involved in cell communication. Previous studies suggest that mitochondria may influence cilia structure and function, including in astrocytes. However, this has not been explored in neurons. This study shows that natural variation in mitochondrial molecular pathways correlates with primary cilia pathways in striatal medium spiny neurons in both rats and mice. Reducing expression of mitofusin 2 (Mfn2), a key mitochondrial protein involved in fusion and mitochondria-endoplasmic reticulum interactions, changes specific molecular ciliary pathways, notably including Crocc, a gene essential for cilia structure, and reduces the levels of its protein product, rootletin, which supports cilia integrity. Our findings reveal an important role for mitochondria in regulating ciliary structure in neurons, highlighting a potential pathway for mitochondrial regulation of neuronal signalling.
    Keywords:  RiboTag sequencing; cilium; gene manipulation; mitochondria; mitofusin 2; single nucleus RNA sequencing
    DOI:  https://doi.org/10.1113/JP287948
  34. medRxiv. 2025 Feb 02. pii: 2025.01.30.25321185. [Epub ahead of print]
    MAJIQ-CLIN: A novel tool for the identification of Mendelian disease-causing variants from RNA-Seq data.
    Undiagnosed Diseases Network
      The current diagnostic rate for patients with suspected Mendelian genetic disorders is only 25 to 58%, even though whole exome sequencing (WES) is part of the standard of care. One reason for the low diagnostic rate is that traditional WES analysis methods struggle to detect RNA splicing aberrations. It is estimated that 15-50% of human pathogenic variants alter splicing, with numerous splice-altering variants being causal for known Mendelian disorders. Developing reliable diagnostic tools to detect, quantify, prioritize, and visualize RNA splicing aberrations from patient RNA sequencing is therefore crucial. We present MAJIQ-CLIN, a method to address this need to augment clinical diagnostic using RNA-Seq and compare it to existing tools. We include the first systematic evaluation of the accuracy of such tools using synthetic data across several aberration types and transcript inclusion levels; we also evaluate accuracy on several datasets of biologically validated solved test cases. We show that MAJIQ-CLIN compares favorably to existing tools in both accuracy and efficiency, then use MAJIQ-CLIN to investigate several unsolved patient cases from the Undiagnosed Diseases Network.
    DOI:  https://doi.org/10.1101/2025.01.30.25321185
  35. Nat Commun. 2025 Feb 20. 16(1): 1789
    Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.
    Dong Liu, Hannah C Webber, Fuyun Bian, Yangfan Xu, Manjari Prakash, Xue Feng, Ming Yang, Hang Yang, In-Jee You, Liang Li, Liping Liu, Pingting Liu, Haoliang Huang, Chien-Yi Chang, Liang Liu, Sahil H Shah, Anna La Torre, Derek S Welsbie, Yang Sun, Xin Duan, Jeffrey Louis Goldberg, Marcus Braun, Zdenek Lansky, Yang Hu.
      Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-025-57135-8
  36. Nat Metab. 2025 Feb 19.
    Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
    Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.
      Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.
    DOI:  https://doi.org/10.1038/s42255-025-01224-x
  37. Ann Hematol. 2025 Feb 17.
    Identification of a novel truncated pathogenic variant in PUS1 gene in two siblings of consanguineous Tunisian family: intrafamilial phenotypic variability related to mtDNA copy number.
    Marwa Ammar, Sana Kmiha, Marwa Maalej, Rahma Felhi, Marwa Kharrat, Olfa Alila-Fersi, Jihen Chouchen, Ines Maaloul, Emna Mkaouar-Rebai, Thouraya Kammoun, Abdelaziz Tlili, Faiza Fakhfakh.
      Congenital sideroblastic anemia (CSA) is a rare genetic disorder caused by defects on heme biosynthesis and mitochondrial energy production. This disease is characterized by the presence of ring sideroblasts in the bone marrow caused by excessive iron accumulation in mitochondria of erythroblasts and by anemia of varying severity. In addition to its clinical variability, CSA is also characterized by genetic heterogeneity which required next-generation sequencing technologies to identify responsible gene. In the present study, whole-exome sequencing followed by Sanger sequencing were performed on a consanguineous family including two patients with congenital sideroblastic anemia. Mitochondrial DNA deletion and copy number were tested respectively by long PCR and QPCR. Subsequent bioinformatic investigations were performed using several programs. WES and Sanger sequencing results revealed a novel pathogenic variant c.579-580insT (p.N194X) in the PUS1 gene. Several bioinformatic tools supported that this variant was disease-causing. This variation leads to an incomplete catalytic site which will be probably non-functional and could disturb heme biosynthesis. In addition, no mtDNA deletion was detected in the two patients whereas mtDNA quantification revealed a decrease of mtDNA copy number in P2 and its increasing in P1. The increase in mtDNA copy number, which is most likely connected to a compensatory mechanism, may be the cause of the moderate phenotypic severity observed in P1 with the same p.N194X variant with P2. In conclusion, we identified a novel truncated pathogenic variant in PUS1 gene in two siblings of consanguineous family with intrafamilial phenotypic variability related to mtDNA copy number.
    Keywords:  MLASA1 syndrome; Mitochondrial diseases; Pathogenic variant; Tunisia; Whole exome sequencing
    DOI:  https://doi.org/10.1007/s00277-025-06259-4
  38. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13715
    GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
    Stephen E Flaherty, LouJin Song, Bina Albuquerque, Anthony Rinaldi, Mary Piper, Dinesh Hirenallur Shanthappa, Xian Chen, John Stansfield, Shoh Asano, Evanthia Pashos, Trenton Thomas Ross, Srinath Jagarlapudi, Abdul Sheikh, Bei Zhang, Zhidan Wu.
       BACKGROUND: Primary mitochondrial myopathies (PMMs) are disorders caused by mutations in genes encoding mitochondrial proteins and proteins involved in mitochondrial function. PMMs are characterized by loss of muscle mass and strength as well as impaired exercise capacity. Growth/Differentiation Factor 15 (GDF15) was reported to be highly elevated in PMMs and cancer cachexia. Previous studies have shown that GDF15 neutralization is effective in improving skeletal muscle mass and function in cancer cachexia. It remains to be determined if the inhibition of GDF15 could be beneficial for PMMs. The purpose of the present study is to assess whether treatment with a GDF15 neutralizing antibody can alleviate muscle atrophy and physical performance impairment in a mouse model of PMM.
    METHODS: The effects of GDF15 neutralization on PMM were assessed using PolgD257A/D257A (POLG) mice. These mice express a proofreading-deficient version of the mitochondrial DNA polymerase gamma, leading to an increased rate of mutations in mitochondrial DNA (mtDNA). These animals display increased circulating GDF15 levels, reduced muscle mass and function, exercise intolerance, and premature aging. Starting at 9 months of age, the mice were treated with an anti-GDF15 antibody (mAB2) once per week for 12 weeks. Body weight, food intake, body composition, and muscle mass were assessed. Muscle function and exercise capacity were evaluated using in vivo concentric max force stimulation assays, forced treadmill running and voluntary home-cage wheel running. Mechanistic investigations were performed via muscle histology, bulk transcriptomic analysis, RT-qPCR and western blotting.
    RESULTS: Anti-GDF15 antibody treatment ameliorated the metabolic phenotypes of the POLG animals, improving body weight (+13% ± 8%, p < 0.0001), lean mass (+13% ± 15%, p < 0.001) and muscle mass (+35% ± 24%, p < 0.001). Additionally, the treatment improved skeletal muscle max force production (+35% ± 43%, p < 0.001) and exercise performance, including treadmill (+40% ± 29%, p < 0.05) and voluntary wheel running (+320% ± 19%, p < 0.05). Mechanistically, the beneficial effects of GDF15 neutralization are linked to the reversal of the transcriptional dysregulation in genes involved in autophagy and proteasome signalling. The treatment also appears to dampen glucocorticoid signalling by suppressing circulating corticosterone levels in the POLG animals.
    CONCLUSIONS: Our findings highlight the potential of GDF15 neutralization with a monoclonal antibody as a therapeutic avenue to enhance physical performance and mitigate adverse clinical outcomes in patients with PMM.
    Keywords:  GDF15; antibody; mice; mitochondria; muscle; primary mitochondrial myopathy
    DOI:  https://doi.org/10.1002/jcsm.13715
  39. Life Sci. 2025 Feb 19. pii: S0024-3205(25)00119-5. [Epub ahead of print]366-367 123486
    Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells.
    Sanna Ryytty, Katriina Nurminen, Petri Mäkinen, Anu Suomalainen, Riikka H Hämäläinen.
       AIMS: Metformin (Met) is a widely used, cost-effective, and relatively safe drug, primarily prescribed for diabetes, that also exhibits beneficial effects in other conditions, such as in cardiovascular diseases, neurological disorders, and cancer. Despite its common use, the safety of Met in patients with primary mitochondrial disease remains uncertain, as both Met and mitochondrial dysfunction increase the risk of lactic acidosis. Here we have examined the effects of Met in patient cells with m.3243A>G mitochondrial DNA mutation.
    MATERIALS AND METHODS: We utilized induced pluripotent stem cells (iPSCs) derived from two m.3243A>G patients, alongside cardiomyocytes differentiated from these iPSCs (iPSC-CMs). The cells were exposed to 10, 100, and 1000 μM Met for 24 h, and the effects on cellular metabolism and mitochondrial function were evaluated.
    KEY FINDINGS: While low concentrations, relative to common therapeutic plasma levels, increased mitochondrial respiration, higher concentrations decreased respiration in both patient and control cells. Furthermore, cells with high level of the m.3243A>G mutation were more sensitive to Met than control cells. Additionally, we observed a clear patient-specific response to Met in cardiomyocytes.
    SIGNIFICANCE: The findings emphasize the critical importance of selecting appropriate Met concentrations in cellular experiments and demonstrate the variability in Met's effects between individuals. Moreover, the results highlight the need for caution when considering Met use in patients with primary mitochondrial disorders.
    Keywords:  Cardiomyocytes; Induced pluripotent stem cells; Metformin; Mitochondrial disease; m.3243A>G
    DOI:  https://doi.org/10.1016/j.lfs.2025.123486
  40. Nucleic Acids Res. 2025 Feb 08. pii: gkaf062. [Epub ahead of print]53(4):
    CRISPuRe-seq: pooled screening of barcoded ribonucleoprotein reporters reveals regulation of RNA polymerase III transcription by the integrated stress response via mTOR.
    David T Harris, Calvin H Jan.
      Genetic screens using CRISPR (Clustered Regularly Interspaced Palindromic Repeats) provide valuable information about gene function. Nearly all pooled screening technologies rely on the cell to link genotype to phenotype, making it challenging to assay mechanistically informative, biochemically defined phenotypes. Here, we present CRISPuRe-seq (CRISPR PuRification), a novel pooled screening strategy that expands the universe of accessible phenotypes through the purification of ribonucleoprotein complexes that link genotypes to expressed RNA barcodes. While screening for regulators of the integrated stress response (ISR), we serendipitously discovered that the ISR represses transfer RNA (tRNA) production under conditions of reduced protein synthesis. This regulation is mediated through inhibition of mTORC1 and corresponding activation of the RNA polymerase III inhibitor MAF1. These data demonstrate that coherent downregulation of tRNA expression and protein synthesis is achieved through cross-talk between the ISR and mTOR, two master integrators of cell state.
    DOI:  https://doi.org/10.1093/nar/gkaf062
  41. bioRxiv. 2025 Jan 28. pii: 2025.01.27.635175. [Epub ahead of print]
    Imbalanced mitochondrial dynamics in human and mouse PD brains.
    Harry J Brown, Rebecca Z Fan, Riley Bell, Said S Salehe, Carlos Martínez Martínez, Yanhao Lai, Kim Tieu.
      Mitochondrial dysfunction is a major pathogenic mechanism in Parkinson's disease (PD). Emerging studies have shown that dysregulation in mitochondrial dynamics (fission/fusion/movement) has a major negative impact on mitochondria - both morphologically and functionally. Partial genetic deletion and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (Drp1) have been demonstrated to be beneficial in experimental models of PD. However, the expression of DRP1 (and other fission and fusion genes/proteins) has not been investigated in the brains of Parkinson's patients. Without these data, the question remains whether targeting DRP1 is a valid therapeutic target for PD. To address this gap of knowledge, first, we used post-mortem substantia nigra specimens of Parkinson's patients and controls. Significant increases in the levels of both DNM1L , which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered in Parkinson's patients. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies (3-, 6- and 12-month) using transgenic mice overexpressing human wild-type SNCA under the mouse Thy-1 promoter. As early as 6 months old, we detected an upregulation of Dnm1l and Drp1 in the nigral DA neurons of the SNCA mice as compared to their WT littermates. Furthermore, these mutant animals exhibited more Drp1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1/Drp1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.
    DOI:  https://doi.org/10.1101/2025.01.27.635175
  42. Brain Res. 2025 Feb 13. pii: S0006-8993(25)00063-0. [Epub ahead of print]1852 149505
    Outlook of SNCA (α-synuclein) transgenic fly models in delineating the sequel of mitochondrial dysfunction in Parkinson's disease.
    Jennifer Sally Samson, Kalyanaraman Rajagopal, Venkatachalam Deepa Parvathi.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with mechanisms that results in loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. Being a complex heterogeneous disorder, there is a requisite in discovering the underlying molecular signatures that could potentially help in resolving challenges associated with diagnosis as well as therapeutic management. SNCA gene that encodes for the protein α-synuclein is widely known for its indispensable role in aggravating the progression of sporadic and familial PD, upon mutations. Likewise, mitochondrial dysfunction is inferred to be playing a central role in both forms of PD. Observations from experimental models and human PD cases displayed strong evidence for disruption of mitochondrial dynamics, inhibition of mitochondrial complex I protein's function and elevation in reactive oxygen species (ROS) by the toxic aggregation of α-synuclein. Further, recent studies have raised the possibility of an underlying relationship, where the α-synuclein toxicity is exacerbated by the mutant mitochondrial complex proteins and vice-versa. In this review, we provide an overview of mechanisms influencing α-synuclein-related neurodegeneration, particularly, emphasizing the role of SNCA (α-synuclein) gene in leading to altered mitochondrial biogenesis during PD. We have described how transgenic Drosophila models were reliable at recapitulating some of the essential characteristics of PD. In addition, we highlight the capability of utilizing transgenic fly models in deciphering the altered α-synuclein toxicity and mitochondrial dysfunction, as induced by defects in the mitochondrial DNA.
    Keywords:  Drosophila melanogaster; Mitochondrial dysfunction; Oxidative stress; Parkinson’s disease; SNCA (α-synuclein); Targeted enhancer/suppressor screening
    DOI:  https://doi.org/10.1016/j.brainres.2025.149505
  43. bioRxiv. 2025 Jan 31. pii: 2024.12.21.629919. [Epub ahead of print]
    Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
    Jorge L Cueva-Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.
      Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
    DOI:  https://doi.org/10.1101/2024.12.21.629919
  44. Cell Metab. 2025 Feb 13. pii: S1550-4131(25)00008-7. [Epub ahead of print]
    An organism-level quantitative flux model of energy metabolism in mice.
    Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E Inouye, Gökhan S Hotamışlıgil, Sheng Hui.
      Mammalian tissues feed on nutrients in the blood circulation. At the organism level, mammalian energy metabolism is comprised of the oxidation, storage, interconversion, and release of circulating nutrients. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wild-type mice that circulating nutrients have metabolic cycling fluxes dominant to their oxidation fluxes, with distinct partitions between cycling and oxidation for individual circulating nutrients. Applications of this framework in obese mouse models showed extensive elevation of metabolic cycling fluxes in ob/ob mice but not in diet-induced obese mice on a per-animal or per-lean mass basis. Our framework is a valuable tool to reveal new features of energy metabolism in physiological and disease conditions.
    Keywords:  energy metabolism; futile cycle; high-fat diet; isotope tracing; metabolic flux analysis; ob/ob; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.008
  45. Nature. 2025 Feb 20.
    Rare genetic disorder treated in womb for the first time.
    Smriti Mallapaty.
      
    Keywords:  Drug discovery; Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-00534-0
  46. Redox Biol. 2025 Feb 08. pii: S2213-2317(25)00051-5. [Epub ahead of print]81 103538
    Complex I superoxide anion production is necessary and sufficient for complex I inhibitor-induced dopaminergic neurodegeneration in Caenorhabditis elegans.
    Katherine S Morton, Alex J George, Joel N Meyer.
      Parkinson's Disease (PD) is the 2nd most prevalent neurodegenerative disease, but there is currently no cure and limited understanding of the pathogenesis resulting in dopaminergic neurodegeneration. Inhibitors of electron transport chain Complex I (CI) have long been associated with and are now used to model PD, but CI inhibition results in multiple effects including ATP depletion and reactive oxygen species (ROS) generation. The lack of tools to isolate effects of CI inhibition have rendered it difficult to determine which mechanistic step is critical for CI inhibitor-induced dopaminergic neurodegeneration. Here we report that CI-derived superoxide anion, not ATP depletion, is the critical driver of CI inhibitor-induced dopaminergic neurodegeneration in the model organism Caenorhabditis elegans. We first use SuperNova, a light-activated ROS-generating protein, fused to CI to demonstrate that in absence of enzymatic inhibition CI-localized ROS production is sufficient to drive morphological damage and loss of function of the dopaminergic neurons. Second, we prevented superoxide anion production during exposure to the CI inhibitors rotenone and pyridaben and report a full rescue of CI inhibitor-induced degeneration and functional loss, without rescue of inhibitor-induced ATP depletion. We highlight the importance of mitochondrial superoxide anion generation in the pathogenesis of PD and build a foundation for further definition of the pathways activated by mitochondrial ROS that led to neuronal dysfunction and death. Identification of these underlying mechanisms allows for future prevention of toxicant exposure-induced PD based on mechanistic knowledge.
    Keywords:  Complex I; Parkinson's disease; S1QEL; SuperNova; Superoxide anion
    DOI:  https://doi.org/10.1016/j.redox.2025.103538
  47. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13740
    Low-Magnitude High-Frequency Vibration Attenuates Sarcopenia by Modulating Mitochondrial Quality Control via Inhibiting miR-378.
    Yu-Feng Long, Can Cui, Qianjin Wang, Zhen Xu, Simon Kwoon-Ho Chow, Ning Zhang, Ronald Man Yeung Wong, Elvis Chun-Sing Chui, Rebecca Schoenmehl, Christoph Brochhausen, Clinton Rubin, Gang Li, Ling Qin, Da-Zhi Yang, Wing-Hoi Cheung.
       BACKGROUND: Sarcopenia, the age-related decline in muscle mass and muscle strength, significantly contributes to falls, diminished quality of life, and mortality. Although mitochondrial dysfunction is increasingly implicated in sarcopenia, the underlying mechanisms are not fully discovered. Low-magnitude high-frequency vibration (LMHFV), a recommended treatment by the Centers for Disease Control and Prevention (CDC) to reduce fall risk, remains poorly understood of the mechanism on improving skeletal muscle quality. This study aims to investigate whether mitochondrial dysfunction contributes to sarcopenia and evaluate whether LMHFV mitigates sarcopenia by improving mitochondrial homeostasis.
    METHODS: The relationship between mitochondria dysfunction and sarcopenia using senescence accelerated mice prone 8 (SAMP8) model was investigated, assessing muscle and mitochondria. The effects of LMHFV on muscle and mitochondria were evaluated in SAMP8 mice during sarcopenia progression. The role of miR-378 in muscle and mitochondrial homeostasis were evaluated in SAMP8 mice and transgenic over-expressing miR-378 mice (TG mice). The target gene of miR-378 was investigated by dual-luciferase reporter assay in C2C12 cells. Subsequently, we evaluated the effect of LMHFV on miR-378 using both mouse models.
    RESULTS: Reduction in muscle strength was observed from the ages of month 8 to 10 in SAMP8 mice (grip strength decreased 27.1%, p = 0.0263; twitch force decreased 29.1%, p = 0.0178; tetanic force decreased 29.9%, p = 0.011), as well as muscle atrophy (cross-section area: 38.3%, p = 0.0121). Mitochondrial morphological deterioration was noticed from month 6 to 10. Mitochondrial homeostasis, including biogenesis, fusion, fission, mitophagy, and ATP production declined from month 6 to 10. Compared to control group at month 10, knocking down miR-378 in SAMP8 mice mitigated sarcopenia (twitch force increased 44.3%, p = 0.0023; tetanic force increased 51.9%, p = 0.0005), improved mitochondrial morphologies (mitochondrial number increased 1.65-fold, p = 0.0023; mitochondrial density increased 1.65-fold, p = 0.0023; mitochondrial relative area increased 9.05-fold, p = 0.0019) along with improved mitochondrial homeostasis. Over-expressing miR-378 in transgenic mice exacerbated muscle atrophy and mitochondrial deterioration significantly. The dual-luciferase reporter assay in C2C12 cells revealed that miR-378 inhibited PGC-1α directivity. LMHFV was found to mitigate sarcopenia by modulating mitochondrial homeostasis, such as attenuating mitochondrial morphological deterioration and improving mitochondrial biogenesis through increasing PGC-1α via inhibiting miR-378 in skeletal muscle.
    CONCLUSIONS: Our findings indicate that mitochondrial biogenesis, fusion, fission, and mitophagy were compromised during progression of sarcopenia, with mitochondrial deterioration preceding the onset of sarcopenia symptoms. The study also demonstrated that LMHFV could attenuate sarcopenia by modulating mitochondrial quality control through inhibiting miR-378, highlighting its therapeutic potential in the management of age-related muscular degeneration.
    Keywords:  miR‐378; mitochondria; sarcopenia; skeletal muscle; vibration
    DOI:  https://doi.org/10.1002/jcsm.13740
  48. FEBS Lett. 2025 Feb 21.
    Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport.
    María Torres-López, Pedro F Spiller, Lin Gao, Paula García-Flores, Michael P Murphy, Patricia Ortega-Sáenz, José López-Barneo.
      Carotid body glomus cells are essential for stimulating breathing in response to hypoxia. They contain specialized mitochondria in which hypoxia induces the accumulation of NADH and H2O2 that modulate membrane ion channel activity. We investigated whether hypoxia induces reverse electron transport (RET) at mitochondrial complex I (MCI). We studied glomus cells from mice with a mutation in ND6, a core protein of MCI, which maintain normal MCI NADH dehydrogenase activity but cannot catalyze RET. The ND6 mutation increases the propensity of MCI to deactivate, and glomus cells with deactivated MCI are insensitive to acute hypoxia. These findings further indicate that MCI function is necessary for glomus cell responsiveness to hypoxia, although MCI RET does not seem to be required for this process.
    Keywords:  ND6 mutation; acute oxygen sensing; carotid body glomus cells; hypoxia; mitochondrial complex I deactivation; reverse electron transport
    DOI:  https://doi.org/10.1002/1873-3468.70017
  49. Pathophysiology. 2025 Feb 13. pii: 9. [Epub ahead of print]32(1):
    Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight.
    Franklyn Nonso Iheagwam, Amarachi Joy Joseph, Eniola Deborah Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh.
      Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate insulin action, or a combination of both. Mitochondrial dysfunction has emerged as a significant contributor to the aetiology of diabetes, affecting various metabolic processes critical for glucose homeostasis. This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics. Additionally, it discusses the clinical implications and complications of mitochondrial dysfunction in diabetes and its complications, diagnostic approaches for assessing mitochondrial function in diabetics, therapeutic strategies, future directions, and research opportunities.
    Keywords:  diabetes mellitus; hyperglycemia; insulin resistance; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/pathophysiology32010009
  50. Clin Genet. 2025 Feb 20.
    Expanding the Phenotypic Spectrum of SPG7 Rare Damaging Variants: Insights From a Hungarian Cohort.
    Idris Janos Jimoh, Peter Balicza, Tamas Szlepak, Dora Csaban, Aniko Gal, Adrienn Geresi, Zoltan Grosz, Agnes Palasti, Judit Boczan, Peter Klivenyi, Maria Judit Molnar.
      Mitochondria-associated paraplegin dysfunction is primarily linked to spastic paraplegia; however, genetic alterations in SPG7 have been associated with a broader spectrum of clinical symptoms. To identify disease-causing variants in the SPG7 gene, 437 patients with spastic ataxia, mitochondrial dysfunction-associated symptoms, or motoneuron lesions detected by EMG have been tested. We aimed to assess the clinical spectrum and determine the frequency of damaging variants within patient groups, particularly those less studied. Using ACMG criteria, we identified 10 pathogenic or likely pathogenic variants, 5 variants of uncertain significance with predicted damaging effects, and a probable risk factor variant in 58 patients. We identified 25 biallelic and 33 monoallelic cases. The most common variant was p. Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). The point prevalence of SPG7-associated conditions in Hungary in 2024 is 0.46 per 100 000. In addition to well-characterized cohorts, SPG7 alterations were frequently identified in cohorts with multisystemic mitochondrial disease and lower motoneuron lesions. Multiple mtDNA deletions and histological abnormalities were consistently observed across all groups. In monoallelic cases, no evidence of a digenic effect involving AFG3L2 was found. Both autosomal dominant and recessive inheritance patterns were documented, with monoallelic cases typically presenting with a milder phenotype.
    Keywords:  SPG7; carrier risks; epidemiology; inheritance; mitochondrial disease; paraplegin; phenotypic spectra
    DOI:  https://doi.org/10.1111/cge.14719
  51. bioRxiv. 2025 Feb 01. pii: 2025.01.31.635900. [Epub ahead of print]
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin- and receptor- mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1101/2025.01.31.635900
  52. Neurology. 2024 Apr 09. 102(7_supplement_1): 6306
    Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database (P3-11.017).
    Emanuele Barca, Adam Kroopnick, Alexander Houck, Kiran Thakur, Rachelle Dugue, Zarazuela Zolkipli-Cunningham, Marni Falk, Amy Goldstein, Matthew Demczko, Ralitza Gavrilova, Austin Larson, Johan Van Hove, Russell Saneto, Richard Buchsbaum, John Thompson, Michio Hirano.
       OBJECTIVE: This analysis of Adult-Onset Leigh Syndrome (LS) patients from the North American Mitochondrial Disease Consortium (NAMDC) Registry aims to enhance clinical insights, improve diagnoses, and uncover potential modifiers.
    BACKGROUND: LS is a rare syndrome linked to defects in more than one hundred genes. Most LS patients develop subacute neurological deterioration or regression before age two years. The pathological and radiological hallmarks are the subacute necrotizing degeneration of basal ganglia, cerebellum, brainstem, and/or cervical spinal cord, frequently triggered by metabolic stress. A small group of patients develop central nervous system involvement later in life.
    DESIGN/METHODS: This retrospective study stemmed from a case of a twenty-five-year-old man with mild developmental delay and sensory-motor neuropathy admitted for worsening weakness. During his hospital stay, he developed a rapidly progressive encephalopathy and classic LS radiological findings. Intrigued by this observation, we interrogated the NAMDC registry to retrieve data from other adult-onset LS individuals. The registry contains demographic, manifestation, genetic, imaging, and biochemistry data from more than 2100 subjects enrolled from 17 centers in North America and Canada.
    RESULTS: We identified six subjects with onset of CNS manifestations after age 18. Most of the subjects had been involved of other organ systems preceding the CNS lesions. Four probands had pathogenic variants in nuclear-encoded mitochondria metabolism genes, one in mitochondrial DNA-encoded ATP synthase subunit gene, and one patient remained genetically undefined. The disease progression varied among the cohort, with probands harboring nuclear variants experiencing a slower course compared to the individual with a mitochondrial DNA defect, who suffered a rapid, progressive, and fatal deterioration.
    CONCLUSIONS: Our data show that mitochondrial patients with LS experience evolving and progressive phenotypes, and the presence of manifestations in other organs often precedes LS in adults, suggesting that clinicians should carefully avoid metabolic stressors known to precipitate neurodegeneration in subjects with the observed genetic variants. Disclosure: Dr. Barca has nothing to disclose. Dr. Kroopnick has nothing to disclose. Dr. Houck has nothing to disclose. Dr. Thakur has received personal compensation for serving as an employee of World Health Organization. Dr. Thakur has received personal compensation for serving as an employee of Pan American Health Organization. Dr. Thakur has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Delve Bio. The institution of Dr. Thakur has received research support from Center for Disease Control and Prevention. The institution of Dr. Thakur has received research support from National Institute of Health. Dr. Dugue has nothing to disclose. Dr. Zolkipli-Cunningham has nothing to disclose. An immediate family member of Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lumiere. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mission Therapeutics. Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Primera Therapeutics. Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Imel Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MiMo Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GenoMind. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casma Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mayflower, Inc.. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precision Biosciences. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Foresite Labs. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stealth BioTherapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Taysha Gene Therapies. Marni Falk has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Larimar Therapeutics. Marni Falk has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Khondrion. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for United MItochondrial Disease Foundation. Marni Falk has stock in Rarefy Therapeutics. Marni Falk has stock in RiboNova Inc. The institution of Marni Falk has received research support from Merck. The institution of Marni Falk has received research support from Saol Therapeutics. The institution of Marni Falk has received research support from Stealth Biotherapeutics. The institution of Marni Falk has received research support from Astellas. The institution of Marni Falk has received research support from UMDF. The institution of Marni Falk has received research support from CureARS Foundation. The institution of Marni Falk has received research support from Mission Therapeutics. The institution of Marni Falk has received research support from Cyclerion. The institution of Marni Falk has received research support from NIH. The institution of Marni Falk has received research support from DOD. The institution of Marni Falk has received research support from FDA. Marni Falk has received intellectual property interests from a discovery or technology relating to health care. Marni Falk has received publishing royalties from a publication relating to health care. Dr. Goldstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reneo Pharmaceuticals . Dr. Demczko has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Manuals. Dr. Gavrilova has nothing to disclose. Austin Larson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Illumina. An immediate family member of Austin Larson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. An immediate family member of Austin Larson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Austin Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for Tisento. Austin Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for UCB. The institution of Austin Larson has received research support from Stealth Biotherapeutics. The institution of Austin Larson has received research support from Astellas. The institution of Austin Larson has received research support from Entrada. The institution of Austin Larson has received research support from Neuren. The institution of an immediate family member of Austin Larson has received research support from Neurocrine. Johan Van Hove has received intellectual property interests from a discovery or technology relating to health care. Dr. Saneto has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for REATA. Dr. Saneto has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GW Pharmaceuticals. The institution of Dr. Saneto has received research support from NIH. The institution of Dr. Saneto has received research support from Zogenix. The institution of Dr. Saneto has received research support from GW Pharmaceuticals. The institution of Dr. Thompson has received research support from NIH. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Modis Therapeutics (a subsidiary of Zogenix). Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epirium Bio. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Innovation Specialist. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Platform Q Health. The institution of Dr. Hirano has received research support from Modis Therapeutics (a subsidiary of Zogenix). The institution of Dr. Hirano has received research support from Cyclerion. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received personal compensation in the range of $0-$499 for serving as a Study Section Reviewer with NIH. Dr. Hirano has a non-compensated relationship as a Research Advisory Board member with Muscular Dystrophy Association that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific and Medical Advisory Board member with United Mitochondrial Disease Foundation that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific Advisory Board member with Barth Syndrome Foundation that is relevant to AAN interests or activities.
    DOI:  https://doi.org/10.1212/WNL.0000000000206383
  53. J Hepatol. 2025 Feb 18. pii: S0168-8278(25)00083-2. [Epub ahead of print]
    Developing splice-switching oligonucleotides for urea cycle disorder using an integrated diagnostic and therapeutic platform.
    Jin Rong Ow, Eri Imagawa, Feng Chen, Wei Yuan Cher, Shermin Yu Tung Chan, Rajasekhar Reddy Gurrampati, Venkataramanan Ramadass, Mun Fai Loke, Tommaso Tabaglio, Hikaru Nishida, Toshiki Tsunogai, Masahide Yazaki, Gaik Siew Ch'ng, Manikandan Lakshmanan, Su Seong Lee, Jackie Yi-Ru Ying, Ernesto Guccione, Kimihiko Oishi, Keng Boon Wee.
       BACKGROUNDS & AIMS: Citrin deficiency (CD) is an autosomal recessive urea cycle disorder caused by biallelic loss-of-function variants in the SLC25A13 gene, leading to life-threatening hyperammonemia and hypoglycemia. Variants in deep introns can cause genetic diseases by altering splicing and are often missed by current diagnostic tools. Splice-switching oligonucleotides (SSOs) can resolve certain intronic variants, but patients harboring such variants need to be identified. We present a lean workflow from molecular diagnostics to SSO development to resolve splice-altering variants in deep introns that is applicable to other genetic disorders.
    METHODS: A deep intronic gene panel was designed to identify deep intronic variants. SSOs were then developed and validated in vitro using minigene assay and induced hepatocytes, and target engagement was verified in vivo by hydrodynamic tail vein injection of minigenes and SSOs.
    RESULTS: With the Deep Intronic-Gene Panel and RNA analysis, we identified a novel SLC25A13 c.469-2922G>T variant that promotes the inclusion of a premature stop codon-containing pseudo-exon, SLC25A13-PE5, thereby causing CD. By a stepwise rational SSO design approach, we identified potent candidates inhibiting SLC25A13-PE5 at EC50 <2nM in vitro. Upon conjugating the SSOs with N-acetylgalactosamine (GalNAc), they were validated to rescue normal protein expression and restore ureagenesis and ammonia clearance, key urea cycle functions, in patient-derived induced hepatocytes. In vivo on-target efficacy of the clinical GalNAc-SSO candidate, in the absence of acute toxicity and inflammation, was observed in a mouse model with exogenous hepatic minigene expression.
    CONCLUSIONS: Our data validates a platform to redefine molecular diagnosis of urea cycle disorders and provides a proof-of-concept for precision therapy of CD patients whose only effective treatment is liver transplantation.
    IMPACT & IMPLICATIONS: Deep intronic variants are common causes of genetic diseases that are commonly neglected. In this study, we demonstrate an integrated precision diagnostic and therapeutic approach for UCD. Specifically, we focus on CD, going from the discovery of a novel splice variant in the SLC25A13 gene with our novel UCD Deep Intronic-Gene Panel, to the development and in vivo validation of an efficacious SSO candidate for the pathogenic splice variant. We envision the possibility of extrapolating this pipeline to the diagnosis and development of treatments for other rare genetic diseases.
    Keywords:  RNA therapeutics pipeline; antisense oligonucleotide; citrin deficiency; citrullinemia; hyperammonemia; inborn errors of metabolism; pseudo-exon
    DOI:  https://doi.org/10.1016/j.jhep.2025.02.007
  54. Case Rep Ophthalmol. 2024 Jan-Dec;15(1):15(1): 852-858
    Leber Hereditary Optic Neuropathy "Plus" with the m.14487 T>C Mutation as the Causality of Hemidystonia: A Case Report.
    Fumio Takano, Kaori Ueda, Norio Chihara, Mina Arai, Mari Sakamoto, Takuji Kurimoto, Yuko Yamada-Nakanishi, Makoto Nakamura.
       Introduction: Leber hereditary optic neuropathy (LHON) complicated with extraocular symptoms is called LHON plus. We describe a case of LHON plus with a rare mutation, which also caused dystonia.
    Case Presentation: An 18-year-old male patient developed symptoms of dystonia at the age of 15 years. Two years later, he noticed decreased visual acuity and central scotoma in the left eye. One month later, the same symptoms occurred in the right eye. Although the optic discs in both eyes revealed mildly redness and edematous change, no abnormal findings were detected on fluorescence fundus angiography and orbital magnetic resonance imaging. Mitochondrial deoxyribonucleic acid (mtDNA) sequencing detected the m.14487 T>C mutation. From clinical course and fundus findings, the case was diagnosed LHON. The optic nerve gradually atrophied and central scotoma remained.
    Conclusion: The m.14487 T>C mutation is one of the causative mutations in patients with dystonia or Leigh encephalopathy and a minor mutation in patients with LHON. However, in the present case, ocular symptoms were more severe than systematic symptoms and the disease course was consistent with LHON. For the above reasons, this case can be diagnosed as LHON plus. Whole mtDNA sequencing is important in diagnosing LHON if none of the three major mutations are detected.
    Keywords:  Dystonia; Leber hereditary optic neuropathy plus; Rare mitochondrial point mutation
    DOI:  https://doi.org/10.1159/000542202
  55. Sci Adv. 2025 Feb 21. 11(8): eadr3723
    TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
    Pradeep K Sheokand, Andrew M James, Benjamin Jenkins, Pawel K Lysyganicz, Denis Lacabanne, Martin S King, Edmund R S Kunji, Symeon Siniossoglou, Albert Koulman, Michael P Murphy, Kasparas Petkevicius.
      The diversity of cellular phospholipids, crucial for membrane homeostasis and function, arises from enzymatic remodeling of their fatty acyl chains. In this work, we reveal that poorly understood TRAM-LAG1-CLN8 domain (TLCD)-containing proteins are phospholipid remodeling enzymes. We demonstrate that TLCD1 is an evolutionarily conserved lysophosphatidylethanolamine acyltransferase, which regulates cellular phospholipid composition and generates previously undescribed fatty acid and thiamine (vitamin B1) esters as its secondary products. Furthermore, we establish that human TLCD protein CLN8, mutations of which cause fatal neurodegenerative Batten disease, is a lysophosphatidylglycerol acyltransferase. We show that CLN8 catalyzes the essential step in the biosynthesis of bis(monoacylglycero)phosphate, a phospholipid critical for lysosome function. Our study unveils a family of acyltransferases integral to cellular membrane phospholipid homeostasis and human disease.
    DOI:  https://doi.org/10.1126/sciadv.adr3723
  56. Nature. 2025 Feb 19.
    Biggest-ever AI biology model writes DNA on demand.
    Ewen Callaway.
      
    Keywords:  Genomics; Machine learning
    DOI:  https://doi.org/10.1038/d41586-025-00531-3
  57. medRxiv. 2025 Feb 03. pii: 2025.01.30.25321437. [Epub ahead of print]
    Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans.
    Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.
      FGF21 is a metabolic hormone induced by fasting, metabolic stress, and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% ( p <0.0001) in healthy controls but increases FGF21 by 32% ( p <0.0001) in people with MitoD-pointing to a functional interaction between the stress response and OxPhos capacity in regulating FGF21. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report novel associations between FGF21 and psychosocial factors related to stress and wellbeing, highlighting a potential role for FGF21 in meeting the energetic needs of acute and chronic psychosocial stress.
    DOI:  https://doi.org/10.1101/2025.01.30.25321437
  58. Nat Commun. 2025 Feb 15. 16(1): 1661
    FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice.
    Ke Zhang, Jing Gan, Baile Wang, Wei Lei, Dong Zhen, Jie Yang, Ningrui Wang, Congcong Wen, Xiaotang Gao, Xiaokun Li, Aimin Xu, Xinguang Liu, Yulin Li, Fan Wu, Zhuofeng Lin.
      Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21's role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated with cardiac diastolic function in patients with HFpEF. Global or adipose FGF21 deficiency exacerbates cardiac diastolic dysfunction and damage in high-fat diet (HFD) plus N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects are notably reversed by FGF21 replenishment. Mechanistically, FGF21 enhances the production of adiponectin (APN), which in turn indirectly acts on cardiomyocytes, or FGF21 directly targets cardiomyocytes, to negatively regulate pyruvate dehydrogenase kinase 4 (PDK4) production by activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates FGF21's protective effects against HFpEF, while genetic PDK4 inactivation markedly mitigates HFpEF in mice. Thus, FGF21 protects against HFpEF via fine-tuning the multiorgan crosstalk among the adipose, liver, and heart.
    DOI:  https://doi.org/10.1038/s41467-025-56885-9
  59. FASEB J. 2025 Feb 28. 39(4): e70391
    DHFR2 RNA directly regulates dihydrofolate reductase and its expression level impacts folate one carbon metabolism.
    Paola Drago, Niamh Bookey, Kit-Yi Leung, Michael Henry, Paula Meleady, Nicholas D E Greene, Anne Parle-McDermott.
      Dihydrofolate reductase activity is required in One Carbon Metabolism to ensure that the biologically active form of folate, tetrahydrofolate, is replenished and available as an enzyme cofactor for numerous cellular reactions, including purine and pyrimidine synthesis. Most cellular enzyme activity was thought to arise from the product of the DHFR gene on chromosome 5, with its paralogue DHFR2 (formerly known as DHFRL1; [chromosome 3]), believed to be responsible for mitochondrial dihydrofolate activity based on recombinant versions of the enzyme. In this paper, we confirm our earlier findings that dihydrofolate reductase activity in mitochondria is derived from the DHFR gene rather than DHFR2 and that endogenous DHFR2 protein is not detectable in most cells and tissues. Using HepG2 cell lines with modulated expression of either DHFR or DHFR2, we observed an impact of DHFR2 RNA on One Carbon Metabolism mediated through an influence on DHFR expression and activity. Knockout of DHFR2 results in a drop in dihydrofolate reductase activity, lowered 10-formyltetrahydrofolate abundance, downregulation of DHFR mRNA, and diminished DHFR protein abundance. We also observed downregulation of Serine Hydroxymethyltransferase and Thymidylate Synthase, two One Carbon Metabolism enzymes that work with DHFR to support de novo thymidylate synthesis. The expression of recombinant DHFR2 resulted in restoration of DHFR mRNA and protein levels while a DHFR knockdown cell line showed upregulation of DHFR2 RNA. We propose that the DHFR2 gene encodes an RNA molecule that regulates cellular dihydrofolate reductase activity through its impact on DHFR mRNA and protein.
    Keywords:  DHFR; DHFR2; lncRNA; regulation; thymidylate
    DOI:  https://doi.org/10.1096/fj.202401039RR
  60. Cell Prolif. 2025 Feb 21. e70002
    Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria-Associated ER Membrane.
    Miao Yu, Min Song, Manna Zhang, Shuangshuang Chen, Baoqiang Ni, Xuechun Li, Wei Lei, Zhenya Shen, Yong Fan, Jianyi Zhang, Shijun Hu.
      m.3243A>G is the most common pathogenic mtDNA mutation. High energy-demanding organs, such as heart, are usually involved in mitochondria diseases. However, whether and how m.3243A>G affects cardiomyocytes remain unknown. We have established patient-specific iPSCs carrying m.3243A>G and induced cardiac differentiation. Cardiomyocytes with high m.3243A>G burden exhibited hypertrophic phenotype. This point mutation is localised in MT-TL1 encoding tRNALeu (UUR). m.3243A>G altered tRNALeu (UUR) conformation and decreased its stability. mtDNA is essential for mitochondrial function. Mitochondria dysfunction occurred and tended to become round. Its interaction with ER, mitochondria-associated ER membrane (MAM), was disrupted with decreased contact number and length. MAM is a central hub for calcium trafficking. Disrupted MAM disturbed calcium homeostasis, which may be the direct and leading cause of cardiomyocyte hypertrophy, as MAM enforcement reversed this pathological state. Considering the threshold effect of mitochondrial disease, mito-TALENs were introduced to eliminate mutant mitochondria and release mutation load. Mutation reduction partially reversed the cellular behaviour and made it approach to that of control one. These findings reveal the pathogenesis underlying m.3243A>G from perspective of organelle interaction, rather than organelle. Beyond mitochondria quality control, its proper interaction with other organelles, such as ER, matters for mitochondria disease. This study may provide inspiration for mitochondria disease intervention.
    Keywords:  cardiomyocyte hypertrophy; induced pluripotent stem cell; mitochondrial mutation; mitochondria‐associated ER membrane
    DOI:  https://doi.org/10.1111/cpr.70002
  61. J Neuromuscul Dis. 2024 Nov;11(6): 1295-1299
    MICU1 related myopathy - a rare report from India.
    Dipti Baskar, Suma Reddy Ganji, Aneesha Thomas, Kiran Polavarapu, Bevinahalli N Nandeesh, Sai Bhargava Sanka, Kosha Srivastava, Ananthapadmanabha Kotambail, Gautham Arunachal, Vijay Kumar Boddu, Saraswati Nashi, Atchayaram Nalini, Seena Vengalil.
      Mitochondrial Calcium Uptake 1 (MICU1) is an important component of mitochondrial calcium channel regulator. Mutations in MICU1 result in a rare syndrome of myopathy with extrapyramidal features. Here we report a rare case of MICU1 related myopathy from India. A 23 years old male presented with 10 years history of proximal muscle weakness with exertional myalgia and fatigue. Examination showed facial dysmorphism with facial weakness and mildly reduced visual acuity. Limb girdle pattern of weakness with hypoactive tendon reflexes were noted without extrapyramidal signs. He had elevated serum creatine level of 1542 IU/L. Muscle MRI had novel findings of selective fatty infiltration of hamstrings, medial gastrocnemius and soleus. Muscle biopsy showed myopathic with secondary neurogenic changes along with few COX deficient fibres. Genetic analysis showed compound heterozygous pathogenic variants in MICU1 gene at intron 9 (c.1072-1 G > C) - splice site variant and exon 5 (c.513T > A) - stop gained variant, both resulting in loss of function of the protein. The variants were segregating in unaffected parents in heterozygous state with variant c.1072-1 G > C in the unaffected father and variant c.513T > A (p. Tyr171*) in the unaffected mother confirming the diagnosis. This report highlights the phenotype of limb girdle weakness with facial dysmorphism and optic atrophy expanding the spectrum of MICU1 related syndrome with novel MRI muscle and histopathological findings.
    Keywords:  India; MICU1; myopathy
    DOI:  https://doi.org/10.1177/22143602241288400
  62. bioRxiv. 2025 Feb 08. pii: 2025.02.03.636312. [Epub ahead of print]
    Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.
    Jorgo Lika, James A Votava, Rupsa Datta, Aleksandr M Kralovec, Frances M Smith, Anna Huttenlocher, Melissa C Skala, Jing Fan.
      Neutrophils are highly abundant innate immune cells that are constantly produced from myeloid progenitors in the bone marrow. Differentiated neutrophils can perform an arsenal of effector functions critical for host defense. This study aims to quantitatively understand neutrophil mitochondrial metabolism throughout differentiation and activation, and to elucidate the impact of mitochondrial metabolism on neutrophil functions. To study metabolic remodeling throughout neutrophil differentiation, murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils were assessed as models. To study the metabolic remodeling upon neutrophil activation, differentiated ER-Hoxb8 neutrophils and primary human neutrophils were activated with various stimuli, including ionomycin, MSU crystals, and PMA. Characterization of cellular metabolism by isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy revealed dynamic changes in mitochondrial metabolism. As neutrophils mature, mitochondrial metabolism decreases drastically, energy production is fully offloaded from oxidative phosphorylation, and glucose oxidation through TCA cycle is substantially reduced. Nonetheless, mature neutrophils retain the capacity for mitochondrial metabolism. Upon stimulation with certain stimuli, TCA cycle is rapidly activated. Mitochondrial pyruvate carrier inhibitors reduce this re-activation of the TCA cycle and inhibit the release of neutrophil extracellular traps. Mitochondrial metabolism also impacts neutrophil redox status, migration, and apoptosis without significantly changing overall bioenergetics. Together, these results demonstrate that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophil function and fate. Furthermore, these findings point to the therapeutic potential of mitochondrial pyruvate carrier inhibitors in a range of conditions where dysregulated neutrophil response drives inflammation and contributes to pathology.
    DOI:  https://doi.org/10.1101/2025.02.03.636312
  63. Nature. 2025 Feb 20.
    Structural dynamics of human fatty acid synthase in the condensing cycle.
    Wooyoung Choi, Chengmin Li, Yifei Chen, Yongqiang Wang, Yifan Cheng.
      Long chain fatty acids are the building blocks of fat in human bodies. In mammals, fatty acid synthase (FASN) contains multiple enzymatic domains to catalyze all chemical reactions needed for de novo fatty acid synthesis1. While the chemical reactions carried out by these enzymatic domains are well defined, how the dimeric FASN with an open architecture continuously catalyzes such reactions to synthesize a complete fatty acid remains elusive. Here, using a strategy of tagging and purifying endogenous FASN in HEK293 for single particle cryogenic electron microscopy studies, we characterized the structural dynamics of endogenous human FASN. We captured the conformational snapshots of various functional substates in the condensing cycle and developed a procedure to analyze particle distribution landscape of FASN with different orientations between its condensing and modifying wings. Together, we reveal that FASN function does not require large rotational motion between its two major functional domains during the condensing cycle, and that the catalytic reactions in condensing cycle carried out by two monomers are unsynchronized. Our data thus provide a new composite view of FASN dynamics during the fatty acid synthesis condensing cycle.
    DOI:  https://doi.org/10.1038/s41586-025-08782-w
  64. bioRxiv. 2025 Feb 08. pii: 2025.02.07.637120. [Epub ahead of print]
    Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
    Kimberly S Huggler, Carlos A Mellado Fritz, Kyle M Flickinger, Gavin R Chang, Meghan F McGuire, Jason R Cantor.
      Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking the first committed step of glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to the outer mitochondrial membrane (OMM). CRISPR screens across hundreds of cancer cell lines indicate that both are dispensable for cell growth in traditional culture media. By contrast, HK2 deletion impairs cell growth in Human Plasma-Like Medium (HPLM). Here, we find that HK2 is required to maintain sufficient cytosolic (OMM-detached) HK activity under conditions that enhance HK1 binding to the OMM. Notably, OMM-detached rather than OMM-docked HK promotes "aerobic glycolysis" (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show that several proposed theories for this phenotype cannot explain the HK2 dependence and instead find that HK2 deletion severely impairs glycolytic ATP production with little impact on total ATP yield for cells in HPLM. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis underlies the Warburg effect.
    DOI:  https://doi.org/10.1101/2025.02.07.637120
  65. J Physiol Biochem. 2025 Feb 19.
    The link between Mitochondria and Sarcopenia.
    Nurul Tihani Kamarulzaman, Suzana Makpol.
      Sarcopenia, a widespread condition, is characterized by a variety of factors influencing its development. The causes of sarcopenia differ depending on the age of the individual. It is defined as the combination of decreased muscle mass and impaired muscle function, primarily observed in association with ageing. As people age from 20 to 80 years old, there is an approximate 30% reduction in muscle mass and a 20% decline in cross-sectional area. This decline is attributed to a decrease in the size and number of muscle fibres. The regression of muscle mass and strength increases the risk of fractures, frailty, reduced quality of life, and loss of independence. Muscle cells, fibres, and tissues shrink, resulting in diminished muscle power, volume, and strength in major muscle groups. One prominent theory of cellular ageing posits a strong positive relationship between age and oxidative damage. Heightened oxidative stress leads to early-onset sarcopenia, characterized by neuromuscular innervation breakdown, muscle atrophy, and dysfunctional mitochondrial muscles. Ageing muscles generate more reactive oxygen species (ROS), and experience decreased oxygen consumption and ATP synthesis compared to younger muscles. Additionally, changes in mitochondrial protein interactions, cristae structure, and networks may contribute to ADP insensitivity, which ultimately leads to sarcopenia. Within this framework, this review provides a comprehensive summary of our current understanding of the role of mitochondria in sarcopenia and other muscle degenerative diseases, highlighting the crucial need for further research in these areas.
    Keywords:  Mitochondria; Mitochondrial protein interactions; Muscle ageing; Oxidative stress; Sarcopenia
    DOI:  https://doi.org/10.1007/s13105-024-01062-7
  66. Nature. 2025 Feb 17.
    What are the best AI tools for research? Nature's guide.
    Elizabeth Gibney.
      
    Keywords:  Language; Machine learning; Software
    DOI:  https://doi.org/10.1038/d41586-025-00437-0
  67. Med Genet. 2025 Apr;37(1): 3-10
    Genetics and diagnostics of inherited retinal diseases in the era of whole genome sequencing.
    Heidi Stöhr, Bernhard H F Weber.
      Inherited retinal diseases are clinically and genetically highly heterogeneous conditions with many phenotypic overlaps, syndromic presentations and atypical manifestations. This article is a narrative review that offers an overview of the technical advancements improving the accuracy and efficiency of molecular genetic diagnostics for hereditary disorders in clinical practice. It focuses particularly on the integration of whole genome sequencing (WGS) into routine diagnostics, critically evaluating its potential by discussing recent data from cohort studies conducted worldwide.
    Keywords:  deep intronic variants; diagnostic yield; inherited retinal disease; structural variants; whole genome sequencing
    DOI:  https://doi.org/10.1515/medgen-2024-2049
  68. Mol Neurodegener. 2025 Feb 19. 20(1): 20
    The integrated stress response in neurodegenerative diseases.
    Maria Astrid Bravo-Jimenez, Shivangi Sharma, Soheila Karimi-Abdolrezaee.
      The integrated stress response (ISR) is a conserved network in eukaryotic cells that mediates adaptive responses to diverse stressors. The ISR pathway ensures cell survival and homeostasis by regulating protein synthesis in response to internal or external stresses. In recent years, the ISR has emerged as an important regulator of the central nervous system (CNS) development, homeostasis and pathology. Dysregulation of ISR signaling has been linked to several neurodegenerative diseases. Intriguingly, while acute ISR provide neuroprotection through the activation of cell survival mechanisms, prolonged ISR can promote neurodegeneration through protein misfolding, oxidative stress, and mitochondrial dysfunction. Understanding the molecular mechanisms and dynamics of the ISR in neurodegenerative diseases aids in the development of effective therapies. Here, we will provide a timely review on the cellular and molecular mechanisms of the ISR in neurodegenerative diseases. We will highlight the current knowledge on the dual role that ISR plays as a protective or disease worsening pathway and will discuss recent advances on the therapeutic approaches that have been developed to target ISR activity in neurodegenerative diseases.
    DOI:  https://doi.org/10.1186/s13024-025-00811-6
  69. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Feb 18. pii: S1388-1981(25)00008-3. [Epub ahead of print]1870(3): 159600
    Unveiling BCO2 function in macular pigment metabolism: Mitochondrial processing and expression in the primate retina.
    Chou Shen, Sepalika Bandara, Sanae S Imanishi, Mahip Kalra, Yoshikazu Imanishi, Johannes von Lintig.
      BCO2 (β-carotene oxygenase 2) converts carotenoids into apocarotenoids by oxidative cleavage across double bonds and controls carotenoid homeostasis in vertebrate tissues. In this study, we examined BCO2's expression, localization, and activity in human cell lines and the retina. We generated peptide antibodies directed against primate BCO2 and validated their specificity using recombinant BCO1 (β-carotene oxygenase 1) and BCO2 proteins expressed in bacteria. The antibodies specifically detected human BCO2 by Western blot. In BCO2 expressing HepG2 cells, the antibodies recognized a 65 kDa mitochondrial protein that co-migrated with a recombinant truncated 522-amino-acid BCO2 variant, suggesting post-translational processing of the 579 amino acid long human BCO2 protein. Immunohistochemical analysis of macaque retina sections revealed BCO2 localization in the retinal pigment epithelium, photoreceptor inner segments, plexiform layer, and ganglion cell layer. Co-staining with COX IV indicated a mitochondrial localization of retinal BCO2 within photoreceptor inner segments. Western blot analysis of human donor retinas, separated into central and peripheral regions, identified higher BCO2 expression in the peripheral retina. Enzymatic activity assays demonstrated that BCO2 interacted with Aster proteins that transport carotenoids within cells. Our studies establish BCO2 as a mitochondrial protein expressed in the primate retina, where it likely plays a pivotal role in the metabolism of macular pigments and the maintenance of retinal health.
    Keywords:  BCO2; Carotenoids; GRAMD1; Mitochondria; Retina
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159600
  70. Expert Rev Proteomics. 2025 Feb 20. 1-16
    Omics and rare diseases: challenges, applications, and future perspectives.
    Daniela Braconi, Haidara Nadwa, Giulia Bernardini, Annalisa Santucci.
       INTRODUCTION: Rare diseases (RDs) are a heterogeneous group of diseases recognized as a relevant global health priority but posing aspects of complexity, such as geographical scattering of affected individuals, improper/late diagnosis, limited awareness, difficult surveillance and monitoring, limited understanding of natural history, and lack of treatment. Usually, RDs have a pediatric onset and are life-long, multisystemic, and associated with a poor prognosis.
    AREAS COVERED: In this work, we review how high-throughput omics technologies such as genomics, transcriptomics, proteomics, metabolomics, epigenomics, and other well-established omics, which are increasingly more affordable and efficient, can be applied to the study of RDs promoting diagnosis, understanding of pathological mechanisms, biomarker discovery, and identification of treatments.
    EXPERT OPINION: RDs, despite their challenges, offer a niche where collaborative efforts and personalized treatment strategies might be feasible using omics technologies. Specialized consortia fostering multidisciplinary collaboration, data sharing, and the development of biobanks and registries can be built; multi-omics approaches, including so far less exploited omics technologies, along with the implementation of AI tools can be undertaken to deepen our understanding of RDs, driving biomarker discovery and clinical interventions. Nevertheless, technical, ethical, legal, and societal issues must be clearly defined and addressed.
    Keywords:  Artificial intelligence; biomarkers; epigenomics; metabolomics; next generation sequencing; precision medicine; proteomics; transcriptomics
    DOI:  https://doi.org/10.1080/14789450.2025.2468300
  71. Trends Mol Med. 2025 Feb 17. pii: S1471-4914(25)00015-2. [Epub ahead of print]
    Gene therapies for neurogenetic disorders.
    Orrin Devinsky, Jeff Coller, Rebecca Ahrens-Nicklas, X Shawn Liu, Nadav Ahituv, Beverly L Davidson, Kathie M Bishop, Yael Weiss, Ana Mingorance.
      Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.
    Keywords:  blood–brain barrier; gene regulation; gene therapy; neurological disorders
    DOI:  https://doi.org/10.1016/j.molmed.2025.01.015
  72. Front Public Health. 2025 ;13 1520467
    Quantifying hope: an EU perspective of rare disease therapeutic space and market dynamics.
    Emmanuelle Cacoub, Nathalie Barreto Lefebvre, Dimitrije Milunov, Manish Sarkar, Soham Saha.
      Rare diseases, affecting millions globally, pose a significant healthcare burden despite impacting a small population. While approximately 70% of all rare diseases are genetic and often begin in childhood, diagnosis remains slow and only 5% have approved treatments. The UN emphasizes improved access to primary care (diagnostic and potentially therapeutic) for these patients and their families. Next-generation sequencing (NGS) offers hope for earlier and more accurate diagnoses, potentially leading to preventative measures and targeted therapies. In here, we explore the therapeutic landscape for rare diseases, analyzing drugs in development and those already approved by the European Medicines Agency (EMA). We differentiate between orphan drugs with market exclusivity and repurposed existing drugs, both crucial for patients. By analyzing market size, segmentation, and publicly available data, this comprehensive study aims to pave the way for improved understanding of the treatment landscape and a wider knowledge accessibility for rare disease patients.
    Keywords:  European Medicines Agency; biotech; drug repurposing; market share; orphan drug designations; pharmaceuticals; rare diseases; revenue model
    DOI:  https://doi.org/10.3389/fpubh.2025.1520467
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒23 at 11:10.