bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–04–13
47 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
  2. Metabolite tunes MDV pathway to maintain mitochondrial fitness.
  3. The Volume of Mitochondria Inherited Impacts mtDNA Homeostasis in Budding Yeast.
  4. Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.
  5. TMEM65 joins the mitochondrial Ca2+ club.
  6. Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant.
  7. Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
  8. A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
  9. Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
  10. Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.
  11. Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
  12. CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
  13. Small molecules restore mutant mitochondrial DNA polymerase activity.
  14. Mitochondria and cell death signalling.
  15. HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
  16. Cells are swapping their mitochondria. What does this mean for our health?
  17. RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.
  18. Adult-Onset Bilateral Optic Neuropathy in a Patient with Non-Familial Childhood-Onset Generalized Dystonia Associated with Mitochondrial DNA 14459G>A Mutation: A Case Report and Review of Literature.
  19. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  20. Mitochondrial damage is associated with an early immune response in inclusion body myositis.
  21. Spermidine toxicity in Saccharomyces cerevisiae due to mitochondrial complex III deficiency.
  22. Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model.
  23. The Structure of the Drp1 Lattice on Membrane.
  24. MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.
  25. Pulmonary mitochondrial DNA release and activation of the cGAS-STING pathway in Lethal Stx12 knockout mice.
  26. TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
  27. Integrated proteome and lipidome analyses place OCIAD1 at mitochondria-peroxisome intersection balancing lipid metabolism.
  28. DRP1, fission and apoptosis.
  29. Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
  30. Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
  31. The molecular landscape of hereditary ataxia: a single-center study.
  32. Fatty acid binding proteins-mediated mitochondrial dysfunction in the development of age-related diseases: A review.
  33. A photostable luminescent iridium(III) complex probe for imaging endogenous mitochondrial sulfur dioxide in living cells.
  34. The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
  35. Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.
  36. Regulation of MCCC1 expression by a Parkinson's disease-associated intronic variant: implications for pathogenesis.
  37. Preliminary investigation on the economic cost of mitochondrial disease in Chinese children.
  38. Single Large-Scale Mitochondrial Deletion Syndromes: Neuroimaging Phenotypes and Longitudinal Progression in Pediatric Patients.
  39. iPSC-Derived Liver Organoids as a Tool to Study Medium Chain Acyl-CoA Dehydrogenase Deficiency.
  40. Genomic medicine and personalized treatment: a narrative review.
  41. Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes.
  42. The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
  43. RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency.
  44. Protocol for dual metabolomics and proteomics using nanoflow liquid chromatography-tandem mass spectrometry.
  45. Early Life Stress Induces Brain Mitochondrial Dynamics Changes and Sex-Specific Adverse Effects in Adulthood.
  46. Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue.
  47. Insulin acts on astrocytes to shift their substrate preference to fatty acids.
  1. Sci Adv. 2025 Apr 11. 11(15): eadu5091
    ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
    Michael J McKenna, Felix Kraus, João P L Coelho, Muskaan Vasandani, Jiuchun Zhang, Benjamin M Adams, Joao A Paulo, J Wade Harper, Sichen Shao.
      Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incompletely understood. Here, we show that ARMC1 partitioning between distinct mitochondrial protein complexes is a key determinant of mitochondrial distribution. In one complex, the mitochondrial trafficking adaptor MIRO recruits ARMC1, which mediates the assembly of a mitochondrial fission regulator (MTFR). MTFR stability depends on ARMC1, and MIRO-MTFR complexes specifically antagonize retrograde mitochondrial movement. In another complex, DNAJC11 facilitates ARMC1 release from mitochondria. Disrupting MIRO-MTFR assembly fails to rescue aberrant mitochondrial distributions clustered in the perinuclear area observed with ARMC1 deletion, while disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, the abundance and trafficking impact of MIRO-MTFR complexes require ARMC1, whose mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.
    DOI:  https://doi.org/10.1126/sciadv.adu5091
  2. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00189-3. [Epub ahead of print]85(7): 1253-1255
    Metabolite tunes MDV pathway to maintain mitochondrial fitness.
    Shiori Sekine, Yusuke Sekine.
      In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.027
  3. bioRxiv. 2025 Mar 26. pii: 2025.03.25.645216. [Epub ahead of print]
    The Volume of Mitochondria Inherited Impacts mtDNA Homeostasis in Budding Yeast.
    Michael W Ray, WeiTing Chen, Chengzhe Duan, Guadalupe Bravo, Kyle Krueger, Erica M Rosario, Alexis A Jacob, Laura L Lackner.
      Most eukaryotic cells maintain mitochondria in well-distributed, reticular networks. The size of the mitochondrial network and copy number of its genome scale with cell size. However, while the size scaling features of mitochondria and their genome are interrelated, the fitness consequences of this interdependence are not well understood. We exploit the asymmetric cell division of budding yeast to test the hypothesis that mitochondrial scaling with cell size impacts mitochondrial DNA (mtDNA) function. We find that the volume of mitochondria inherited by daughter cells affects the ability of cells to maintain functional mtDNA; daughter cells that inherit a significantly reduced volume of mitochondria have an increased frequency of losing respiratory competence. In cells with such mitochondrial inheritance defects, mtDNA integrity can be maintained by upregulating mtDNA copy number. Collectively, these data support a bet-hedging model whereby the faithful inheritance of an adequate volume of mitochondria ensures enough mtDNA copies are transmitted to daughter cells to counteract pre-existing and/or inevitable mtDNA mutations.
    Summary: Ray et al. demonstrate that the volume of mitochondria inherited impacts mtDNA homeostasis in the model system budding yeast. They propose a model by which inheritance of an adequate mitochondrial volume results in the transmission of sufficient mtDNA copies to counteract existing and/or inevitable mutations.
    DOI:  https://doi.org/10.1101/2025.03.25.645216
  4. bioRxiv. 2025 Mar 27. pii: 2025.03.27.645657. [Epub ahead of print]
    Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.
    Jimmy Ly, Yi Fei Tao, Matteo Di Bernardo, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.
      Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile the localization of protein isoforms generated by alternate start codon selection during translation. We identify hundreds of pairs of differentially-localized protein isoforms, many of which affect mitochondrial targeting and are essential for mitochondrial function. The emergence of dual-localized mitochondrial protein isoforms coincides with mitochondrial acquisition during early eukaryotic evolution. We further reveal that eukaryotes use diverse mechanisms-such as leaky ribosome scanning, alternative transcription, and paralog duplication-to maintain the production of dual-localized isoforms. Finally, we identify multiple isoforms that are specifically dysregulated by rare disease patient mutations and demonstrate how these mutations can help explain unique clinical presentations. Together, our findings illuminate the evolutionary and pathological relevance of alternative translation initiation, offering new insights into the molecular underpinnings of mitochondrial biology.
    DOI:  https://doi.org/10.1101/2025.03.27.645657
  5. Nat Metab. 2025 Apr 08.
    TMEM65 joins the mitochondrial Ca2+ club.
    Yasemin Sancak.
      
    DOI:  https://doi.org/10.1038/s42255-025-01271-4
  6. Oxf Med Case Reports. 2025 Apr;2025(4): omae166
    Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant.
    Salim Haddad, Elie Salloum, Abdullah Silan, Gazel Kalecioğlu, Maria Abdulnour, Sultaneh Haddad, Diana Alasmar, Mahmoud Alayash, Ahmed Noman Ghaleb.
      Mutations in the NDUFV1 gene are associated with mitochondrial complex I deficiency and have been linked to various clinical conditions such as Leigh syndrome, severe infantile lactic acidosis, newborn cardiomyopathy, progressive leukoencephalopathy, and other encephalomyopathies. Genetic alterations revealed mitochondrial complex 1 deficiency, nuclear type 4 |AR: two compound heterozygous missense mutations in the NDUFV1 gene, c.640G < A (p.E214K) chr11:67377981 (Exon 1) and c.248C < T (p.S83L) chr11:67376115 (Exon 3) gene. Our case identifies a previously unknown pathogenic effect of the variant 'c.248C > T' in the NDUFV1 gene, observed in a 4-year-old boy with left-sided facial paralysis and balance impairment. While this discovery is significant, further exploration of NDUFV1 gene variants is essential for a comprehensive understanding and effective treatment strategies.
    Keywords:  NDUFV1 mutation; mitochondrial complex I deficiency; mitochondrial diseases; white matter
    DOI:  https://doi.org/10.1093/omcr/omae166
  7. FASEB J. 2025 Apr 15. 39(7): e70497
    Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
    Elin L Strachan, Eugene T Dillon, Mairéad Sullivan, Jeffrey C Glennon, Amandine Peyrel, Jérôme Sarniguet, Kevin Dubois, Benjamin Delprat, Breandán N Kennedy, Niamh C O'Sullivan.
      Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
    Keywords:   Drosophila ; mitochondria; optic atrophy; visual impairment; zebrafish
    DOI:  https://doi.org/10.1096/fj.202403271R
  8. EMBO Mol Med. 2025 Apr 09.
    A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
    Abi S Ghifari, Martin Ott.
      
    DOI:  https://doi.org/10.1038/s44321-025-00232-4
  9. Hum Mol Genet. 2025 Apr 11. pii: ddaf047. [Epub ahead of print]
    Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
    Benjamin Munro, Declan Hines, Juliane S Mueller, Rita Horvath.
      Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are rare, clinically heterogeneous mitochondrial disorders resulting from nuclear variants in genes of the mitochondrial DNA replication or maintenance machinery. Supplementation with pyrimidine deoxynucleosides have been beneficial in patients and mice with TK2-related MDDS, however, it has not been systematically explored in other forms of MDDS. To investigate the effect of deoxynucleoside supplementation in mitigating the disease in mitochondrial DNA depletion due to pathogenic RRM2B variants, we generated a novel zebrafish knock-out model of this disease and studied the effect of different combinations of deoxynucleosides. Zebrafish larvae carrying a homozygous nonsense mutation in rrm2b present with impaired movement, reduced mtDNA copy number and elevated lactate. Supplementation with different combination of deoxynucleosides was performed, resulting in increased mtDNA copy numbers when supplemented with the two purine deoxynucleosides (dGuo and dAdo), while other combinations had no effect or even further compromised mtDNA copy number in zebrafish. In parallel with increased mtDNA copy number, we detected improved movement and reduction of lactate in the rrm2b-/- fish, confirming the beneficial effect of deoxynucleosides on the whole organism. This treatment did not result in any deleterious effect in wild type and heterozygous fish. Our data suggest that supplementation with deoxynucleosides may be beneficial and should be further investigated in RRM2B-related disease, adding to the growing evidence that it is a valid therapeutic approach which can be trialled for treating a wider range of genetic forms of MDDS.
    Keywords:  Deoxynucleoside supplementation; MDDS; Mitochondrial DNA depletion syndromes; RRM2B; zebrafish
    DOI:  https://doi.org/10.1093/hmg/ddaf047
  10. Cells. 2025 Mar 22. pii: 480. [Epub ahead of print]14(7):
    Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.
    Çağla Çakmak Durmaz, Felix Langerscheidt, Imra Mantey, Xinyu Xia, Hans Zempel.
      Impaired function of Polymerase-γ (Pol-γ) results in impaired replication of the mitochondrial genome (mtDNA). Pathogenic mutations in the POLG gene cause dysfunctional Pol-γ and dysfunctional mitochondria and are associated with a spectrum of neurogenetic disorders referred to as POLG spectrum disorders (POLG-SDs), which are characterized by neurologic dysfunction and premature death. Pathomechanistic studies and human cell models of these diseases are scarce. SH-SY5Y cells (SHC) are an easy-to-handle and low-cost human-derived neuronal cell model commonly used in neuroscientific research. Here, we aimed to study the effect of reduced Pol-γ function using stable lentivirus-based shRNA-mediated knockdown of POLG in SHC, in both the proliferating cells and SHC-derived neurons. POLG knockdown resulted in approximately 50% reductions in POLG mRNA and protein levels in naïve SHC, mimicking the residual Pol-γ activity observed in patients with common pathogenic POLG mutations. Knockdown cells exhibited decreased mtDNA content, reduced levels of mitochondrial-encoded proteins, and altered mitochondrial morphology and distribution. Notably, while chemical induction of mtDNA depletion via ddC could be rescued by the mitochondrial biosynthesis stimulators AICAR, cilostazol and resveratrol (but not MitoQ and formoterol) in control cells, POLG-knockdown cells were resistant to mitochondrial biosynthesis-mediated induction of mtDNA increase, highlighting the specificity of the model, and pathomechanistically hinting towards inefficiency of mitochondrial stimulation without sufficient Pol-γ activity. In differentiated SHC-derived human neurons, POLG-knockdown cells showed impaired neuronal differentiation capacity, disrupted cytoskeletal organization, and abnormal perinuclear clustering of mitochondria. In sum, our model not only recapitulates key features of POLG-SDs such as impaired mtDNA content, which cannot be rescued by mitochondrial biosynthesis stimulation, but also reduced ATP production, perinuclear clustering of mitochondria and impaired neuronal differentiation. It also offers a simple, cost-effective and human (and, as such, disease-relevant) platform for investigating disease mechanisms, one with screening potential for therapeutic approaches for POLG-related mitochondrial dysfunction in human neurons.
    Keywords:  Polymerase-γ; SH-SY5Y; mitochondria; mtDNA; neurogenetics; neuronal differentiation
    DOI:  https://doi.org/10.3390/cells14070480
  11. EMBO Mol Med. 2025 Apr 09.
    Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
    Pavel A Nash, Keira M Turner, Christopher A Powell, Lindsey Van Haute, Pedro Silva-Pinheiro, Felix Bubeck, Ellen Wiedtke, Eloïse Marques, Dylan G Ryan, Dirk Grimm, Payam A Gammage, Michal Minczuk.
      Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments.
    Keywords:  Adeno-Associated Viruses (AAV); Gene Therapy; Skeletal Muscle; Zinc Finger Nuclease (mtZFN); mtDNA Heteroplasmy Modification
    DOI:  https://doi.org/10.1038/s44321-025-00231-5
  12. J Inherit Metab Dis. 2025 May;48(3): e70025
    CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    D Mróz, J Jagłowska, R A Wevers, S Ziętkiewicz.
      
    Keywords:  3‐methylglutaconic aciduria; CLPB; congenital neutropenia; disaggregase; mitochondrial chaperonopathy
    DOI:  https://doi.org/10.1002/jimd.70025
  13. Nature. 2025 Apr 09.
    Small molecules restore mutant mitochondrial DNA polymerase activity.
    Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.
      Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.
    DOI:  https://doi.org/10.1038/s41586-025-08856-9
  14. Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510
    Mitochondria and cell death signalling.
    Ella Hall-Younger, Stephen Wg Tait.
      Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102510
  15. J Biol Chem. 2025 Apr 08. pii: S0021-9258(25)00343-6. [Epub ahead of print] 108494
    HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
    Jane-Jane Chen.
      Most iron in humans is bound in heme used as a prosthetic group for hemoglobin. Heme-regulated inhibitor (HRI) is responsible for coordinating heme availability and protein synthesis. Originally characterized in rabbit reticulocyte lysates, HRI was shown in 1976 to phosphorylate the α-subunit of eIF2, revealing a new molecular mechanism for regulating protein synthesis. Since then, HRI research has mostly been focused on the biochemistry of heme inhibition through direct binding, and heme sensing in balancing heme and globin synthesis to prevent proteotoxicity in erythroid cells. Beyond inhibiting translation of highly translated mRNAs, eIF2α phosphorylation also selectively increases translation of certain poorly translated mRNAs, notably ATF4 mRNA, for reprogramming of gene expression to mitigate stress, known as the integrated stress response (ISR). In recent years, there have been novel mechanistic insights of HRI-ISR in oxidative stress, mitochondrial function and erythroid differentiation during heme deficiency. Furthermore, HRI-ISR is activated upon mitochondrial stress in several cell types, establishing the bifunctional nature of HRI protein. The role of HRI and ISR in cancer development and vulnerability is also emerging. Excitingly, the UBR4 ubiquitin ligase complex has been demonstrated to silence the HRI-ISR by degradation of activated HRI proteins, suggesting additional regulatory processes. Together, these recent advancements indicate that the HRI-ISR mechanistic axis is a target for new therapies for hematological and mitochondrial diseases, as well as oncology. This review covers the historical overview of HRI biology, the biochemical mechanisms of regulating HRI, and the biological impacts of the HRI-ISR pathway in human diseases.
    Keywords:  ATF4; E3 ubiquitin ligase; Erythropoiesis; Heme; Mitochondrial stress; Protein kinase; Protein synthesis; Proteostasis; Stress response; eIF2
    DOI:  https://doi.org/10.1016/j.jbc.2025.108494
  16. Nature. 2025 Apr;640(8058): 302-304
    Cells are swapping their mitochondria. What does this mean for our health?
    Gemma Conroy.
      
    Keywords:  Cancer; Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-01064-5
  17. Nat Commun. 2025 Apr 07. 16(1): 3292
    RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.
    Leïla Dumas, Sauyeun Shin, Quentin Rigaud, Marie Cargnello, Beatriz Hernández-Suárez, Pauline Herviou, Nathalie Saint-Laurent, Marjorie Leduc, Morgane Le Gall, David Monchaud, Erik Dassi, Anne Cammas, Stefania Millevoi.
      Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.
    DOI:  https://doi.org/10.1038/s41467-025-58118-5
  18. Neuroophthalmology. 2025 ;49(3): 206-211
    Adult-Onset Bilateral Optic Neuropathy in a Patient with Non-Familial Childhood-Onset Generalized Dystonia Associated with Mitochondrial DNA 14459G>A Mutation: A Case Report and Review of Literature.
    M Thaller, A P Samra, U J Chaudhary, M Roque, H Pall, S P Mollan, V Srinivasan.
      The occurrence of Leber Hereditary Optic Neuropathy in association with dystonia is exceedingly rare. There have been only a few previously reported cases describing this clinical phenotype with the mitochondrial DNA 14459 G>A/ND6 mutation. This mutation has been described to also manifest as isolated Leber Hereditary Optic Neuropathy or Leigh Syndrome/Leigh-like Syndrome in a very small number of patients. We report the case of a 27-year-old female who presented with bilateral sequential optic neuropathy on a background of non-familial generalized dystonia. Magnetic resonance imaging performed during childhood had shown bilateral high signal changes in the basal ganglia. Extensive testing for a possible autoimmune etiology was unrevealing. Her vision did not improve with aggressive steroid and plasma exchange treatment. Targeted genetic testing revealed a mitochondrial DNA 14459 G>A/ND6 mutation. Genetic analysis for the mitochondrial DNA 14459 G>A/ND6 mutation should be tested in a patient presenting with bilateral sequential optic neuropathy with co-morbid dystonia.
    Keywords:  Lebers hereditary optic neuropathy; idiopathic dystonia; mitochondria; optical coherence tomography; vision
    DOI:  https://doi.org/10.1080/01658107.2024.2405697
  19. bioRxiv. 2025 Mar 25. pii: 2025.03.24.645001. [Epub ahead of print]
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN . Application of in situ cryo-electron tomography (cryo-ET) made it possible to visualize the consequences of mitochondrial depolarization at higher resolution than heretofore attainable. Parkin-expressing U2OS cells were treated with the depolarizing agents oligomycin and antimycin A (OA), subjected to cryo-FIB milling, and mitochondrial structure was characterized by in situ cryo-ET. Phagophores were visualized in association with mitochondrial fragments. Bridge-like lipid transporter (BLTP) densities potentially corresponding to ATG2A were seen connected to mitophagic phagophores. Mitochondria in OA-treated cells were fragmented and devoid of matrix calcium phosphate crystals. The intermembrane gap of cristae was narrowed and the intermembrane volume reduced, and some fragments were devoid of cristae. A subpopulation of ATP synthases re-localized from cristae to the inner boundary membrane (IBM) apposed to the outer membrane (OMM). The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by sub-tomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation is enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    DOI:  https://doi.org/10.1101/2025.03.24.645001
  20. Brain. 2025 Apr 07. pii: awaf118. [Epub ahead of print]
    Mitochondrial damage is associated with an early immune response in inclusion body myositis.
    Felix Kleefeld, Emily Cross, Daniel Lagos, Sara Walli, Benedikt Schoser, Andreas Hentschel, Tobias Ruck, Christopher Nelke, Katrin Hahn, Denisa Hathazi, Andrew L Mammen, Maria Casal-Dominguez, Marta Gut, Ivo Glynne Gut, Simon Heath, Anne Schänzer, Hans-Hilmar Goebel, Iago Pinal-Fernandez, Andreas Roos, Corinna Preuße, Werner Stenzel, Rita Horvath.
      Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy. Recent findings demonstrated significant molecular similarities between PM-Mito and Inclusion Body Myositis (IBM), suggesting a trajectory from early to late IBM and prompting the inclusion of PM-Mito as an IBM precursor (early IBM) within the IBM spectrum. Both PM-Mito and IBM show mitochondrial abnormalities, suggesting mitochondrial disturbance is a critical element of IBM pathogenesis. The primary objective of this cross-sectional study was to characterize the mitochondrial phenotype in PM-Mito at histological, ultrastructural, and molecular levels and to study the interplay between mitochondrial dysfunction and inflammation. Skeletal muscle biopsies of 27 patients with PM-Mito and 27 with typical IBM were included for morphological and ultrastructural analysis. Mitochondrial DNA (mtDNA) copy number and deletions were assessed by qPCR and long-range PCR, respectively. In addition, full-length single-molecule sequencing of the mtDNA enabled precise mapping of deletions. Protein and RNA levels were studied using unbiased proteomic profiling, immunoblotting, and bulk RNA sequencing. Cell-free mtDNA (cf-mtDNA) was measured in the serum of IBM patients. We found widespread mitochondrial abnormalities in both PM-Mito and IBM, illustrated by elevated numbers of COX-negative and SDH-positive fibers and prominent ultrastructural abnormalities with disorganized and concentric cristae within enlarged and dysmorphic mitochondria. MtDNA copy numbers were significantly reduced, and multiple large-scale mtDNA deletions were already evident in PM-Mito, compared to healthy age-matched controls, similar to the IBM group. The canonical cGAS/STING inflammatory pathway was activated in PM-Mito and IBM, and we detected elevated levels of circulating cf-mtDNA indicative of mtDNA leakage. In PM-Mito and IBM, these findings were accompanied by dysregulation of proteins and transcripts linked to the mitochondrial membranes. In summary, we identified that mitochondrial dysfunction with multiple mtDNA deletions and depletion, disturbed mitochondrial ultrastructure, and defects of the inner mitochondrial membrane are features of PM-Mito and IBM, underlining the concept of an IBM-spectrum disease (IBM-SD). Notably, mitochondrial abnormalities precede tissue remodeling and infiltration by specific T-cell subpopulations (e.g., KLRG1+) characteristic of late IBM. The activation of inflammatory, DNA-sensing pathways might be related to mtDNA release, which would indicate a significant role of mitochondria-associated inflammation in the pathogenesis of IBM-SD. This study highlights the critical role of early mitochondrial abnormalities in the pathomechanism of IBM, which may lead to new approaches to therapy.
    Keywords:  IBM-SD; PM-Mito; mitochondria; polymyositis with mitochondrial pathology
    DOI:  https://doi.org/10.1093/brain/awaf118
  21. Biogerontology. 2025 Apr 10. 26(2): 91
    Spermidine toxicity in Saccharomyces cerevisiae due to mitochondrial complex III deficiency.
    Wei-Hsuan Su, Jessica J Smith, Evien Cheng, Megan S Nishitani, Catherine Y Choi, Kelsey R Lee, Alexia Pardos Salzano, Samuel E Schriner.
      Spermidine is a naturally occurring polyamine present in all cells and is necessary for viability in eukaryotic cells. The cellular levels of spermidine decline as an organism ages, and its supplementation has been found to extend lifespan in yeast, worms, flies, mice, and human cultured cells. The lifespan extending effect of spermidine is thought to be due to its ability to induce autophagy, a turnover of cellular components. Mitochondrial dysfunction is believed to be a major driver of the aging process. We asked whether spermidine could rescue mitochondrial dysfunction using the yeast Saccharomyces cerevisiae lacking mtDNA (ρ0 cells) as a model. Not only was spermidine unable to rescue survival in ρ0 cells, but it appeared to exhibit toxicity resulting in a shortened lifespan. This toxicity appears to not be due to the loss of mitochondrial respiration, elevated oxidative stress, or depleted ATP. Spermidine toxicity could be recapitulated by the genetic or pharmacological inactivation of mitochondrial complex III. It can also be prevented by the impairment of autophagy, through the inactivation of ATG8, or by impairment of mitochondrial complex II through the inactivation of SDH2. Spermidine toxicity in ρ0 cells was present in yeast strains BY4741 and W303, but not D273-10B, demonstrating genetic variance in the phenotype. Thus, caution may be suggested regarding the use of spermidine to alleviate aging in humans. Depending on the genotype of the individual, spermidine could potentially harm the very individuals it is intended to help.
    Keywords:  Aging; Mitochondrial DNA; Mitochondrial dysfunction; Spermidine; Yeast
    DOI:  https://doi.org/10.1007/s10522-025-10233-y
  22. Clin Genet. 2025 Apr 10.
    Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model.
    Edgar Buhl, Suchika Garg, Marie Monaghan, Amy Preston, Marcus Likeman, Julianne Dare, Julie Evans, Lucie S Taylor, Ian Berry, Kathryn Urankar, Paul G D Spry, Cathy Williams, Robert W Taylor, Charlotte L Alston, James J L Hodge, Anirban Majumdar.
      Infantile Cerebellar-Retinal Degeneration (ICRD) is an autosomal recessive neuro-disability associated with hypotonia, seizures, optic atrophy, and retinal degeneration. Recessive variants of the mitochondrial aconitase gene (ACO2) are a known cause of ICRD. Here, we present a paediatric male patient with ICRD, where whole genome sequencing of the family trio revealed segregating heterozygous variants of unknown significance in ACO2. At 4 months, he displayed generalised hypotonia, and by 6 years, visual electrophysiology indicated bilateral optic atrophy. Magnetic Resonance Imaging (MRI) at age seven confirmed optic nerve and cerebellar atrophy, and together with symptoms of developmental delay, align with ICRD. We established a Drosophila animal model to explore the impact of ACO2 loss- and gain-of-function. Manipulating the fly ortholog, mAcon1, through pan-neuronal knock-down or over-expression negatively affected longevity, locomotion, activity, whilst disrupting sleep and circadian rhythms. Mis-expression of mAcon1 in the eye led to impaired visual synaptic transmission and neurodegeneration. These experiments mirrored certain aspects of the human disease, providing a foundation for understanding its biological processes and pathogenic mechanisms, and offering insights into potential targets to screen for future treatments or preventive measures for ACO2-related ICRD.
    Keywords:   Drosophila melanogaster ; ACO2 ; mAcon1 ; ERG; MRI; infantile cerebellar‐retinal degeneration; locomotion; optic atrophy; sleep
    DOI:  https://doi.org/10.1111/cge.14745
  23. J Mol Biol. 2025 Apr 02. pii: S0022-2836(25)00191-3. [Epub ahead of print] 169125
    The Structure of the Drp1 Lattice on Membrane.
    Ruizhi Peng, Kristy Rochon, Anelise N Hutson, Scott M Stagg, Jason A Mears.
      Mitochondrial health relies on the membrane fission mediated by dynamin-related protein 1 (Drp1). Previous structural studies of Drp1 on remodeled membranes were hampered by heterogeneity, leaving a critical gap in the understanding of the mitochondrial fission mechanisms. Here we present a cryo-electron microscopy structure of full-length human Drp1 decorated on membrane tubules. Using the reconstruction of average subtracted tubular regions (RASTR) technique, we report that Drp1 forms a locally ordered lattice along the tubule without global helical symmetry. The filaments in the lattice are similar to dynamin rungs with conserved stalk interactions. Adjacent filaments are connected by GTPase domain interactions in a novel stacked conformation. We identified two states of the Drp1 lattice among the heterogenous dataset representing conformational changes around hinge 1. Additionally, we observed contact between Drp1 and membrane that can be assigned to the variable domain sequence. Together these structures revealed a putative mechanism by which Drp1 constricts mitochondria membranes in a stepwise, "ratchet" manner.
    Keywords:  Drp1; cryo-EM; membrane remodeling; mitochondria
    DOI:  https://doi.org/10.1016/j.jmb.2025.169125
  24. Cells. 2025 Mar 22. pii: 482. [Epub ahead of print]14(7):
    MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.
    Benney T Endoni, Olha M Koval, Chantal Allamargot, Tara Kortlever, Lan Qian, Riley J Sadoski, Denise Juhr, Isabella M Grumbach.
      Mitochondria-ER contact sites (MERCS) are vital for mitochondrial dynamics, lipid exchange, Ca2+ homeostasis, and energy metabolism. We examined whether mitochondrial metabolism changes during the cell cycle depend on MERCS dynamics and are regulated by the outer mitochondrial protein mitochondrial rho GTPase 1 (MIRO1). Wound healing was assessed in mice with fibroblast-specific deletion of MIRO1. Wild-type and MIRO1-/- fibroblasts and vascular smooth muscle cells were evaluated for proliferation, cell cycle progression, number of MERCS, distance, and protein composition throughout the cell cycle. Restoration of MIRO1 mutants was used to test the role of MIRO1 domains; Ca2+ transients and mitochondrial metabolism were evaluated using biochemical, immunodetection, and fluorescence techniques. MERCS increased in number during G1/S compared with during G0, which was accompanied by a notable rise in protein-protein interactions involving VDAC1 and IP3R as well as GRP75 and MIRO1 by proximity-ligation assays. Split-GFP ER/mitochondrial contacts of 40 nm also increased. Mitochondrial Ca2+ concentration ([Ca2+]), membrane potential, and ATP levels correlated with the formation of MERCS during the cell cycle. MIRO1 deficiency blocked G1/S progression and the cell-cycle-dependent formation of MERCS and altered ER Ca2+ release and mitochondrial Ca2+ uptake. MIRO1 mutants lacking the Ca2+-sensitive EF hands or the transmembrane domain did not rescue cell proliferation or the formation of MERCS. MIRO1 controls an increase in the number of MERCS during cell cycle progression and increases mitochondrial [Ca2+], driving metabolic activity and proliferation through its EF hands.
    Keywords:  Ca2+; ER; MAM; MERCS; MIRO1; cell cycle; fibroblasts; mitochondria; vascular smooth muscle cells
    DOI:  https://doi.org/10.3390/cells14070482
  25. Cell Commun Signal. 2025 Apr 08. 23(1): 174
    Pulmonary mitochondrial DNA release and activation of the cGAS-STING pathway in Lethal Stx12 knockout mice.
    Dan-Hua Liu, Fang Li, Run-Zhou Yang, Zhuanbin Wu, Xiao-Yan Meng, Sen-Miao Li, Wen-Xiu Li, Jia-Kang Li, Dian-Dian Wang, Rui-Yu Wang, Shu-Ang Li, Pei-Pei Liu, Jian-Sheng Kang.
      STX12 (syntaxin12 or syntaxin13), a member of the SNARE protein family, plays a crucial role in intracellular vesicle transport and membrane fusion. Our previous research demonstrated that Stx12 knockout mice exhibit perinatal lethality with iron deficiency anemia. Despite its importance, the comprehensive physiological and pathological mechanism of STX12 remains largely unknown. Here, we revealed that STX12 deficiency causes the depolarization of mitochondrial membrane potential in zebrafish embryos and mouse embryonic fibroblasts. Additionally, the loss of STX12 decreased the levels of mitochondrial complex subunits, accompanied by mitochondrial DNA (mtDNA) release and activated cGAS-STING pathway and Type I interferon pathway in the lung tissue of Stx12-/- mice. Additionally, we observed a substantial increase in cytokines and neutrophil infiltration within the lung tissues of Stx12 knockout mice, indicating severe inflammation, which could be a contributing factor for Stx12-/- mortality. Various interventions have failed to rescue the lethal phenotype, suggesting that systemic effects may contribute to lethality. Further research is warranted to elucidate potential intervention strategies. Overall, our findings uncover the critical role of STX12 in maintaining mitochondrial function and mtDNA stability in pulmonary cells, and reveal that STX12 depletion results in pulmonary mtDNA release and activates mtDNA-dependent innate immunity.
    Keywords:  Inflammation; Mitochondria; STX12; cGAS-STING; mtDNA release
    DOI:  https://doi.org/10.1186/s12964-025-02141-y
  26. Nat Metab. 2025 Apr 08.
    TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
    Joanne F Garbincius, Oniel Salik, Henry M Cohen, Carmen Choya-Foces, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Joshua J Doolittle, Anya S Wilkinson, Emma K Murray, Michael P Lazaropoulos, Alycia N Hildebrand, Dhanendra Tomar, John W Elrod.
      The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01250-9
  27. J Cell Sci. 2025 Apr 11. pii: jcs.263729. [Epub ahead of print]
    Integrated proteome and lipidome analyses place OCIAD1 at mitochondria-peroxisome intersection balancing lipid metabolism.
    Vanessa Linke, Mateusz Chodkowski, Kacper Kaszuba, Mariusz Radkiewicz, Tina A Schrader, Hirak Das, Vikas Rana, Dorota Stadnik, Michał Dadlez, Bettina Warscheid, Michael Schrader, Agnieszka Chacinska.
      OCIAD1 (Ovarian Cancer Immunoreactive Antigen Domain Containing 1) is a membrane protein largely localized to mitochondria, however, its function in health or disease is not well understood. To comprehensively characterize the molecular changes upon lack of OCIAD1, we used mass spectrometry to study the mitochondrial and cellular proteome and lipidome. We find extensive lipidome rearrangement in OCIAD1 KO cells, characterized by two main phenotypes of decreased ether phospholipids and decreased phospholipids with an odd number of carbons. The lipidomic changes suggest alterations in peroxisomal lipid metabolism. At the same time, proteins responsible for mitochondrial fatty acid β oxidation are significantly increased. Together with a global loss in peroxisomal proteins, aberrant peroxisomal morphology, and a meta-analysis of proximity labeling data, this gives a function to the previously observed partial localization of OCIAD1 to peroxisomes. We suggest a role for OCIAD1 in balancing mitochondrial and peroxisomal lipid metabolism, and a direct impact on the key enzymes FAR1 and ABCD3.
    Keywords:  Lipid metabolism; Lipidomics; Mitochondrial biology; Peroxisomes; Proteomics
    DOI:  https://doi.org/10.1242/jcs.263729
  28. Cell Death Discov. 2025 Apr 07. 11(1): 150
    DRP1, fission and apoptosis.
    Nan Wang, Xinwai Wang, Beiwu Lan, Yufei Gao, Yuanyuan Cai.
      Mitochondrial fission is a critical physiological process in eukaryotic cells, participating in various vital activities such as mitosis, mitochondria quality control, and mitophagy. Recent studies have revealed a tight connection between mitochondrial fission and the mitochondrial metabolism, as well as apoptosis, which involves multiple cellular events and interactions between organelles. As a pivotal molecule in the process of mitochondrial fission, the function of DRP1 is regulated at multiple levels, including transcription, post-translational modifications. This review follows the guidelines for Human Gene Nomenclature and will focus on DRP1, discussing its activity regulation, its role in mitochondrial fission, and the relationship between mitochondrial fission and apoptosis.
    DOI:  https://doi.org/10.1038/s41420-025-02458-0
  29. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 02. pii: S0925-4439(25)00169-3. [Epub ahead of print]1871(5): 167824
    Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
    Wei-Lin Huang, Tuany Eichwald, Alexander Stover, Milad Gazanfari, Philip H Schwartz, Alexandra Latini, Jose E Abdenur.
      Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C > G) and intron-5 (c.492 + 2 T > C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.
    Keywords:  Antioxidant enzymes; Free radicals; Mitochondrial biogenesis; Mitochondrial capacity; Mitochondrial disorders; Respiratory chain complexes
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167824
  30. Biochim Biophys Acta Mol Cell Res. 2025 Apr 09. pii: S0167-4889(25)00059-X. [Epub ahead of print] 119954
    Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
    Michal Cagalinec, Mohd Adnan, Silvia Borecka, Geert Bultynck, Vinay Choubey, Shira Yanovsky-Dagan, Shlomit Ezer, Daniela Gasperikova, Tamar Harel, Dana Jurkovicova, Allen Kaasik, Jean-Charles Liévens, Tangui Maurice, Marco Peviani, Elodie Marie Richard, Jan Skoda, Martina Skopkova, Pauline Tarot, Robbe Van Gorp, Liga Zvejniece, Benjamin Delprat.
      Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.
    Keywords:  ATAD3A related disorders; Amyotrophic lateral sclerosis; Calcium signaling; Endoplasmic reticulum stress; Familial Parkinson's disease; Harel-Yoon syndrome; Metabolomics; Mitochondria quality control; Mitochondria-associated endoplasmic reticulum membranes; Rare neurodegenerative diseases; Wolfram syndrome; cancer
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119954
  31. Hum Genet. 2025 Apr 10.
    The molecular landscape of hereditary ataxia: a single-center study.
    Elisa Bregant, Elena Betto, Chiara Dal Secco, Jessica Zucco, Federica Baldan, Lorenzo Allegri, Incoronata Renata Lonigro, Flavio Faletra, Lorenzo Verriello, Giuseppe Damante, Catia Mio.
      Hereditary ataxia (HA) is a heterogeneous group of complex neurological disorders, which represent a diagnostic challenge due to their diverse phenotypes and genetic etiologies. Next-generation sequencing (NGS) has revolutionized the field of neurogenetics, improving the identification of ataxia-associated genes. Notwithstanding, repeat expansions analysis remains a cornerstone in the diagnostic workflow of these diseases. Here we describe the molecular characterization of a consecutive single-center series of 70 patients with genetically uncharacterized HA. Patients' samples were analyzed for known HA-associated repeat expansions as first tier and negative ones were analyzed by whole exome sequencing (WES) as second tier. Overall, we identified pathogenic/likely pathogenic variants in 40% (n = 28/70) and variants of unknown significance (VUS) in 20% (n = 14/70) of cases. In particular, 10 patients (14.3%, n = 10/70) presented pathogenic repeat expansions while 18 cases (30%, n = 18/60) harbored at least a single nucleotide variant (SNV) or a copy number variant (CNV) in HA or HSP-related genes. WES allowed assessing complex neurological diseases (i.e., leukodystrophies, cerebrotendinous xanthomatosis and atypical xeroderma pigmentosum), which are not usually referred as pure genetic ataxias. Our data suggests that the combined use of repeat expansion analysis and WES, coupled to detailed clinical phenotyping, is able to detect the molecular alteration underpinning ataxia in almost 50% cases, regardless of the hereditary pattern. Indeed, NGS-based tests are fundamental to acknowledge novel HA-associated genes useful to explain the remaining wide fraction of negative tests. Nowadays, this gap is problematic since these patients could not benefit from an etiological diagnosis of their disease that allows prognostic trajectories and prenatal/preimplantation diagnosis.
    DOI:  https://doi.org/10.1007/s00439-025-02744-y
  32. Int J Biol Macromol. 2025 Apr 07. pii: S0141-8130(25)03465-8. [Epub ahead of print] 142913
    Fatty acid binding proteins-mediated mitochondrial dysfunction in the development of age-related diseases: A review.
    Xingxing Ren, Chaoyuan Jin, Qilin Li, Congyi Fu, Yu Fang, Zihang Xu, Zi Liang, Tianshi Wang.
      Fatty acid-binding proteins (FABPs) act as lipid chaperones and play a role in the pathological processes of various lipid signaling pathways. Mitochondria are crucial for the regulation of lipid metabolism. As an aging marker, lipid-mediated mitochondrial dysfunction has been observed in the etiology of numerous diseases, including neurodegenerative diseases, metabolic syndromes, cardiovascular diseases, and tumorigenesis. Members of the FABP family have been identified to regulate mitochondrial function. Targeting FABPs specifically may provide a promising approach to improve mitochondrial function and treat age-related diseases. This review summarizes the connection between FABPs and mitochondrial function and highlights certain FABPs involved in age-related diseases that hold significant therapeutic promise.
    Keywords:  Aging; Cardiovascular diseases; FABPs; Metabolic syndromes; Mitochondria; Neurodegenerative diseases; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142913
  33. Spectrochim Acta A Mol Biomol Spectrosc. 2025 Mar 31. pii: S1386-1425(25)00453-6. [Epub ahead of print]338 126147
    A photostable luminescent iridium(III) complex probe for imaging endogenous mitochondrial sulfur dioxide in living cells.
    Mengzhao Jia, Jia Wu, Xiaolei Wu, Daniel Shiu-Hin Chan, Bingjie Hu, Chun-Yuen Wong, Chung-Hang Leung, Kai Yang, Wanhe Wang.
      Sulfur dioxide (SO2) is an important signaling gas molecule, but its aberration is highly associated with inflammatory diseases and cancers. Luminescence probes for SO2 have emerged as essential instruments for elucidating its biological roles and facilitating disease diagnosis, owing to their high sensitivity and capabilities for real-time detection. Nevertheless, the majority of current probes lack subcellular selectivity and suffer from limited photostability. In this work, we develop an Ir(III)-based luminescence probe (Ir3) for the rapid, real-time, and accurate detection of SO2 in aqueous solution. This probe exhibits low cytotoxicity and provides exceptional imaging of mitochondrial SO2 in living cells. We anticipate that this probe will serve as a foundational tool for the advancement of effective imaging technologies for SO2, thereby enhancing the clinical and biomedical applications of Ir(III) complex-based detection probes.
    Keywords:  Imaging; Iridium(III) complex; Mitochondria; Photostability; Sulfur dioxide
    DOI:  https://doi.org/10.1016/j.saa.2025.126147
  34. Nat Commun. 2025 Apr 04. 16(1): 3221
    The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
    Jakub Bunk, Mohammed F Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F Rahbani, Lawrence Kazak.
      Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.
    DOI:  https://doi.org/10.1038/s41467-025-58294-4
  35. J Neurochem. 2025 Apr;169(4): e70059
    Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.
    Thasneem Musthafa, Syed Kavish Nizami, Ankita Mishra, Gaiti Hasan, Renjitha Gopurappilly.
      Parkinson's disease (PD) has emerged as a multisystem disorder affecting multiple cellular and organellar systems in addition to the dopaminergic neurons. Disease-specific induced pluripotent stem cells (iPSCs) model early developmental changes and cellular perturbations that are otherwise inaccessible from clinical settings. Here, we report the early changes in patient-derived iPSCs carrying a homozygous recessive mutation, R741Q, in the PLA2G6 gene. A gene-edited R747W iPSC line mirrored these phenotypes, thus validating our initial findings. Bioenergetic dysfunction and hyperpolarization of mitochondrial membrane potentials were hallmarks of the PD iPSCs. Further, a concomitant increase in glycolytic activity indicated a possible compensation for mitochondrial respiration. Elevated basal reactive oxygen species (ROS) and decreased catalase expression were also observed in the disease iPSCs. No change in autophagy was detected. These inceptive changes could be potential targets for early intervention of prodromal PD in the absence of disease-modifying therapies. However, additional investigations are crucial to delineate the cause-effect relationships of these observations.
    Keywords:  PLA2G6; Parkinson's disease; disease modeling; human iPSC; mitochondrial dysfunction
    DOI:  https://doi.org/10.1111/jnc.70059
  36. J Hum Genet. 2025 Apr 11.
    Regulation of MCCC1 expression by a Parkinson's disease-associated intronic variant: implications for pathogenesis.
    Shunsaku Sogabe, Hiroko Nakano, Yusuke Ogasahara, Pei-Chieng Cha, Yuko Ando, Mariko Taniguchi-Ikeda, Ryusaku Matsumoto, Motoi Kanagawa, Kazuhiro Kobayashi, Shigeo Murayama, Takashi Aoi, Tatsushi Toda, Wataru Satake.
      Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. While some familial cases result from single-gene mutations, most are sporadic, involving complex genetic and environmental interactions. Among PD risk loci identified through genome-wide association studies, MCCC1 encodes a mitochondrial enzyme essential for leucine catabolism; however, the causal variant remains unclear. Here, we investigated whether the intronic variant rs12637471 regulates MCCC1 mRNA expression and influences PD risk. Postmortem brain analysis revealed significantly elevated MCCC1 mRNA levels in G-allele carriers, consistent with peripheral tissue eQTL data from GTEx. Using CRISPR/Cas9-edited induced pluripotent stem cells, we generated isogenic lines differing only at rs12637471 and observed increased MCCC1 expression in G-allele dopaminergic neurons. Given MCCC1's mitochondrial role, its dysregulation may impact mitochondrial homeostasis, autophagy, or inflammation, potentially contributing to PD pathogenesis.
    DOI:  https://doi.org/10.1038/s10038-025-01335-z
  37. Orphanet J Rare Dis. 2025 Apr 10. 20(1): 172
    Preliminary investigation on the economic cost of mitochondrial disease in Chinese children.
    Chaolong Xu, Dan Zhao, Xin Duan, Zhimei Liu, Tongyue Li, Yunxi Zhang, Zixuan Zhang, Tianyu Song, Ying Zou, Huafang Jiang, Fang Fang.
       BACKGROUND: The prevalence of mitochondrial diseases is increasing, leading to a significant economic burden on families and society. However, nationwide cost data on their effects on China's economy remain limited. This study aimed to investigate the economic cost of mitochondrial diseases in Chinese children, analyse the relevant influencing factors, and provide a foundation for strategies to reduce the healthcare burden.
    METHODS: In this single-centre, cross-sectional study, an online questionnaire was randomly administered to paediatric patients diagnosed with mitochondrial diseases between January 2012 and January 2022. The questionnaire included questions regarding demographic data, clinical information, and expenditure-related costs. Multivariate analysis of economic cost was performed using a generalised linear gamma conjugate model (A1).
    RESULTS: The responses to 102 questionnaires were analysed. The median direct economic cost incurred for the diagnosis of mitochondrial disease was $8,520.19, with direct medical and non-medical costs of $6,769.06 and $2,092.98, respectively, and an indirect cost of $3,162.93. Healthcare insurance covers 27.29% of direct medical expenses. Multivariate analysis showed that the economic cost of diagnosing mitochondrial diseases was significantly correlated with the year of disease onset (P < 0.001). The median annual economic cost for treatment and symptom management after diagnosis was $12,292.79, with direct medical and non-medical costs of $10,887.53 and $1,360.44, respectively, and an indirect cost of $5,442.21. Healthcare insurance covered only 15.16% of direct medical expenses. No significant differences were observed between the subgroups after diagnosis and the annual economic costs of treatment or symptom management.
    CONCLUSION: The study findings indicated that the economic burden of both the diagnosis and treatment of patients with mitochondrial diseases was substantial. Increased emphasis should be placed on primary and secondary prevention strategies to further reduce the overall economic burden of rare genetic diseases, such as mitochondrial diseases.
    Keywords:  Children; China; Economic costs; Mitochondrial disease
    DOI:  https://doi.org/10.1186/s13023-025-03708-1
  38. AJNR Am J Neuroradiol. 2025 Apr 10.
    Single Large-Scale Mitochondrial Deletion Syndromes: Neuroimaging Phenotypes and Longitudinal Progression in Pediatric Patients.
    Cesar A P F Alves, Maria Camilla Rossi-Espagnet, Francisco Perez, Amirreza Manteghinejad, James T Peterson, Rebecca Ganetzky, Antonio Napolitano, Francesco Grassi, Ibrahim George-Sankoh, Harun Yildiz, Colleen Muraresku, Marni J Falk, Diego Martinelli, Daniela Longo, Adeline Vanderver, Carlo Gandolfo, Russell P Saneto, Amy Goldstein, Arastoo Vossough.
       BACKGROUND AND PURPOSE: Single large-scale mitochondrial deletion syndrome (SLSMD) comprises devastating mitochondrial diseases often classified into 3 major clinical syndromes: Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), and Pearson syndrome (PS). Nevertheless, there remains large clinical variability and overlap among these SLSMD groups. Therefore, further stratification is required for more precise prognostication and clinical management. Through detailed description and analysis of longitudinal neuroimaging changes, we sought to determine the neuroradiologic hallmarks of SLSMDs and define their expected imaging progression to further delineate their natural history.
    MATERIALS AND METHODS: A retrospective, longitudinal study of 40 children with SLSMDs at 3 mitochondrial disease centers was performed. MRI review assessed the prevalence and progression of brain lesions in different regions with statistical significance testing and Kaplan-Meier analysis. Hierarchical cluster analysis was performed for involved brain regions to stratify findings into imaging phenotype groups.
    RESULTS: Among 40 patients with SLSMD (median age 9.26 years; interquartile range: 5.16-13.1), 67.5% had KSS, 15% had KSS with a prior history of PS (PS→KSS), and 10% had PS only. A well-delineated phenotype could not be specified for 1 (2.5%) and 2 (5%) individuals who had CPEO-plus (CPEO + extraocular symptoms). Regardless of presentation, initial MRI of patients with KSS revealed lesions within selective areas of the upper brainstem tegmentum. Follow-up MRIs in 26 patients showed well-defined progression along other select brainstem and white matter regions. Log-rank tests demonstrated varying onset times by lesion type. Cluster analysis revealed 2 distinct neuroimaging groups: 1) KSS, CPEO-plus, and PS→KSS versus 2) PS and not otherwise specified individuals. KSS, CPEO-plus, and PS→KSS showed indistinguishable neuroimaging features regardless of the initial clinical presentation.
    CONCLUSIONS: We describe the first comprehensive longitudinal neuroimaging pattern analysis in a multicenter, international SLSMDs disease pediatric cohort, delineating a predictable progression of brain lesions, regardless of clinical phenotype.
    DOI:  https://doi.org/10.3174/ajnr.A8670
  39. J Inherit Metab Dis. 2025 May;48(3): e70028
    iPSC-Derived Liver Organoids as a Tool to Study Medium Chain Acyl-CoA Dehydrogenase Deficiency.
    Ligia A Kiyuna, José M Horcas-Nieto, Christoff Odendaal, Miriam Langelaar-Makkinje, Albert Gerding, Mathilde J C Broekhuis, Flavio Bonanini, Madhulika Singh, Dorota Kurek, Amy C Harms, Thomas Hankemeier, Floris Foijer, Terry G J Derks, Barbara M Bakker.
      Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disease, characterized by biallelic variants in the ACADM gene. Interestingly, even with the same genotype, patients often present with very heterogeneous symptoms, ranging from fully asymptomatic to life-threatening hypoketotic hypoglycemia. The mechanisms underlying this heterogeneity remain unclear. Therefore, there is a need for in vitro models of MCADD that recapitulate the clinical phenotype as a tool to study the pathophysiology of the disease. Fibroblasts of control and symptomatic MCADD patients with the c.985A>G (p.K329E) were reprogrammed into induced pluripotent stem cells (iPSCs). iPSCs were then differentiated into hepatic expandable organoids (EHOs), further matured to Mat-EHOs, and functionally characterized. EHOs and Mat-EHOs performed typical hepatic metabolic functions, such as albumin and urea production. The organoids metabolized fatty acids, as confirmed by acyl-carnitine profiling and high-resolution respirometry. MCAD protein was fully ablated in MCADD organoids, in agreement with the instability of the mutated MCAD protein. MCADD organoids accumulated medium-chain acyl-carnitines, with a strongly elevated C8/C10 ratio, characteristic of the biochemical phenotype of the disease. Notably, C2 and C14 acyl-carnitines were found decreased in MCADD Mat-EHOs. Finally, MCADD organoids exhibited differential expression of genes involved in ω-oxidation, mitochondrial β-oxidation, TCA cycle, and peroxisomal coenzyme A metabolism, particularly upregulation of NUDT7. iPSC-derived organoids of MCADD patients recapitulated the major biochemical phenotype of the disease. Mat-EHOs expressed relevant pathways involved in putative compensatory mechanisms, notably CoA metabolism and the TCA cycle. The upregulation of NUDT7 expression may play a role in preventing excessive accumulation of dicarboxylic acids in MCADD. This patient-specific hepatic organoid system is a promising platform to study the phenotypic heterogeneity between MCADD patients.
    Keywords:  MCADD; coenzyme a; iPSC; medium‐chain acyl‐carnitines; organoids; peroxisomes
    DOI:  https://doi.org/10.1002/jimd.70028
  40. Ann Med Surg (Lond). 2025 Mar;87(3): 1406-1414
    Genomic medicine and personalized treatment: a narrative review.
    Adil Khan, Anchal Ramesh Barapatre, Nadir Babar, Joy Doshi, Mohamd Ghaly, Kirtan Ghanshyam Patel, Shayan Nawaz, Uswa Hasana, Swara Punit Khatri, Shilpa Pathange, Abhinya Reddy Pesaru, Chaitanya Swaroop Puvvada, Marium Billoo, Usama Jamil.
      Genomic medicine, which integrates genomics and bioinformatics into clinical care and diagnostics, is transforming healthcare by enabling personalized treatment approaches. Advances in technologies such as DNA sequencing, proteomics, and computational power have laid the foundation for individualized therapies that account for genetic variations influencing disease risk, progression, and treatment response. This review explores the historical milestones leading to current applications of genomic medicine, such as targeted therapies, gene therapies, and precision medicine, in fields including cardiovascular diseases, oncology, and rare genetic disorders. It highlights the use of next-generation sequencing and third-generation sequencing to improve diagnostic accuracy and treatment outcomes, emphasizing the role of genomic data in advancing personalized treatments. Furthermore, emerging therapies such as CRISPR/Cas-based genome editing and adeno-associated viral vectors showcase the potential of gene therapy in addressing complex diseases, including rare genetic disorders. Despite promising advancements, challenges remain in fully integrating genomic medicine into routine clinical practice, including cost barriers, data interpretation complexities, and the need for widespread genomic literacy among healthcare professionals. The future of genomic medicine holds transformative potential for revolutionizing the diagnosis, treatment, and management of both common and rare diseases.
    Keywords:  cardiology; genomic medicine; genomics
    DOI:  https://doi.org/10.1097/MS9.0000000000002965
  41. Free Radic Biol Med. 2025 Apr 07. pii: S0891-5849(25)00221-7. [Epub ahead of print]
    Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes.
    Qing Gao, Per Hägglund, Luke F Gamon, Michael J Davies.
      The multi-subunit pyruvate dehydrogenase complex (PDC) plays a crucial role in glucose oxidation as it determines whether pyruvate is used for mitochondrial oxidative phosphorylation or is converted to lactate for aerobic glycolysis. PDC contains three lipoic acid groups, covalently attached at lysine residues to give lipoyllysine, which are responsible for acyl group transfer and critical to complex activity. We have recently reported that both free lipoic acid, and lipoyllysine in alpha-keto glutarate dehydrogenase, are highly susceptible to singlet oxygen (1O2)-induced oxidation. We therefore hypothesized that PDC activity and structure would be influenced by 1O2 (generated using Rose Bengal and light) via modification of the lipoyllysines and other residues. PDC activity was decreased by photooxidation, with this being dependent on light exposure, O2, the presence of Rose Bengal, and D2O consistent with 1O2-mediated reactions. These changes were modulated by pre-illumination addition of free lipoic acid and lipoamide. Activity loss occurred concurrently with lipoyllysine and sidechain modification (determined by mass spectrometry) and protein aggregation (detected by SDS-PAGE). Peptide mass mapping provided evidence for modification at 42 residues (Met, Trp, His and Tyr; with modification extents of 20-50%) and each of the lipoyllysine sites (6-20% modification). Structure modelling indicated the modifications occur across all 4 subunit types, and occur in functional domains or at multimer interfaces, consistent with damage at multiple sites contributing to the overall loss of activity. These data indicate that PDC activity and structure are susceptible to 1O2-induced damage with potential effects on cellular pathways of glucose metabolism.
    Keywords:  Pyruvate dehydrogenase complex; crosslinking; glucose metabolism; lipoic acid; lipoyllysine; mitochondria; photooxidation; protein oxidation; singlet oxygen; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.011
  42. Nat Metab. 2025 Apr 09.
    The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
    Zhongfu Ying, Yanmin Xin, Zihuang Liu, Tianxin Tan, Yile Huang, Yingzhe Ding, Xuejun Hong, Qiuzhi Li, Chong Li, Jingyi Guo, Gaoshen Liu, Qi Meng, Shihe Zhou, Wenxin Li, Yao Yao, Ge Xiang, Linpeng Li, Yi Wu, Yang Liu, Miaohui Mu, Zifeng Ruan, Wenxi Liang, Junwei Wang, Yaofeng Wang, Baojian Liao, Yang Liu, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu.
      The mitochondrial unfolded protein response (UPRmt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPRmt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPRmt activation at the early phase of pluripotency acquisition. UPRmt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPRmt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis3,4, our findings on the connection between the UPRmt and EMT have important pathological implications and reveal potential targets for tumour treatment.
    DOI:  https://doi.org/10.1038/s42255-025-01261-6
  43. Mol Genet Metab. 2025 Apr 07. pii: S1096-7192(25)00096-4. [Epub ahead of print]145(1): 109105
    RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency.
    Undiagnosed Diseases Network
      One in 10 individuals has a rare disease, with exome and genome sequencing yielding an overall diagnostic rate of approximately 30 %. RNA sequencing can augment genome analysis and improve diagnosis. We present a young woman with global developmental delay, poor growth, distinctive facial features, osteopenia, premature ovarian insufficiency, and ocular abnormalities who had non-diagnostic genome sequencing. RNAseq performed on her skin fibroblasts showed that NBAS gene expression was significantly reduced compared with controls. Manual inspection of the binary alignment map (BAM) files revealed compound heterozygous variants in NBAS: a rare deep intronic variant NM_015909.4:c.2423 + 403G > C which creates a hypomorphic pseudoexon not seen in control samples (gnomad allele frequency (AF) 0.000006572); and a rare premature termination codon (PTC) NM_015909.4:c.4753C > T; p.Arg1585Ter (gnomad AF 0.000006572). Both variants are predicted to cause nonsense mediated decay of transcripts, as the pseudoexon contains a PTC. Biallelic variants in NBAS are associated with two major phenotypes, i.e., infantile liver failure syndrome 2 (MIM # 616483) and short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM # 614800). Our patient, the first reported with one loss of function and one splice variant resulting in an out of frame transcript in NBAS, manifested a severe phenotype compared with previously reported individuals. This case demonstrates the utility of incorporating RNAseq to generate diagnostic candidates and expands the phenotypic spectrum of NBAS deficiency.
    Keywords:  Clinical diagnostics; Genetics; Metabolic genetics; RNA sequencing; Rare disease
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109105
  44. STAR Protoc. 2025 Apr 05. pii: S2666-1667(25)00151-0. [Epub ahead of print]6(2): 103745
    Protocol for dual metabolomics and proteomics using nanoflow liquid chromatography-tandem mass spectrometry.
    Weiwei Lin, Fatemeh Mousavi, Benjamin C Blum, Christian F Heckendorf, Matthew Lawton, Noah Lampl, Ryan Hekman, Mark McComb, Andrew Emili.
      Nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS) benefits untargeted metabolomics by enhancing sensitivity and integrating proteomics for the same sample. Here, we present a protocol to enable nLC-MS for dual metabolomics and proteomics. We describe steps for solid-phase micro-extraction (SPME)-assisted metabolite cleaning and enrichment, which avoids capillary column blockage. We then detail nLC-MS data acquisition and analysis. This protocol has been applied in diverse specimens including biofluids, cell lines, and tissues. For complete details on the use and execution of this protocol, please refer to Lin et al.1.
    Keywords:  Bioinformatics; Mass Spectrometry; Metabolomics; Proteomics; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.103745
  45. J Neurosci Res. 2025 Apr;103(4): e70023
    Early Life Stress Induces Brain Mitochondrial Dynamics Changes and Sex-Specific Adverse Effects in Adulthood.
    Angeliki-Maria Vlaikou, Markus Nussbaumer, Aikaterini Iliou, Maria P Papageorgiou, Chrysoula Komini, Daniela Theodoridou, Dimitra Benaki, Emmanuel Mikros, Evangelos Gikas, Maria Syrrou, Michaela D Filiou.
      Early life stress exposure exerts detrimental effects in adulthood and is a risk factor for psychiatric disorders. Studies addressing the molecular mechanisms of early life stress have primarily focused on hormones and stress circuits. However, little is known on how mitochondria and mitochondrial dynamics (i.e., the orchestration of mitochondrial fission, fusion, mitophagy, and biogenesis) modulate early life stress responses. Here, we used a maternal separation with early weaning (MSEW) paradigm to investigate the behavioral and molecular early life stress-elicited effects in male and female C57BL/6 mice in adulthood. We first applied a behavioral test battery to assess MSEW-driven, anxiety-related and stress-coping alterations. We then looked for MSEW-induced, mitochondria-centered changes in cingulate cortex, hippocampus and cerebellum, as well as in plasma by combining protein, mRNA, mitochondrial DNA copy number (mtDNAcn) and metabolomics analyses. We found that MSEW mice are more anxious, show decreased antioxidant capacity in the cingulate cortex and have higher mRNA levels of the fission regulator Fis1 and the mitophagy activator Pink1 in the hippocampus, indicating a shift towards mitochondrial degradation. Hippocampal mRNA level alterations of apoptotic markers further suggest an MSEW-driven activation of apoptosis accompanied by a dysregulation of purine catabolism in the cerebellum in MSEW mice. Sex-specific analysis revealed distinct MSEW-induced changes in male and female mice at the molecular level. Our work reveals a previously unexplored role of mitochondrial dynamics in regulating early life stress effects and highlights a mitochondria-centered dysregulation as a persistent outcome of early life stress in adulthood.
    Keywords:  anxiety; fission; maternal separation; mice; mitochondria; mitophagy
    DOI:  https://doi.org/10.1002/jnr.70023
  46. Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00112-3. [Epub ahead of print]
    Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue.
    Christopher Auger, Mark Li, Masanori Fujimoto, Kenji Ikeda, Jin-Seon Yook, Timothy R O'Leary, María Paula Huertas Caycedo, Cai Xiaohan, Satoshi Oikawa, Anthony R P Verkerke, Kosaku Shinoda, Patrick R Griffin, Kenji Inaba, Roland H Stimson, Shingo Kajimura.
      Adipose tissue thermogenesis contributes to energy balance via mitochondrial uncoupling protein 1 (UCP1) and UCP1-independent pathways. Among UCP1-independent thermogenic mechanisms, one involves Ca2+ cycling via SERCA2b in adipose tissue; however, the underlying molecular basis remains elusive. Here, we report that an endoplasmic reticulum (ER) membrane-anchored peptide, C4orf3 (also known as another regulin [ALN]), uncouples SERCA2b Ca2+ transport from its ATP hydrolysis, rendering the SERCA2b-C4orf3 complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2b-dependent Ca2+ transport without affecting SERCA2 expression, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. Notably, genetic depletion of C4orf3 resulted in compensatory activation of UCP1-dependent thermogenesis following cold challenge. We demonstrated that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study identifies C4orf3 as the molecular resistor to SERCA2b-mediated Ca2+ import that plays a key role in UCP1-independent thermogenesis and energy balance.
    Keywords:  Ca(2+) cycling; UCP1-independent; energy balance; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.009
  47. iScience. 2025 Apr 18. 28(4): 111642
    Insulin acts on astrocytes to shift their substrate preference to fatty acids.
    Bouchra Taib, Pragney Deme, Sujasha Gupta, Seung Wan Yoo, Saja S Khuder, Ahmet Hoke, Zhigang Li, Rexford S Ahima, Norman J Haughey.
      It is increasingly recognized that brain can β-oxidize fatty acids for use as an energy substrate. However, mechanism(s) by which neural cells switch their preference from glucose to fatty acids are not fully elucidated. Here we provide evidence that insulin acts directly on astrocytes to promote the uptake of glucose and fatty acids while modifying their substrate preference through a sequential shift in the expression of genes associated with fatty acid uptake, synthesis, transport, and metabolism. Under these conditions, fatty acids are converted into TCA cycle intermediates to satisfy astrocyte energy demands, allowing pyruvate derived from glucose to be directed toward the production of lactate; a preferred fuel for neurons. This shift in astrocyte energy substrate preference is required for insulin to enhance long-term potentiation in the Schaffer collateral. These findings establish a homeostatic mechanism where insulin promotes LTP by switching the energy substrate preference of astrocytes to fatty acids.
    Keywords:  Biological sciences; Cellular neuroscience; Natural sciences; Neuroscience; Systems neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.111642
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