bims-curels Biomed News
on Leigh syndrome
Issue of 2024–09–08
nine papers selected by
Cure Mito Foundation
  1. A Review over Mitochondrial Diseases Due to mtDNA Mutations: Recent Advances and Remedial Aspects.
  2. Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models.
  3. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
  4. Mitochondrial transplants to treat mitochondrial dysfunction.
  5. Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
  6. Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
  7. Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.
  8. Unconstrained precision mitochondrial genome editing with αDdCBEs.
  9. Experiences of quality of life and access to health services among rare disease caregivers: a scoping review.
  1. Infect Disord Drug Targets. 2024 Sep 04.
    A Review over Mitochondrial Diseases Due to mtDNA Mutations: Recent Advances and Remedial Aspects.
    Alok Bharadwaj.
      Mitochondria, also called 'powerhouse of the cell', is meant for energy generation in eukaryotic cells. This action is performed by mitochondria through the oxidative phosphor-ylation (OXPHOS) of the respiratory chain (RC). Based on the functioning of the cell, the number of mitochondria varies up to thousands in number. Mutations in the mitochondrial DNA (mtDNA) and/or nuclear DNA (nDNA) genes may lead to the generation of primary mitochondrial disease (PMD) that affects the structure and function of mitochondria. The di-agnosis of such mitochondrial diseases occurs in early childhood and it can lead to serious, fetal and multi-organ diseases. Understanding epigenetic events and changes in the pathway can help improve the effectiveness of treatment. However, there are several reasons lack of the disease symptoms (age, sign, symptoms, morbidity and lethality), restricted availability of pre-clinical models along with extensive phenotypes that hamper the development of efficient drugs. Despite the introduction of new treatments and the encouraging results of treatments and therapies, there is no effective cure for PMD. This article contains information about the changes associated with cytopathic diseases that make possible the analysis of various diseases by genetic techniques. Increasing our under-standing of how mitochondrial DNA mutations affect mitochondrial metabolism and subse-quently result in neurodegenerative disease will prove vital to the development of targeted therapies and treatments.
    Keywords:  Mitochondrial diseases; genetic techniques; mitochon-drial genome.; mtDNA mutations; multi-organ diseases; remedial aspects
    DOI:  https://doi.org/10.2174/0118715265304029240801092834
  2. Nat Commun. 2024 Sep 04. 15(1): 7730
    Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models.
    Emma Puighermanal, Marta Luna-Sánchez, Alejandro Gella, Gunter van der Walt, Andrea Urpi, María Royo, Paula Tena-Morraja, Isabella Appiah, Maria Helena de Donato, Fabien Menardy, Patrizia Bianchi, Anna Esteve-Codina, Laura Rodríguez-Pascau, Cristina Vergara, Mercè Gómez-Pallarès, Giovanni Marsicano, Luigi Bellocchio, Marc Martinell, Elisenda Sanz, Sandra Jurado, Francesc Xavier Soriano, Pilar Pizcueta, Albert Quintana.
      Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.
    DOI:  https://doi.org/10.1038/s41467-024-51884-8
  3. Nat Metab. 2024 Sep 02.
    Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
    Ritsuko Nakai, Stella Varnum, Rachael L Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J Krysa, Eva F Cohen, Nicholas Borcherding, Russell P Saneto, Rick C Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R Brestoff.
      Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
    DOI:  https://doi.org/10.1038/s42255-024-01125-5
  4. Nat Metab. 2024 Sep 02.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  5. Hum Mol Genet. 2024 Sep 03. 33(18): 1630-1641
    Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
    Sonia Figuccia, Rossella Izzo, Andrea Legati, Alessia Nasca, Paola Goffrini, Daniele Ghezzi, Camilla Ceccatelli Berti.
      Aminoacyl-transfer RiboNucleic Acid synthetases (ARSs) are essential enzymes that catalyze the attachment of each amino acid to their cognate tRNAs. Mitochondrial ARSs (mtARSs), which ensure protein synthesis within the mitochondria, are encoded by nuclear genes and imported into the organelle after translation in the cytosol. The extensive use of next generation sequencing (NGS) has resulted in an increasing number of variants in mtARS genes being identified and associated with mitochondrial diseases. The similarities between yeast and human mitochondrial translation machineries make yeast a good model to quickly and efficiently evaluate the effect of variants in mtARS genes. Genetic screening of patients with a clinical suspicion of mitochondrial disorders through a customized gene panel of known disease-genes, including all genes encoding mtARSs, led to the identification of missense variants in WARS2, NARS2 and RARS2. Most of them were classified as Variant of Uncertain Significance. We exploited yeast models to assess the functional consequences of the variants found in these genes encoding mitochondrial tryptophanyl-tRNA, asparaginyl-tRNA, and arginyl-tRNA synthetases, respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate, Cox2 steady-state level and mitochondrial protein synthesis were analyzed in yeast strains deleted in MSW1, SLM5, and MSR1 (the yeast orthologues of WARS2, NARS2 and RARS2, respectively), and expressing the wild type or the mutant alleles. Pathogenicity was confirmed for most variants, leading to their reclassification as Likely Pathogenic. Moreover, the beneficial effects observed after asparagine and arginine supplementation in the growth medium suggest them as a potential therapeutic approach.
    Keywords:  mitochondrial aminoacyl-tRNA synthetases; mitochondrial diseases; novel variants; yeast model
    DOI:  https://doi.org/10.1093/hmg/ddae104
  6. Ann Neurol. 2024 Sep 04.
    Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
    Agustin Hidalgo-Gutierrez, Jonathan Shintaku, Javier Ramon, Eliana Barriocanal-Casado, Alba Pesini, Russell P Saneto, Gloria Garrabou, Jose Cesar Milisenda, Ana Matas-Garcia, Laura Gort, Olatz Ugarteburu, Yue Gu, Lahari Koganti, Tian Wang, Saba Tadesse, Megi Meneri, Monica Sciacco, Shuang Wang, Kurenai Tanji, Marshall S Horwitz, Michael O Dorschner, Mahesh Mansukhani, Giacomo Pietro Comi, Dario Ronchi, Ramon Marti, Antonia Ribes, Frederic Tort, Michio Hirano.
       OBJECTIVE: Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.
    METHODS: Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells.
    RESULTS: We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies.
    INTERPRETATION: Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024.
    DOI:  https://doi.org/10.1002/ana.27071
  7. Traffic. 2024 Sep;25(9): e12951
    Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.
    Huimei Liu, Hui Mao, Xueqian Ouyang, Ruirui Lu, Lanfang Li.
      Mitochondria, the dynamic organelles responsible for energy production and cellular metabolism, have the metabolic function of extracting energy from nutrients and synthesizing crucial metabolites. Nevertheless, recent research unveils that intercellular mitochondrial transfer by tunneling nanotubes, tumor microtubes, gap junction intercellular communication, extracellular vesicles, endocytosis and cell fusion may regulate mitochondrial function within recipient cells, potentially contributing to disease treatment, such as nonalcoholic steatohepatitis, glioblastoma, ischemic stroke, bladder cancer and neurodegenerative diseases. This review introduces the principal approaches to intercellular mitochondrial transfer and examines its role in various diseases. Furthermore, we provide a comprehensive overview of the inhibitors and activators of intercellular mitochondrial transfer, offering a unique perspective to illustrate the relationship between intercellular mitochondrial transfer and diseases.
    Keywords:  cell fusion; endocytosis; extracellular vesicles; gap junction intercellular communication; intercellular mitochondrial transfer; tumor microtube; tunneling nanotubes
    DOI:  https://doi.org/10.1111/tra.12951
  8. Hum Gene Ther. 2024 Aug 30.
    Unconstrained precision mitochondrial genome editing with αDdCBEs.
    Santiago R Castillo, Brandon W Simone, Karl J Clark, Patricia Devaux, Stephen C Ekker.
      DddA-derived cytosine base editors (DdCBEs) enable the targeted introduction of C•G-to-T•A conversions in mitochondrial DNA (mtDNA). DdCBEs work in pairs, with each arm composed of a transcription activator-like effector (TALE), a split double-stranded DNA deaminase half, and a uracil glycosylase inhibitor. This pioneering technology has helped improve our understanding of cellular processes involving mtDNA and has paved the way for the development of models and therapies for genetic disorders caused by pathogenic mtDNA variants. Nonetheless, given the intrinsic properties of TALE proteins, several target sites in human mtDNA are predicted to remain out of reach to DdCBEs and other TALE-based technologies. Specifically, due to the conventional requirement for a thymine immediately upstream of the TALE target sequences (i.e., the 5'-T constraint), over 150 loci in the human mitochondrial genome are presumed to be inaccessible to DdCBEs. Previous attempts at circumventing this requirement, either by developing monomeric DdCBEs or utilizing DNA-binding domains alternative to TALEs, have resulted in suboptimal specificity profiles with reduced therapeutic potential. Here, aiming to challenge and elucidate the relevance of the 5'-T constraint in the context of DdCBE-mediated mtDNA editing, and to expand the range of motifs that are editable by this technology, we generated DdCBEs containing TALE proteins engineered to recognize all 5' bases. These modified DdCBEs are herein referred to as αDdCBEs. Notably, 5'-T-noncompliant canonical DdCBEs efficiently edited mtDNA at diverse loci. However, they were frequently outperformed by αDdCBEs, which exhibited significant improvements in activity and specificity, regardless of the most 5' bases of their TALE binding sites. Furthermore, we showed that αDdCBEs are compatible with the enhanced DddAtox variants DddA6 and DddA11, and we validated TALE shifting with αDdCBEs as an effective approach to optimize base editing outcomes. Overall, αDdCBEs enable efficient, specific, and unconstrained mitochondrial base editing.
    DOI:  https://doi.org/10.1089/hum.2024.073
  9. Orphanet J Rare Dis. 2024 Aug 31. 19(1): 319
    Experiences of quality of life and access to health services among rare disease caregivers: a scoping review.
    Tina Černe, Lijana Zaletel Kragelj, Eva Turk, Danica Rotar Pavlič.
       BACKGROUND: Research on rare diseases focuses less on caregivers, who play an important role in meeting the medical and social needs of the people they care for. Caregivers of people with rare diseases face negative outcomes due to problems with diagnosis, caring for complex conditions and expensive treatments. However, the factors that affect their quality of life are poorly understood. Poor mental and physical health of caregivers has a direct impact on the person they are caring for.
    METHODS: To explore the literature on this topic, we conducted a scoping review in which we identified and analysed relevant studies to find out how extensively this topic has been researched. The articles were retrieved from the bibliographic databases PubMed, Ovid Medline and Ebsco Cinahl.
    RESULTS: We initially identified 299 references and then included thirty-four articles. The included articles address three main topics, namely caregiver quality of life, health care accessibility, and the impact of health care accessibility on caregiver QOL.
    CONCLUSION: This study provides information that is important to multiple providers of services as it can help to better understand caregivers and people with rare diseases and improve the quality of services offered. It highlights areas with the greatest need for change and offers insight into the complexity of caring for people with rare diseases, assisting policymakers in developing policies to support informal caregivers.
    Keywords:  Access to health care; Caregivers; Quality of life; Rare diseases
    DOI:  https://doi.org/10.1186/s13023-024-03327-2
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