bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒09‒08
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
  2. Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models.
  3. Mitochondrial transplants to treat mitochondrial dysfunction.
  4. Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
  5. mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
  6. Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
  7. A Review over Mitochondrial Diseases Due to mtDNA Mutations: Recent Advances and Remedial Aspects.
  8. Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.
  9. Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
  10. The Potential of Mitochondrial Therapeutics in the Treatment of Oxidative Stress and Inflammation in Aging.
  11. A Novel Molecular-Genetic Approach to the Monitoring of Dynamics of Mitochondrial Function Improvement during Treatment.
  12. Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons.
  13. Unconstrained precision mitochondrial genome editing with αDdCBEs.
  14. Regulation of mitochondrial quality control of intestinal stem cells in homeostasis and diseases.
  15. Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
  16. Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
  17. Older age reduces mtDNA mutation inheritance.
  18. Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
  19. POLG epilepsy presenting as new-onset refractory status epilepticus (NORSE) in pregnancy.
  20. Mitochondrial Extracellular Vesicles: A Promising Avenue for Diagnosing and Treating Lung Diseases.
  21. Mitophagy and cGAS-STING crosstalk in neuroinflammation.
  22. Transparent mice made with light-absorbing dye reveal organs at work.
  1. 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
  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.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  4. 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
  5. bioRxiv. 2024 Aug 07. pii: 2024.08.06.606942. [Epub ahead of print]
    mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
    Madison Lehmer, Roberto Zoncu.
      Lysosomes regulate mitochondrial function through multiple mechanisms including the master regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) protein kinase, which is activated at the lysosomal membrane by nutrient, growth factor and energy signals. mTORC1 promotes mitochondrial protein composition changes, respiratory capacity, and dynamics, though the full range of mitochondrial-regulating functions of this protein kinase remain undetermined. We find that acute chemical modulation of mTORC1 signaling decreased mitochondrial oxygen consumption, increased mitochondrial membrane potential and reduced susceptibility to stress-induced mitophagy. In cellular models of Friedreich's Ataxia (FA), where loss of the Frataxin (FXN) protein suppresses Fe-S cluster synthesis and mitochondrial respiration, the changes induced by mTORC1 inhibitors lead to improved cell survival. Proteomic-based profiling uncover compositional changes that could underlie mTORC1-dependent modulation of FXN-deficient mitochondria. These studies highlight mTORC1 signaling as a regulator of mitochondrial composition and function, prompting further evaluation of this pathway in the context of mitochondrial disease.
    DOI:  https://doi.org/10.1101/2024.08.06.606942
  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. 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
  8. Front Genet. 2024 ;15 1437959
    Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.
    Michela Di Nottia, Teresa Rizza, Enrico Baruffini, Claudia Nesti, Alessandra Torraco, Daria Diodato, Diego Martinelli, Flavio Dal Canto, Alexandru Ionut Gilea, Martina Zoccola, Barbara Siri, Carlo Dionisi-Vici, Enrico Bertini, Filippo Maria Santorelli, Paola Goffrini, Rosalba Carrozzo.
      Background: Mitochondria adjust their shape in response to the different energetic and metabolic requirements of the cell, through extremely dynamic fusion and fission events. Several highly conserved dynamin-like GTPases are involved in these processes and, among those, the OPA1 protein is a key player in the fusion of inner mitochondrial membranes. Hundreds of monoallelic or biallelic pathogenic gene variants have been described in OPA1, all associated with a plethora of clinical phenotypes without a straightforward genotype-phenotype correlation.Methods: Here we report two patients harboring novel de novo variants in OPA1. DNA of two patients was analyzed using NGS technology and the pathogenicity has been evaluated through biochemical and morphological studies in patient's derived fibroblasts and in yeast model.
    Results: The two patients here reported manifest with neurological signs resembling Leigh syndrome, thus further expanding the clinical spectrum associated with variants in OPA1. In cultured skin fibroblasts we observed a reduced amount of mitochondrial DNA (mtDNA) and altered mitochondrial network characterized by more fragmented mitochondria. Modeling in yeast allowed to define the deleterious mechanism and the pathogenicity of the identified gene mutations.
    Conclusion: We have described two novel-single OPA1 mutations in two patients characterized by early-onset neurological signs, never documented, thus expanding the clinical spectrum of this complex syndrome. Moreover, both yeast model and patients derived fibroblasts showed mitochondrial defects, including decreased mtDNA maintenance, correlating with patients' clinical phenotypes.
    Keywords:  OPA1; encephalomyopathy; mitochondrial diseases; mitochondrial dynamics; optic atrophy
    DOI:  https://doi.org/10.3389/fgene.2024.1437959
  9. J Biol Chem. 2024 Aug 28. pii: S0021-9258(24)02229-4. [Epub ahead of print] 107728
    Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
    Juanjuan Zhang, Wenxu Li, Zhen Liu, Yingqi Chen, Xiaoyang Wei, Lu Peng, Man Xu, Yanchun Ji.
      Leber's Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G>A homoplasmic mutation damaged the highly conserved basepairing (28C-42G) in anticodon stem of tRNAThr, caused deficient t6A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G>A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including initiation phase, formation and maturation of autophagosome. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G>A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G>A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis.
    Keywords:  Leber’s hereditary optic neuropathy (LHON); apoptosis; autophagy; mitochondrial tRNA(Thr) mutation; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2024.107728
  10. Mol Neurobiol. 2024 Sep 04.
    The Potential of Mitochondrial Therapeutics in the Treatment of Oxidative Stress and Inflammation in Aging.
    Jitendra Kumar Sinha, Khanak Jorwal, Krishna Kumar Singh, Sung Soo Han, Rakesh Bhaskar, Shampa Ghosh.
      Mitochondria are central to cellular energy production, and their dysfunction is a major contributor to oxidative stress and chronic inflammation, pivotal factors in aging, and related diseases. With aging, mitochondrial efficiency declines, leading to an increase in ROS and persistent inflammatory responses. Therapeutic interventions targeting mitochondrial health show promise in mitigating these detrimental effects. Antioxidants such as MitoQ and MitoVitE, and supplements like coenzyme Q10 and NAD + precursors, have demonstrated potential in reducing oxidative stress. Additionally, gene therapy aimed at enhancing mitochondrial function, alongside lifestyle modifications such as regular exercise and caloric restriction can ameliorate age-related mitochondrial decline. Exercise not only boosts mitochondrial biogenesis but also improves mitophagy. Enhancing mitophagy is a key strategy to prevent the accumulation of dysfunctional mitochondria, which is crucial for cellular homeostasis and longevity. Pharmacological agents like sulforaphane, SS-31, and resveratrol indirectly promote mitochondrial biogenesis and improve cellular resistance to oxidative damage. The exploration of mitochondrial therapeutics, including emerging techniques like mitochondrial transplantation, offers significant avenues for extending health span and combating age-related diseases. However, translating these findings into clinical practice requires overcoming challenges in precisely targeting dysfunctional mitochondria and optimizing delivery mechanisms for therapeutic agents. Continued research is essential to refine these approaches and fully understand the interplay between mitochondrial dynamics and aging.
    Keywords:  Aging; Calorie restriction; Chronic inflammation; Mitochondrial biogenesis; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-024-04474-0
  11. Front Biosci (Landmark Ed). 2024 Aug 21. 29(8): 297
    A Novel Molecular-Genetic Approach to the Monitoring of Dynamics of Mitochondrial Function Improvement during Treatment.
    Mariya A Smetanina, Valeria A Korolenya, Maxim L Filipenko.
      Making a correct genetically based diagnosis in patients with diseases associated with mitochondrial dysfunction can be challenging both genetically and clinically, as can further management of such patients on the basis of molecular-genetic data assessing the state of their mitochondria. In this opinion article, we propose a novel approach (which may result in a clinical protocol) to the use of a precise molecular-genetic tool in order to monitor the state of mitochondria (which reflects their function) during treatment of certain conditions, by means of not only signs and symptoms but also the molecular-genetic basis of the current condition. This is an example of application of personalized genomic medicine at the intersection of a person's mitochondrial genome information and clinical care. Advantages of the proposed approach are its relatively low cost (compared to various types of sequencing), an ability to use samples with a low input amount of genetic material, and rapidness. When this approach receives positive outside reviews and gets an approval of experts in the field (in terms of the standards), it may then be picked up by other developers and introduced into clinical practice.
    Keywords:  ND4-region mtDNA deletions; mitochondrial DNA; mtDNA; mtDNA copy number; mtDNA heteroplasmy; treatment/recovery progress monitoring
    DOI:  https://doi.org/10.31083/j.fbl2908297
  12. Sci Rep. 2024 09 04. 14(1): 20565
    Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons.
    Danielle L Tomasello, M Inmaculada Barrasa, David Mankus, Katia I Alarcon, Abigail K R Lytton-Jean, X Shawn Liu, Rudolf Jaenisch.
      Studies on MECP2 function and its implications in Rett Syndrome (RTT) have traditionally centered on neurons. Here, using human embryonic stem cell (hESC) lines, we modeled MECP2 loss-of-function to explore its effects on astrocyte (AST) development and dysfunction in the brain. Ultrastructural analysis of RTT hESC-derived cerebral organoids revealed significantly smaller mitochondria compared to controls (CTRs), particularly pronounced in glia versus neurons. Employing a multiomics approach, we observed increased gene expression and accessibility of a subset of nuclear-encoded mitochondrial genes upon mutation of MECP2 in ASTs compared to neurons. Analysis of hESC-derived ASTs showed reduced mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in RTT versus CTRs. Additionally, RTT ASTs exhibited increased cytosolic amino acids under basal conditions, which were depleted upon increased energy demands. Notably, mitochondria isolated from RTT ASTs exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons. These findings underscore MECP2 mutation's differential impact on mitochondrial and metabolic pathways in ASTs versus neurons, suggesting that dysfunctional AST mitochondria may contribute to RTT pathophysiology by affecting neuronal health.
    Keywords:  Amino acid metabolism; Astrocyte; Electrophysiology; MECP2; Mitochondrial transplantation; Neurodevelopment; Rett syndrome; Single nuclei ATAC-seq; Single nuclei RNA-seq; Stem cells
    DOI:  https://doi.org/10.1038/s41598-024-71040-y
  13. 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
  14. Antioxid Redox Signal. 2024 Sep 03.
    Regulation of mitochondrial quality control of intestinal stem cells in homeostasis and diseases.
    Xudan Lei, Zhenni Xu, Yujun Huang, Lingxiao Huang, Jinyi Lang, Mingyue Qu, Dengqun Liu.
      SIGNIFICANCE: Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases.RECENT ADVANCES: In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating of ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological condition and protects against intestinal injury remains to be comprehensively reviewed.
    CRITICAL ISSUES: In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy and proteostasis impact ISC proliferation, differentiation and regeneration, respectively.
    FUTURE DIRECTIONS: We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases.
    DOI:  https://doi.org/10.1089/ars.2023.0489
  15. Life Sci Alliance. 2024 Nov;pii: e202402764. [Epub ahead of print]7(11):
    Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
    Vanessa Xavier, Silvia Martinelli, Ryan Corbyn, Rachel Pennie, Kai Rakovic, Ian R Powley, Leah Officer-Jones, Vincenzo Ruscica, Alison Galloway, Leo M Carlin, Victoria H Cowling, John Le Quesne, Jean-Claude Martinou, Thomas MacVicar.
      Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing and maturation of mitochondrial RNA (mtRNA) and mitoribosome assembly are localised to mitochondrial RNA granules. The bidirectional transcription of circular mtDNA can lead to the hybridisation of polycistronic transcripts and the formation of immunogenic mitochondrial double-stranded RNA (mt-dsRNA). However, the mechanisms that regulate mt-dsRNA localisation and homeostasis are largely unknown. With super-resolution microscopy, we show that mt-dsRNA overlaps with the RNA core and associated proteins of mitochondrial RNA granules but not nucleoids. Mt-dsRNA foci accumulate upon the stimulation of cell proliferation and their abundance depends on mitochondrial ribonucleotide supply by the nucleoside diphosphate kinase, NME6. Consequently, mt-dsRNA foci are profuse in cultured cancer cells and malignant cells of human tumour biopsies. Our results establish a new link between cell proliferation and mitochondrial nucleic acid homeostasis.
    DOI:  https://doi.org/10.26508/lsa.202402764
  16. Nat Commun. 2024 Sep 03. 15(1): 7665
    Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    Lars Mohren, Friedrich Erdlenbruch, Elsa Leitão, Fabian Kilpert, G Sebastian Hönes, Sabine Kaya, Christopher Schröder, Andreas Thieme, Marc Sturm, Joohyun Park, Agatha Schlüter, Montserrat Ruiz, Moisés Morales de la Prida, Carlos Casasnovas, Kerstin Becker, Ulla Roggenbuck, Sonali Pechlivanis, Frank J Kaiser, Matthis Synofzik, Thomas Wirth, Mathieu Anheim, Tobias B Haack, Paul J Lockhart, Karl-Heinz Jöckel, Aurora Pujol, Stephan Klebe, Dagmar Timmann, Christel Depienne.
      Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.
    DOI:  https://doi.org/10.1038/s41467-024-52148-1
  17. Nat Aging. 2024 Sep 04.
    Older age reduces mtDNA mutation inheritance.
    Polyxeni Papadea, Nils-Göran Larsson.
      
    DOI:  https://doi.org/10.1038/s43587-024-00701-4
  18. Nat Commun. 2024 Sep 03. 15(1): 7677
    Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
    Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.
      Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.
    DOI:  https://doi.org/10.1038/s41467-024-50632-2
  19. Pract Neurol. 2024 Aug 28. pii: pn-2024-004232. [Epub ahead of print]
    POLG epilepsy presenting as new-onset refractory status epilepticus (NORSE) in pregnancy.
    Viva Levee, Karthikeyan Sivaganesh, Andrew Schaeffer, Kushan Karunaratne.
      A 21-year-old woman developed explosive new-onset refractory status epilepticus when 18 weeks pregnant. She had been previously well with no history of seizures and a normal developmental history. She had initially presented with focal impaired awareness seizures but subsequently developed status epilepticus requiring intensive care unit admission and was successfully treated with multiple anti-seizure medications. Once stabilised she was stepped down to the inpatient neurology ward and then transferred to the tertiary centre for a planned late termination of pregnancy, which was the patient's choice. Following transfer, she again developed refractory status epilepticus, requiring intensive care readmission. Subsequent investigations identified a compound heterozygous POLG genetic mutation. We discuss the challenges in the acute clinical situation and important considerations in the diagnosis and management of POLG-related epilepsy.
    Keywords:  EPILEPSY; MITOCHONDRIAL DISORDERS
    DOI:  https://doi.org/10.1136/pn-2024-004232
  20. ACS Nano. 2024 Sep 03.
    Mitochondrial Extracellular Vesicles: A Promising Avenue for Diagnosing and Treating Lung Diseases.
    Fengxia Ding, Mi Zhou, Yinying Ren, Yan Li, Jinying Xiang, Yuehan Li, Jinyue Yu, Ying Hong, Zhou Fu, Hongbo Li, Zhengxia Pan, Bo Liu.
      Mitochondria, pivotal organelles governing cellular biosynthesis, energy metabolism, and signal transduction, maintain dynamic equilibrium through processes such as biogenesis, fusion, fission, and mitophagy. Growing evidence implicates mitochondrial dysfunction in a spectrum of respiratory diseases including acute lung injury/acute respiratory distress syndrome, bronchial asthma, pulmonary fibrosis, chronic obstructive pulmonary disease, and lung cancer. Consequently, identifying methods capable of ameliorating damaged mitochondrial function is crucial for the treatment of pulmonary diseases. Extracellular vesicles (EVs), nanosized membrane vesicles released by cells into the extracellular space, facilitate intercellular communication by transferring bioactive substances or signals between cells or organs. Recent studies have identified abundant mitochondrial components within specific subsets of EVs, termed mitochondrial extracellular vesicles (mitoEVs), whose contents and compositions vary with disease progression. Moreover, mitoEVs have demonstrated reparative mitochondrial functions in injured recipient cells. However, a comprehensive understanding of mitoEVs is currently lacking, limiting their clinical translation prospects. This Review explores the biogenesis, classification, functional mitochondrial cargo, and biological effects of mitoEVs, with a focus on their role in pulmonary diseases. Emphasis is placed on their potential as biological markers and innovative therapeutic strategies in pulmonary diseases, offering fresh insights for mechanistic studies and drug development in various pulmonary disorders.
    Keywords:  Biomarkers; Cellular communication; Extracellular vesicle; MitoEVs; Mitochondria; Mitochondrial dysfunction; Pulmonary diseases; Therapeutic strategies
    DOI:  https://doi.org/10.1021/acsnano.4c02940
  21. Acta Pharm Sin B. 2024 Aug;14(8): 3327-3361
    Mitophagy and cGAS-STING crosstalk in neuroinflammation.
    Xiaogang Zhou, Jing Wang, Lu Yu, Gan Qiao, Dalian Qin, Betty Yuen-Kwan Law, Fang Ren, Jianming Wu, Anguo Wu.
      Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS-STING pathway, which is crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress response. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway. We critically evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, which activates the cGAS-STING pathway. This activation prompts the production of pro-inflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS-STING pathways. Effective mitophagy may suppress the cGAS-STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS-STING pathway, leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism underlying these diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.
    Keywords:  Crosstalk; Innate immunity; Mitochondrial DNA; Mitophagy; Neurodegenerative diseases; Neuroinflammation; Therapeutic avenues; cGAS–STING
    DOI:  https://doi.org/10.1016/j.apsb.2024.05.012
  22. Nature. 2024 Sep 05.
    Transparent mice made with light-absorbing dye reveal organs at work.
    Jude Coleman.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02887-4
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