bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–09–08
fifty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial transplants to treat mitochondrial dysfunction.
  2. Poly(A) Tail Length of Messenger RNA Regulates Translational Efficiency of the Mitochondria-Targeting Delivery System.
  3. A Review over Mitochondrial Diseases Due to mtDNA Mutations: Recent Advances and Remedial Aspects.
  4. Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
  5. Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.
  6. Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
  7. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
  8. Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
  9. From mitochondrial dysfunction to neuroinflammation in Parkinson's disease: Pathogenesis and mitochondrial therapeutic approaches.
  10. Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
  11. Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
  12. A Novel Molecular-Genetic Approach to the Monitoring of Dynamics of Mitochondrial Function Improvement during Treatment.
  13. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
  14. Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
  15. Endocrinological features and epileptic encephalopathy in COX deficiency due to SCO1 mutations: case series and review of literature.
  16. The Potential of Mitochondrial Therapeutics in the Treatment of Oxidative Stress and Inflammation in Aging.
  17. Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.
  18. Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models.
  19. Unconstrained precision mitochondrial genome editing with αDdCBEs.
  20. Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
  21. SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
  22. Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins.
  23. Older age reduces mtDNA mutation inheritance.
  24. Major Causes of Conflicting Interpretations of Variant Pathogenicity in Rare Disease: A Systematic Analysis.
  25. TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
  26. Biogenesis and secretion of mitovesicles, small extracellular vesicles of mitochondrial origin at the crossroads between brain health and disease.
  27. Robustness and reliability of single-cell regulatory multi-omics with deep mitochondrial mutation profiling.
  28. Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.
  29. Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.
  30. F-ATP synthase inhibitory factor 1 and mitochondria-organelle interactions: New insight and implications.
  31. Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
  32. Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.
  33. mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
  34. Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.
  35. Mechanisms and Effects of Activation of Innate Immunity by Mitochondrial Nucleic Acids.
  36. Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a 'snap-through' instability.
  37. Patient mutations in DRP1 perturb synaptic maturation of cortical neurons.
  38. Young small extracellular vesicles rejuvenate replicative senescence by remodeling Drp1 translocation-mediated mitochondrial dynamics.
  39. Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.
  40. Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
  41. Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.
  42. Mitophagy and cGAS-STING crosstalk in neuroinflammation.
  43. Leveraging Generative AI to Accelerate Biocuration of Medical Actions for Rare Disease.
  44. Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.
  45. A framework for sharing of clinical and genetic data for precision medicine applications.
  46. Phenotypic spectrum of iron-sulfur cluster assembly gene IBA57 mutations: c.286 T > C identified as a hotspot mutation in Chinese patients with a stable natural history.
  47. Deciphering the impact of genomic variation on function.
  48. ImAge quantitates aging and rejuvenation.
  49. POLG epilepsy presenting as new-onset refractory status epilepticus (NORSE) in pregnancy.
  50. Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet - an exploratory study.
  1. Nat Metab. 2024 Sep 02.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  2. ACS Biomater Sci Eng. 2024 Sep 04.
    Poly(A) Tail Length of Messenger RNA Regulates Translational Efficiency of the Mitochondria-Targeting Delivery System.
    Naoto Yoshinaga, Keiji Numata.
      Mitochondria are essential for cellular functions, such as energy production. Human mitochondrial DNA (mtDNA), encoding 13 distinct genes, two rRNA, and 22 tRNA, is crucial for maintaining vital functions, along with nuclear-encoded mitochondrial proteins. However, mtDNA is prone to somatic mutations due to replication errors and reactive oxygen species exposure. These mutations can accumulate, leading to heteroplasmic conditions associated with severe metabolic diseases. Therefore, developing methodologies to improve mitochondrial health is highly demanded. Introducing nucleic acids directly into mitochondria is a promising strategy to control mitochondrial gene expression. Messenger RNA (mRNA) delivery especially offers several advantages such as faster gene expression and reduced risk of genome integration if accidentally delivered to the cell nucleus. In this study, we investigated the effect of the poly(A) tail length of mRNA on the mitochondrial translation to achieve efficient expression. We used a peptide-based mitochondrial targeting system, mitoNEET-(RH)9, comprising a mitochondria-targeting sequence (MTS) and a cationic sequence, to deliver mRNA with various poly(A) tails into the mitochondria. The poly(A) tail length significantly affected translational efficiency, with a medium length of 60 nucleotides maximizing protein expression in various cell lines due to enhanced interaction with mitochondrial RNA-binding proteins. Our findings highlight the importance of optimizing poly(A) tail length for efficient mitochondrial mRNA translation, providing a potential strategy for improving mitochondrial gene therapy. These results pave the way for further exploration of the mechanisms and clinical applications of mitochondrial mRNA delivery systems.
    Keywords:  mRNA; mitochondria; mitochondria-targeting peptide; polyplexes
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c01169
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. FEBS Lett. 2024 Sep 03.
    Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
    Lishu Guo.
      The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.
    Keywords:  F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition
    DOI:  https://doi.org/10.1002/1873-3468.15008
  9. Int Immunopharmacol. 2024 Sep 01. pii: S1567-5769(24)01536-4. [Epub ahead of print]142(Pt A): 113015
    From mitochondrial dysfunction to neuroinflammation in Parkinson's disease: Pathogenesis and mitochondrial therapeutic approaches.
    Negar Ebadpour, Mahmoud Mahmoudi, Ramiar Kamal Kheder, Mohammad Abavisani, Zahra Baridjavadi, Narges Abdollahi, Seyed-Alireza Esmaeili.
      Parkinson's disease (PD) is a prevalent and intricate neurological condition resulting from a combination of several factors, such as genetics, environment, and the natural process of aging. Degeneration of neurons in the substantia nigra pars compacta (SN) can cause motor and non-motor impairments in patients with PD. In PD's etiology, inflammation and mitochondrial dysfunction play significant roles in the disease's development. Studies of individuals with PD have revealed increased inflammation in various brain areas. Furthermore, mitochondrial dysfunction is an essential part of PD pathophysiology. Defects in the components of the mitochondrial nucleus, its membrane or internal signaling pathways, mitochondrial homeostasis, and morphological alterations in peripheral cells have been extensively documented in PD patients. According to these studies, neuroinflammation and mitochondrial dysfunction are closely connected as pathogenic conditions in neurodegenerative diseases like PD. Given the mitochondria's role in cellular homeostasis maintenance in response to membrane structural flaws or mutations in mitochondrial DNA, their dynamic nature may present therapeutic prospects in this area. Recent research investigates mitochondrial transplantation as a potential treatment for Parkinson's disease in damaged neurons. This review delves into the impact of inflammation and mitochondrial dysfunction on PD occurrence, treatment approaches, and the latest developments in mitochondrial transplantation, highlighting the potential consequences of these discoveries.
    Keywords:  Mitochondria; Mitotherapy; Neurodegenerative disease; Neuroinflammation; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.intimp.2024.113015
  10. 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
  11. 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
  12. 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
  13. J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
    Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model
    DOI:  https://doi.org/10.1016/j.jbc.2024.107740
  14. J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746
    Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
    Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.
      Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
    Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1016/j.jbc.2024.107746
  15. Endocr Connect. 2024 Aug 01. pii: EC-24-0221. [Epub ahead of print]
    Endocrinological features and epileptic encephalopathy in COX deficiency due to SCO1 mutations: case series and review of literature.
    Alessandro Barbato, Giulia Gori, Michele Sacchini, Francesca Pochiero, Sara Bargiacchi, Giovanna Traficante, Viviana Palazzo, Lucia Tiberi, Claudia Bianchini, Davide Mei, Elena Parrini, Tiziana Pisano, Elena Procopio, Renzo Guerrini, Angela Peron, Stefano Stagi.
       CONTEXT: Cytochrome C oxidase (COX) is the fourth component of the respiratory chain and is located within the internal membrane of mitochondria. COX deficiency causes an inherited mitochondrial disease with significant genetic and phenotypic heterogeneity. Four clinical subtypes have been identified, each with distinct phenotypes and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is a form of COX deficiency associated with pathogenetic variants in the SCO1 gene.
    CASE DESCRIPTION: We describe three patients with MC4DN4 with developmental and epileptic encephalopathy (DEE), hypopituitarism and SCO1 pathogenic variants. These patients' phenotypes considerably differ from previously reported MC4DN4 phenotypes as they associated DEE with progressive hypopituitarism and survival beyond the first months after birth. Pituitary deficiency in these patients progressively worsened and mainly involved growth hormone secretion and thyroid function.
    CONCLUSIONS: Our findings expand knowledge of phenotypic variability in MC4DN4 and suggests that SCO1 is a candidate gene for genetic hypopituitarism and DEE.
    DOI:  https://doi.org/10.1530/EC-24-0221
  16. 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
  17. Nat Commun. 2024 Sep 05. 15(1): 7746
    Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.
    Min Yang, Jing Ge, Yu-Lian Liu, Huan-Yu Wang, Zhi-Han Wang, Dan-Pei Li, Rui He, Yu-Yu Xie, Hong-Yan Deng, Xue-Min Peng, Wen-She Wang, Jia-Dai Liu, Zeng-Zhe Zhu, Xue-Feng Yu, Pema Maretich, Shingo Kajimura, Ru-Ping Pan, Yong Chen.
      Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52218-4
  18. 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
  19. 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
  20. Autophagy. 2024 Sep 03. 1-3
    Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
    Hao Liu, Jianming Xie, Cien Zhen, Lin Zeng, Hualin Fan, Haixia Zhuang, Du Feng.
      Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term "nucleoid-phagy", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.
    Keywords:  Autophagy; CGAS-STING1; LIR; TFAM; mitochondria DNA
    DOI:  https://doi.org/10.1080/15548627.2024.2395145
  21. Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952
    SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
    Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.
      Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.
    Keywords:  Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)
    DOI:  https://doi.org/10.1016/j.mito.2024.101952
  22. J Neurochem. 2024 Aug 30.
    Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins.
    Neville Vassallo.
      Mitochondria are essential organelles known to serve broad functions, including in cellular metabolism, calcium buffering, signaling pathways and the regulation of apoptotic cell death. Maintaining the integrity of the outer (OMM) and inner mitochondrial membranes (IMM) is vital for mitochondrial health. Cardiolipin (CL), a unique dimeric glycerophospholipid, is the signature lipid of energy-converting membranes. It plays a significant role in maintaining mitochondrial architecture and function, stabilizing protein complexes and facilitating efficient oxidative phosphorylation (OXPHOS) whilst regulating cytochrome c release from mitochondria. CL is especially enriched in the IMM and at sites of contact between the OMM and IMM. Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid-β, tau and α-synuclein, which form metastable toxic oligomeric species that interact with biological membranes. Electrophysiological studies have shown that these oligomers form ion-conducting nanopores in membranes mimicking the IMM's phospholipid composition. Poration of mitochondrial membranes disrupts the ionic balance, causing osmotic swelling, loss of the voltage potential across the IMM, release of pro-apoptogenic factors, and leads to cell death. The interaction between CL and amyloid oligomers appears to favour their membrane insertion and pore formation, directly implicating CL in amyloid toxicity. Additionally, pore formation in mitochondrial membranes is not limited to amyloid proteins and peptides; other biological peptides, as diverse as the pro-apoptotic Bcl-2 family members, gasdermin proteins, cobra venom cardiotoxins and bacterial pathogenic toxins, have all been described to punch holes in mitochondria, contributing to cell death processes. Collectively, these findings underscore the vulnerability of mitochondria and the involvement of CL in various pathogenic mechanisms, emphasizing the need for further research on targeting CL-amyloid interactions to mitigate mitochondrial dysfunction.
    Keywords:  amyloid proteins; cardiolipin; cytotoxins; membranes; mitochondria; pores
    DOI:  https://doi.org/10.1111/jnc.16213
  23. 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
  24. J Pers Med. 2024 Aug 15. pii: 864. [Epub ahead of print]14(8):
    Major Causes of Conflicting Interpretations of Variant Pathogenicity in Rare Disease: A Systematic Analysis.
    Tatyana E Lazareva, Yury A Barbitoff, Yulia A Nasykhova, Andrey S Glotov.
      The identification of the genetic causes of inherited disorders from next-generation sequencing (NGS) data remains a complicated process, in particular due to challenges in interpretation of the vast amount of generated data and hundreds of candidate variants identified. Inconsistencies in variant classification, where genetic centers classify the same variant differently, can hinder accurate diagnoses for rare diseases. Publicly available databases that collect data on human genetic variations and their association with diseases provide ample opportunities to discover conflicts in variant interpretation worldwide. In this study, we explored patterns of variant classification discrepancies using data from ClinVar, a public archive of variant interpretations. We found that 5.7% of variants have conflicting interpretations (COIs) reported, and the vast majority of interpretation conflicts arise for variants of uncertain significance (VUS). As many as 78% of clinically relevant genes harbor variants with COIs, and genes with high COI rates tended to have more exons and longer transcripts, with a greater proportion of genes linked to several distinct conditions. The enrichment analysis of COI-enriched genes revealed that the products of these genes are involved in cardiac disorders, muscle development, and function. To improve diagnoses, we believe that specific variant interpretation rules could be developed for such genes. Additionally, our findings underscore the need for the publication of variant pathogenicity evidence and the importance of considering every variant as VUS unless proven otherwise.
    Keywords:  ClinVar; conflicting interpretations of pathogenicity; genetic variants; variant interpretation
    DOI:  https://doi.org/10.3390/jpm14080864
  25. J Mol Med (Berl). 2024 Aug 29.
    TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
    Giuseppina Bruno, Michele Pietrafesa, Fabiana Crispo, Annamaria Piscazzi, Francesca Maddalena, Guido Giordano, Vincenza Conteduca, Marianna Garofoli, Almudena Porras, Franca Esposito, Matteo Landriscina.
      Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.
    Keywords:  Colorectal cancer; Metabolism; Mitochondrial biogenesis; Peroxisome proliferation-activated receptor gamma coactivator α1-alpha; TNF receptor-associated protein 1; Transcription factor A mitochondrial
    DOI:  https://doi.org/10.1007/s00109-024-02479-9
  26. Curr Opin Physiol. 2024 Aug;pii: 100765. [Epub ahead of print]40
    Biogenesis and secretion of mitovesicles, small extracellular vesicles of mitochondrial origin at the crossroads between brain health and disease.
    Yohan Kim, Pasquale D'Acunzo, Efrat Levy.
      In the brain, mitochondrial components are released into the extracellular space via several mechanisms, including a recently identified type of extracellular vesicles called mitovesicles. While vesiculation of neuronal mitochondria yields various intracellular types of vesicles, with either a single or a double membrane, mitovesicles secreted into the extracellular space are a unique subtype of these mitochondria-derived vesicles, with a double membrane and a specific set of mitochondrial DNA, RNA, proteins, and lipids. Based on the most relevant literature describing mitochondrial vesiculation and mitochondrial exocytosis, we propose a model for their secretion when the amphisome, a hybrid endosome-autophagosome organelle, fuses with the plasma membrane, releasing mitovesicles and exosomes into the extracellular space. In aging and neurodegenerative disorders, mitochondrial dysfunction, in association with endolysosomal abnormalities, alter mitovesicle number and content, with downstream effect on brain health.
    DOI:  https://doi.org/10.1016/j.cophys.2024.100765
  27. bioRxiv. 2024 Aug 24. pii: 2024.08.23.609473. [Epub ahead of print]
    Robustness and reliability of single-cell regulatory multi-omics with deep mitochondrial mutation profiling.
    Chen Weng, Jonathan S Weissman, Vijay G Sankaran.
      The detection of mitochondrial DNA (mtDNA) mutations in single cells holds considerable potential to define clonal relationships coupled with information on cell state in humans. Previous methods focused on higher heteroplasmy mutations that are limited in number and can be influenced by functional selection, introducing biases for lineage tracing. Although more challenging to detect, intermediate to low heteroplasmy mtDNA mutations are valuable due to their high diversity, abundance, and lower propensity to selection. To enhance mtDNA mutation detection and facilitate fine-scale lineage tracing, we developed the single-cell Regulatory multi-omics with Deep Mitochondrial mutation profiling (ReDeeM) approach, an integrated experimental and computational framework. Recently, some concerns have been raised about the analytical workflow in the ReDeeM framework. Specifically, it was noted that the mutations detected in a single molecule per cell are enriched on edges of mtDNA molecules, suggesting they resemble artifacts reported in other sequencing approaches. It was then proposed that all mutations found in one molecule per cell should be removed. We detail our error correction method, demonstrating that the observed edge mutations are distinct from previously reported sequencing artifacts. We further show that the proposed removal leads to massive elimination of bona fide and informative mutations. Indeed, mutations accumulating on edges impact a minority of all mutation calls (for example, in hematopoietic stem cells, the excess mutations on the edge account for only 4.3%-7.6% of the total). Recognizing the value of addressing edge mutations even after applying consensus correction, we provide an additional filtering option in the ReDeeM-R package. This approach effectively eliminates the position biases, leads to a mutational signature indistinguishable from bona fide mitochondrial mutations, and removes excess low molecule high connectedness mutations. Importantly, this option preserves the large majority of unique mutations identified by ReDeeM, maintaining the ability of ReDeeM to provide a more than 10-fold increase in variant detection compared to previous methods. Additionally, the cells remain well-connected. While there is room for further refinement in mutation calling strategies, the significant advances and biological insights provided by the ReDeeM framework are unique and remain intact. We hope that this detailed discussion and analysis enables the community to employ this approach and contribute to its further development.
    DOI:  https://doi.org/10.1101/2024.08.23.609473
  28. 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
  29. Life (Basel). 2024 Jul 31. pii: 962. [Epub ahead of print]14(8):
    Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.
    Ilyoung Jeong, Eun-Jeong Cho, Jang-Soo Yook, Youngju Choi, Dong-Ho Park, Ju-Hee Kang, Seok-Hun Lee, Dae-Yun Seo, Su-Jeen Jung, Hyo-Bum Kwak.
      Sarcopenia, the age-related decline in muscle mass and function, poses a significant health challenge as the global population ages. Mitochondrial dysfunction is a key factor in sarcopenia, as evidenced by the role of mitochondrial reactive oxygen species (mtROS) in mitochondrial biogenesis and dynamics, as well as mitophagy. Resistance exercise training (RET) is a well-established intervention for sarcopenia; however, its effects on the mitochondria in aging skeletal muscles remain unclear. This review aims to elucidate the relationship between mitochondrial dynamics and sarcopenia, with a specific focus on the implications of RET. Although aerobic exercise training (AET) has traditionally been viewed as more effective for mitochondrial enhancement, emerging evidence suggests that RET may also confer beneficial effects. Here, we highlight the potential of RET to modulate mtROS, drive mitochondrial biogenesis, optimize mitochondrial dynamics, and promote mitophagy in aging skeletal muscles. Understanding this interplay offers insights for combating sarcopenia and preserving skeletal muscle health in aging individuals.
    Keywords:  aging; mitochondria; resistance exercise training; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/life14080962
  30. Pharmacol Res. 2024 Sep 02. pii: S1043-6618(24)00338-4. [Epub ahead of print]208 107393
    F-ATP synthase inhibitory factor 1 and mitochondria-organelle interactions: New insight and implications.
    Lishu Guo.
      Mitochondria are metabolic hub, and act as primary sites for reactive oxygen species (ROS) and metabolites generation. Mitochondrial Ca2+ uptake contributes to Ca2+ storage. Mitochondria-organelle interactions are important for cellular metabolic adaptation, biosynthesis, redox balance, cell fate. Organelle communications are mediated by Ca2+/ROS signals, vesicle transport and membrane contact sites. The permeability transition pore (PTP) is an unselective channel that provides a release pathway for Ca2+/ROS, mtDNA and metabolites. F-ATP synthase inhibitory factor 1 (IF1) participates in regulation of PTP opening and is required for the translocation of transcriptional factors c-Myc/PGC1α to mitochondria to stimulate metabolic switch. IF1, a mitochondrial specific protein, has been suggested to regulate other organelles including nucleus, endoplasmic reticulum and lysosomes. IF1 may be able to mediate mitochondria-organelle interactions and cellular physiology through regulation of PTP activity.
    Keywords:  Ca(2+); F-ATP synthase inhibitory factor 1; Metabolites; Mitochondria; Mitochondria-organelle interactions; Permeability transition; ROS
    DOI:  https://doi.org/10.1016/j.phrs.2024.107393
  31. bioRxiv. 2024 Aug 20. pii: 2024.08.19.608708. [Epub ahead of print]
    Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
    Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Edward T Chouchani, Anna G Orr, Adam L Orr.
      Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with mitochondrial ROS imaging and multiomic profiling, we found that CIII is the dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity in a non-cell- autonomous manner. As proof-of-concept, suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
    DOI:  https://doi.org/10.1101/2024.08.19.608708
  32. Aging Cell. 2024 Aug 29. e14282
    Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.
    John Sturgis, Rupesh Singh, Quinn R Caron, Ivy S Samuels, Thomas Micheal Shiju, Aditi Mukkara, Paul Freedman, Vera L Bonilha.
      Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a polymerase gamma (POLG) exonuclease-deficient model, the PolgD257A mutator mice (D257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial (mt) dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the D257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mt morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress and parkin-mediated mitophagy in the ages analyzed in the retina or RPE of D257A mice. Additionally, D257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mt markers displayed different abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mtDNA mutations leads to impaired mt function and accelerated aging, resulting in retinal degeneration.
    Keywords:  D257A; mitochondria; mitochondrial DNA (mtDNA); polymerase gamma (POLG); retina; retinal degeneration
    DOI:  https://doi.org/10.1111/acel.14282
  33. 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
  34. J Nanobiotechnology. 2024 Sep 06. 22(1): 549
    Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.
    Yan Qu, Bowen Meng, Simin Cai, Benyi Yang, Yifan He, Chaoran Fu, Xiangxia Li, Peiyi Li, Zeyuan Cao, Xueli Mao, Wei Teng, Songtao Shi.
      Over 50 billion cells undergo apoptosis each day in an adult human to maintain tissue homeostasis by eliminating damaged or unwanted cells. Apoptotic deficiency can lead to age-related diseases with reduced apoptotic metabolites. However, whether apoptotic metabolism regulates aging is unclear. Here, we show that aging mice and apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) mice exhibit decreased apoptotic levels along with increased aging phenotypes in the skeletal bones, which can be rescued by the treatment with apoptosis inducer staurosporine (STS) and stem cell-derived apoptotic vesicles (apoVs). Moreover, embryonic stem cells (ESC)-apoVs can significantly reduce senescent hallmarks and mtDNA leakage to rejuvenate aging bone marrow mesenchymal stem cells (MSCs) and ameliorate senile osteoporosis when compared to MSC-apoVs. Mechanistically, ESC-apoVs use TCOF1 to upregulate mitochondrial protein transcription, resulting in FLVCR1-mediated mitochondrial functional homeostasis. Taken together, this study reveals a previously unknown role of apoptotic metabolites in ameliorating bone aging phenotypes and the unique role of TCOF1/FLVCR1 in maintaining mitochondrial homeostasis.
    Keywords:  Apoptosis; Apoptotic vesicles; Mitochondrial homeostasis; Senile osteoporosis
    DOI:  https://doi.org/10.1186/s12951-024-02820-x
  35. Int Immunol. 2024 Aug 30. pii: dxae052. [Epub ahead of print]
    Mechanisms and Effects of Activation of Innate Immunity by Mitochondrial Nucleic Acids.
    Prashant Rai, Michael B Fessler.
      In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic (e.g., cyclic GMP-AMP synthase [cGAS]; retinoic acid-inducible gene-I [RIG-I]-like receptors) and endolysosomal (Toll-like Receptor [TLR]7, -9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.
    Keywords:  Cyclic GMP-AMP Synthase; Mitochondrial DNA; Mitophagy; Toll-like Receptor 7; Toll-like Receptor 9
    DOI:  https://doi.org/10.1093/intimm/dxae052
  36. bioRxiv. 2024 Aug 20. pii: 2024.08.19.608723. [Epub ahead of print]
    Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a 'snap-through' instability.
    Haleh Alimohamadi, Elizabeth Wei-Chia Luo, Rena Yang, Shivam Gupta, Kelsey A Nolden, Taraknath Mandal, R Blake Hill, Gerard C L Wong.
      Mitochondrial fission is controlled by dynamin proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membrane to achieve fission, but details are not well understood. However, dynamins can also remodel membranes by inducing negative Gaussian curvature, the type of curvature required for completion of fission. Here, we examine how these drastically different mechanisms synergistically exert their influences on a membrane, via a mechanical model calibrated with small-angle X-ray scattering structural data. We find that free dynamin can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of dynamin assembly, and paradoxically disassembly, can lead to diverse pathways to scission.
    Teaser: Dynamin mechano-constriction by assembly and curvature-driven instability by free monomers synergistically drive mitochondrial fission.
    DOI:  https://doi.org/10.1101/2024.08.19.608723
  37. bioRxiv. 2024 Aug 26. pii: 2024.08.23.609462. [Epub ahead of print]
    Patient mutations in DRP1 perturb synaptic maturation of cortical neurons.
    T B Baum, C Bodnya, J Costanzo, V Gama.
      With the advent of exome sequencing, a growing number of children are being identified with de novo loss of function mutations in the dynamin 1 like ( DNM1L) gene encoding the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1); these mutations result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro . High-resolution time-lapse imaging of axonal transport in mutant DRP1 cortical neurons reveals mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicates mutation dependent alterations in synaptic development and calcium regulation gene expression. Disruptions in calcium dynamics were confirmed using live functional recordings of 100 DIV (days in vitro) mutant DRP1 cortical neurons. These findings and deficits in pre- and post-synaptic marker colocalization using super resolution microscopy, strongly suggest that altered mitochondrial morphology of DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
    DOI:  https://doi.org/10.1101/2024.08.23.609462
  38. J Nanobiotechnology. 2024 Sep 05. 22(1): 543
    Young small extracellular vesicles rejuvenate replicative senescence by remodeling Drp1 translocation-mediated mitochondrial dynamics.
    Yingying Peng, Tingting Zhao, Shuxuan Rong, Shuqing Yang, Wei Teng, Yunyi Xie, Yan Wang.
       BACKGROUND: Human mesenchymal stem cells have attracted interest in regenerative medicine and are being tested in many clinical trials. In vitro expansion is necessary to provide clinical-grade quantities of mesenchymal stem cells; however, it has been reported to cause replicative senescence and undefined dysfunction in mesenchymal stem cells. Quality control assessments of in vitro expansion have rarely been addressed in ongoing trials. Young small extracellular vesicles from the remnant pulp of human exfoliated deciduous teeth stem cells have demonstrated therapeutic potential for diverse diseases. However, it is still unclear whether young small extracellular vesicles can reverse senescence-related declines.
    RESULTS: We demonstrated that mitochondrial structural disruption precedes cellular dysfunction during bone marrow-derived mesenchymal stem cell replication, indicating mitochondrial parameters as quality assessment indicators of mesenchymal stem cells. Dynamin-related protein 1-mediated mitochondrial dynamism is an upstream regulator of replicative senescence-induced dysfunction in bone marrow-derived mesenchymal stem cells. We observed that the application of young small extracellular vesicles could rescue the pluripotency dissolution, immunoregulatory capacities, and therapeutic effects of replicative senescent bone marrow-derived mesenchymal stem cells. Mechanistically, young small extracellular vesicles could promote Dynamin-related protein 1 translocation from the cytoplasm to the mitochondria and remodel mitochondrial disruption during replication history.
    CONCLUSIONS: Our findings show that Dynamin-related protein 1-mediated mitochondrial disruption is associated with the replication history of bone marrow-derived mesenchymal stem cells. Young small extracellular vesicles from human exfoliated deciduous teeth stem cells alleviate replicative senescence by promoting Dynamin-related protein 1 translocation onto the mitochondria, providing evidence for a potential rejuvenation strategy.
    Keywords:  Mesenchymal stem cell; Mitochondrial dynamics; Replicative senescence; Small extracellular vesicles; Stem cells from the remnant pulp of human exfoliated deciduous teeth (SHED)
    DOI:  https://doi.org/10.1186/s12951-024-02818-5
  39. J Physiol. 2024 Sep 02.
    Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.
    Itamar C G Jesus, Flavia M Araujo.
      
    Keywords:  biological clock; metabolism; mitochondria; protein synthesis; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287210
  40. 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
  41. Research (Wash D C). 2024 ;7 0465
    Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.
    Zhen Jin, Yan Mao, Qiqi Guo, Yujing Yin, Abdukahar Kiram, Danxia Zhou, Jing Yang, Zheng Zhou, Jiachen Xue, Zhenhua Feng, Zhen Liu, Yong Qiu, Tingting Fu, Zhenji Gan, Zezhang Zhu.
      Although microgravity has been implicated in osteoporosis, the precise molecular mechanism remains elusive. Here, we found that microgravity might induce mitochondrial protein buildup in skeletal muscle, alongside reduced levels of LONP1 protein. We revealed that disruptions in mitochondrial proteolysis, induced by the targeted skeletal muscle-specific deletion of the essential mitochondrial protease LONP1 or by the acute inducible deletion of muscle LONP1 in adult mice, cause reduced bone mass and compromised mechanical function. Moreover, the bone loss and weakness phenotypes were recapitulated in skeletal muscle-specific overexpressing ΔOTC mice, a known protein degraded by LONP1. Mechanistically, mitochondrial proteostasis imbalance triggered the mitochondrial unfolded protein response (UPRmt) in muscle, leading to an up-regulation of multiple myokines, including FGF21, which acts as a pro-osteoclastogenic factor. Surprisingly, this mitochondrial proteostasis stress influenced muscle-bone crosstalk independently of ATF4 in skeletal muscle. Furthermore, we established a marked association between serum FGF21 levels and bone health in humans. These findings emphasize the pivotal role of skeletal muscle mitochondrial proteostasis in responding to alterations in loading conditions and in coordinating UPRmt to modulate bone metabolism.
    DOI:  https://doi.org/10.34133/research.0465
  42. 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
  43. medRxiv. 2024 Aug 22. pii: 2024.08.22.24310814. [Epub ahead of print]
    Leveraging Generative AI to Accelerate Biocuration of Medical Actions for Rare Disease.
    Enock Niyonkuru, J Harry Caufield, Leigh Carmody, Michael Gargano, Sabrina Toro, Trish Whetzel, Hannah Blau, Mauricio Soto, Elena Casiraghi, Leonardo Chimirri, Justin T Reese, Giorgio Valentini, Melissa A Haendel, Christopher J Mungall, Peter N Robinson.
       BACKGROUND: Structured representations of clinical data can support computational analysis of individuals and cohorts, and ontologies representing disease entities and phenotypic abnormalities are now commonly used for translational research. The Medical Action Ontology (MAxO) provides a computational representation of treatments and other actions taken for the clinical management of patients. Currently, manual biocuration is used to assign MAxO terms to rare diseases, enabling clinical management of rare diseases to be described computationally for use in clinical decision support and mechanism discovery. However, it is challenging to scale manual curation to comprehensively capture information about medical actions for the more than 10,000 rare diseases.
    METHODS: We present AutoMAxO, a semi-automated workflow that leverages Large Language Models (LLMs) to streamline MAxO biocuration for rare diseases. AutoMAxO first uses LLMs to retrieve candidate curations from abstracts of relevant publications. Next, the candidate curations are matched to ontology terms from MAxO, Human Phenotype Ontology (HPO), and MONDO disease ontology via a combination of LLMs and post-processing techniques. Finally, the matched terms are presented in a structured form to a human curator for approval.
    RESULTS: We used this approach to process 4,918 unique medical abstracts and identified annotations for 21 rare genetic diseases, we extracted 18,631 candidate disease-treatment curations, 538 of which were confirmed and transferred to the MAxO annotation dataset.
    CONCLUSION: The results of this project underscore the potential of generative AI to accelerate precision medicine by enabling a robust and comprehensive curation of the primary literature to represent information about diseases and procedures in a structured fashion. Although we focused on MAxO in this project, similar approaches could be taken for other biomedical curation tasks.
    DOI:  https://doi.org/10.1101/2024.08.22.24310814
  44. medRxiv. 2024 Aug 22. pii: 2024.08.22.24312327. [Epub ahead of print]
    Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.
    Shloka Negi, Sarah L Stenton, Seth I Berger, Brandy McNulty, Ivo Violich, Joshua Gardner, Todd Hillaker, Sara M O'Rourke, Melanie C O'Leary, Elizabeth Carbonell, Christina Austin-Tse, Gabrielle Lemire, Jillian Serrano, Brian Mangilog, Grace VanNoy, Mikhail Kolmogorov, Eric Vilain, Anne O'Donnell-Luria, Emmanuèle Délot, Karen H Miga, Jean Monlong, Benedict Paten.
      More than 50% of families with suspected rare monogenic diseases remain unsolved after whole genome analysis by short read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing, and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare disease cohort of 98 samples, including 41 probands and some family members, using nanopore sequencing, achieving per sample ∼36x average coverage and 32 kilobase (kb) read N50 from a single flow cell. Our Napu pipeline generated assemblies, phased variants, and methylation calls. LRS covered, on average, coding exons in ∼280 genes and ∼5 known Mendelian disease genes that were not covered by SRS. In comparison to SRS, LRS detected additional rare, functionally annotated variants, including SVs and tandem repeats, and completely phased 87% of protein-coding genes. LRS detected additional de novo variants, and could be used to distinguish postzygotic mosaic variants from prezygotic de novos . Eleven probands were solved, with diverse underlying genetic causes including de novo and compound heterozygous variants, large-scale SVs, and epigenetic modifications. Our study demonstrates LRS's potential to enhance diagnostic yield for rare monogenic diseases, implying utility in future clinical genomics workflows.
    DOI:  https://doi.org/10.1101/2024.08.22.24312327
  45. Nat Med. 2024 Sep 03.
    A framework for sharing of clinical and genetic data for precision medicine applications.
    NYGC ALS Consortium
      Precision medicine has the potential to provide more accurate diagnosis, appropriate treatment and timely prevention strategies by considering patients' biological makeup. However, this cannot be realized without integrating clinical and omics data in a data-sharing framework that achieves large sample sizes. Systems that integrate clinical and genetic data from multiple sources are scarce due to their distinct data types, interoperability, security and data ownership issues. Here we present a secure framework that allows immutable storage, querying and analysis of clinical and genetic data using blockchain technology. Our platform allows clinical and genetic data to be harmonized by combining them under a unified framework. It supports combined genotype-phenotype queries and analysis, gives institutions control of their data and provides immutable user access logs, improving transparency into how and when health information is used. We demonstrate the value of our framework for precision medicine by creating genotype-phenotype cohorts and examining relationships within them. We show that combining data across institutions using our secure platform increases statistical power for rare disease analysis. By offering an integrated, secure and decentralized framework, we aim to enhance reproducibility and encourage broader participation from communities and patients in data sharing.
    DOI:  https://doi.org/10.1038/s41591-024-03239-5
  46. J Hum Genet. 2024 Sep 03.
    Phenotypic spectrum of iron-sulfur cluster assembly gene IBA57 mutations: c.286 T > C identified as a hotspot mutation in Chinese patients with a stable natural history.
    Huafang Jiang, Chaolong Xu, Ruoyu Duan, Zhimei Liu, Xiaotun Ren, Jiuwei Li, Chunhong Chen, Hongmei Wang, Tongli Han, Xiaojuan Tian, Xin Duan, Minhan Song, Tongyue Li, Fang Fang.
      Mutations in IBA57 disrupt iron-sulfur clusters maturation, causing a rare mitochondrial disease. Clinical manifestations vary from neonatal lethality to childhood-onset spastic paraparesis, yet the ethnic heterogeneity and natural history remain unclear, necessitating further exploration. This study aimed to delineate the genotype-phenotype correlation of IBA57 mutations by analyzing diverse clinical presentations. We report 11 Chinese patients and include literature-reported cases, totaling 61 patients enrolled for analysis. Clinical, neuroimaging, genetic, and disease progression information were collected. Among these, 46 presented as multiple mitochondrial dysfunctions syndrome 3 (MMDS3), with 58.7% originating from Chinese population. Based on disease course, we propose three clinical subtypes: neonatal, infant and childhood subtypes. Neonatal cases universally displayed hypotonia and respiratory distress at presentation, deceased within three months. Most infancy and childhood cases exhibited developmental regression and impaired motor function. Cavitating leukoencephalopathy was a typical neuroimaging finding in MMDS3 patients. The c.286 T > C mutation was reported in 85.2% of Chinese patients. A significantly lower mortality rate was observed compared to the non-Chinese group (P = 0.002), with a survival rate exceeding 90% at 5 years, indicating a relatively stable disease progression. Fifteen cases from three families manifested the spastic paraplegia 74 phenotype, demonstrating normal development before onset, with common clinical manifestations including spastic paraplegia (14/15), visual impairment (10/13), and peripheral neuropathy (9/13). In conclusion, this study indicates a hotspot mutation in Chinese and analyses the disease progression with different clinical subtypes.
    DOI:  https://doi.org/10.1038/s10038-024-01291-0
  47. Nature. 2024 Sep;633(8028): 47-57
    Deciphering the impact of genomic variation on function.
    IGVF Consortium
      Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations.
    DOI:  https://doi.org/10.1038/s41586-024-07510-0
  48. Nat Aging. 2024 Aug 29.
    ImAge quantitates aging and rejuvenation.
    Martin Alvarez-Kuglen, Kenta Ninomiya, Haodong Qin, Delany Rodriguez, Lorenzo Fiengo, Chen Farhy, Wei-Mien Hsu, Brian Kirk, Aaron Havas, Gen-Sheng Feng, Amanda J Roberts, Rozalyn M Anderson, Manuel Serrano, Peter D Adams, Tatyana O Sharpee, Alexey V Terskikh.
      For efficient, cost-effective and personalized healthcare, biomarkers that capture aspects of functional, biological aging, thus predicting disease risk and lifespan more accurately and reliably than chronological age, are essential. We developed an imaging-based chromatin and epigenetic age (ImAge) that captures intrinsic age-related trajectories of the spatial organization of chromatin and epigenetic marks in single nuclei, in mice. We show that such trajectories readily emerge as principal changes in each individual dataset without regression on chronological age, and that ImAge can be computed using several epigenetic marks and DNA labeling. We find that interventions known to affect biological aging induce corresponding effects on ImAge, including increased ImAge upon chemotherapy treatment and decreased ImAge upon caloric restriction and partial reprogramming by transient OSKM expression in liver and skeletal muscle. Further, ImAge readouts from chronologically identical mice inversely correlated with their locomotor activity, suggesting that ImAge may capture elements of biological and functional age. In sum, we developed ImAge, an imaging-based biomarker of aging with single-cell resolution rooted in the analysis of spatial organization of epigenetic marks.
    DOI:  https://doi.org/10.1038/s43587-024-00685-1
  49. 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
  50. J Lipid Res. 2024 Aug 30. pii: S0022-2275(24)00143-3. [Epub ahead of print] 100638
    Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet - an exploratory study.
    Maija Vaittinen, Mariana Ilha, Ratika Sehgal, Maria A Lankinen, Jyrki Ågren, Pirjo Käkelä, Kirsi A Virtanen, Markku Laakso, Ursula Schwab, Jussi Pihlajamäki.
      Fatty acid desaturase (FADS1) variant-rs174550 strongly regulates polyunsaturated fatty acid (PUFA) biosynthesis. Additionally, the FADS1 has been shown to be related to mitochondrial function. Thus, we investigated whether changes in mitochondrial function are associated with the genetic variation in FADS1 (rs174550) in human adipocytes isolated from individuals consuming diets enriched with either dietary alpha-linolenic (ALA) or linoleic acid (LA). Two cohorts of men homozygous for the genotype of FADS1 (rs174550) were studied: FADSDIET2 dietary intervention study with ALA- and LA-enriched diets and Kuopio Obesity Surgery study (KOBS), respectively. We could demonstrate that differentiated human adipose-derived stromal cells from subjects with the TT genotype had higher mitochondrial metabolism compared with subjects with the CC genotype of FADS1-rs174550 in the FADSDIET2. Responses to PUFA-enriched diets differed between the genotypes of FADS1-rs174550, showing that ALA, but not LA, -enriched diet stimulated mitochondrial metabolism more in subjects with the CC genotype when compared with subjects with the TT genotype. ALA, but not LA, proportion in plasma phospholipid fraction correlated positively with adipose tissue mitochondrial-DNA amount in subjects with the CC genotype of FADS1-rs174550 in the KOBS. These findings demonstrate that the FADS1-rs174550 is associated with modification in mitochondrial function in human adipocytes. Additionally, subjects with the CC genotype, when compared with the TT genotype, benefit more from the ALA-enriched diet, leading to enhanced energy metabolism in human adipocytes. Altogether, the FADS1-rs174550 could be a genetic marker to identify subjects who are most suitable to receive dietary PUFA supplementation, establishing also a personalized therapeutic strategy to improve mitochondrial function in metabolic diseases.
    Keywords:  Adipocytes; Alpha-linolenic acid; Dietary fat; FADS1; Fatty acid oxidation; Human adipose-derived stromal cell; Lipids/oxidation; Mitochondria; Omega-3 fatty acids; Polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.jlr.2024.100638
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