bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–12–15
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
  2. Constraint reveals the mitochondrial genome sites most important for health and disease.
  3. Long-Read Sequencing Increases Diagnostic Yield for Rare Disease.
  4. Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging.
  5. Cryopreserved PBMCs can be used for the analysis of mitochondrial respiration and serve as a diagnostic tool for mitochondrial diseases.
  6. Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
  7. Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease.
  8. Reactive oxygen species control protein degradation at the mitochondrial import gate.
  9. Clinical study of ferredoxin-reductase-related mitochondriopathy: Genotype-phenotype correlation and proposal of ancestry-based carrier screening in the Mexican population.
  10. Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
  11. Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo.
  12. Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.
  13. Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
  14. Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.
  15. A little bird flies high thanks to mighty mitochondria.
  16. Conserved and Unique Mitochondrial Target Sequence of TRPV4 Can Independently Regulate Mitochondrial Functions.
  17. Tissue specific roles of fatty acid oxidation.
  18. Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions.
  19. Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake.
  20. Ensemble and consensus approaches to prediction of recessive inheritance for missense variants in human disease.
  21. Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study.
  22. Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner.
  23. The adenine nucleotide translocase family underlies cardiac ischemia-reperfusion injury through the mitochondrial permeability pore independently of cyclophilin D.
  24. Cell-specific oxidative metabolism of the renal cortex.
  25. KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.
  26. Detection of single nucleotide variants in the mitochondrial genome of healthy mice and humans.
  27. Coupling of mitochondrial state with active zone plasticity in early brain aging.
  28. Expanded-access use of elamipretide in a critically ill patient with Barth syndrome.
  29. Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells.
  30. Acute CCl4-induced intoxication reduces complex I, but not complex II-based mitochondrial bioenergetics - protective role of succinate.
  31. Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.
  32. PDSS1 mutations-associated steroid-resistant nephrotic syndrome: case report and review of literature.
  33. Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders.
  34. Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
  35. Association of mitochondrial haplogroup H with reduced risk of type 2 Diabetes among Gulf Region Arabs.
  36. Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling.
  37. Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation.
  38. [A case of neonatal Mitochondrial DNA depletion syndrome type 13 caused by FBXL4 gene mutation].
  39. Clinicopathological collaboration in adult muscle disease: a pragmatic pathway to approach diagnostic dilemmas.
  40. Disagreement on foundational principles of biological aging.
  41. π-HuB: the proteomic navigator of the human body.
  42. Diagnostic Use of Genome Sequencing in Patients With 11p15.5 Imprinting Disorder Features: A Pilot Study.
  43. A rare cause of autosomal recessive ataxia with very late diagnosis and prolonged disease course.
  44. Using genomic databases to determine the frequency and population-based heterogeneity of autosomal recessive conditions.
  45. Synergistic label-free fluorescence imaging and miRNA studies reveal dynamic human neuron-glial metabolic interactions following injury.
  46. Bad bar charts are pervasive across biology.
  47. Mitochondrial fission is required for thermogenesis in brown adipose tissue.
  48. Arginase-II gene deficiency reduces skeletal muscle aging in mice.
  49. Loss of function in NSD2 causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome.
  50. How to build the virtual cell with artificial intelligence: Priorities and opportunities.
  51. Current concepts and molecular pathology of neurodegenerative diseases.
  52. Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease.
  53. Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
  54. OpenVariant: a toolkit to parse and operate multiple input file formats.
  55. Targeting hyperactive mitochondria in activated HSCs and inhibition of liver fibrogenesis in mice using sorafenib complex micelles.
  56. Modeling the consequences of age-linked rDNA hypermethylation with dCas9-directed DNA methylation in human cells.
  57. Vimentin and Desmin Intermediate Filaments Maintain Mitochondrial Membrane Potential.
  58. Copy-number analysis from genome sequencing data of 11,754 rare-disease parent-child trios: A model for identifying autosomal recessive human gene knockouts including a novel gene for autosomal recessive retinopathy.
  59. Genome-wide epistasis analysis reveals significant epistatic signals associated with Parkinson's disease risk.
  60. ProHap enables human proteomic database generation accounting for population diversity.
  1. Brain Commun. 2024 ;6(6): fcae404
    Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
    Jacques Bureau, Florence Manero, Olivier Baris, Alexia Bodin, Christophe Verny, Arnaud Chevrollier, Guy Lenaers, Philippe Codron.
      Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches.
    Keywords:  Leber hereditary optic neuropathy; Opa1; dominant optic atrophy; hereditary optic neuropathy; mitochondria
    DOI:  https://doi.org/10.1093/braincomms/fcae404
  2. Nature. 2024 Dec 11.
    Constraint reveals the mitochondrial genome sites most important for health and disease.
      
    Keywords:  Databases; Diseases; Genetics
    DOI:  https://doi.org/10.1038/d41586-024-04039-0
  3. Am J Med Genet A. 2025 Jan;197(1): e63729
    Long-Read Sequencing Increases Diagnostic Yield for Rare Disease.
      
    DOI:  https://doi.org/10.1002/ajmg.a.63729
  4. J Cereb Blood Flow Metab. 2024 Dec 12. 271678X241306054
    Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging.
    Gopal V Velmurugan, Hemendra J Vekaria, Samir P Patel, Patrick G Sullivan, W Brad Hubbard.
      Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.
    Keywords:  Mitochondrial transfer; aging; astrocyte EV-mito; brain capillaries; capillary isolation
    DOI:  https://doi.org/10.1177/0271678X241306054
  5. Anal Biochem. 2024 Dec 05. pii: S0003-2697(24)00289-6. [Epub ahead of print] 115745
    Cryopreserved PBMCs can be used for the analysis of mitochondrial respiration and serve as a diagnostic tool for mitochondrial diseases.
    Zuzana Korandová, Petr Pecina, Alena Pecinová, Eliška Koňaříková, Markéta Tesařová, Josef Houštěk, Hana Hansíková, Hana Ptáčková, Jiří Zeman, Tomáš Honzík, Tomáš Mráček.
      Mitochondrial diseases are severe, inherited metabolic disorders that affect the paediatric population. They affect the functioning of mitochondrial oxidative phosphorylation (OXPHOS) apparatus either directly or indirectly. Since mutations in mtDNA are responsible for only 25% of paediatric cases and next-generation sequencing does not always provide a conclusive diagnosis, the biochemical approach still represents a valuable tool in diagnostics. Mitochondrial defects can be identified in tissue biopsies (muscle or skin). However, they also often manifest in peripheral blood cells. We developed a protocol for isolation and cryopreservation of peripheral blood mononuclear cells (PBMCs) from 5 ml of children's blood using Ficoll centrifugation which can be utilised for subsequent functional measurements on thawed samples. Furthermore, we evaluated the diagnostic utility of the optimised high-resolution oxygraphy protocol using digitonin-permeabilized cryopreserved PBMCs on 47 samples from patients with confirmed or suspected mitochondrial disease. Overall, the diagnosis was confirmed in 72% of cases, while the analysis of cryopreserved PBMCs provided a false negative outcome in 13% of cases. Our study demonstrates a sensitive, fast, and non-invasive approach for the diagnostics of various types of mitochondrial disorders, especially those of nuclear genetic origin manifesting in paediatric patients.
    Keywords:  OXPHOS; PBMC; cryopreservation; diagnostics; glycolysis; mitochondrial diseases; oxidative phosphorylation; peripheral blood mononuclear cells; respirometry
    DOI:  https://doi.org/10.1016/j.ab.2024.115745
  6. bioRxiv. 2024 Nov 26. pii: 2024.11.24.625104. [Epub ahead of print]
    Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
    Matthew D Campbell, Monica Sanchez-Contreras, Britta D Sibley, Phoebe Keiser, Carla Ruiz Sanchez, Carolyn N Mann, David J Marcinek, Behzad Najafian, Mariya T Sweetwyne.
      Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is yet unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state that may stress mitochondria. To address this, we crossed floxed hemagglutinin (HA) -mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or distal tubule and collecting duct (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation. Mitochondrial respiration in fresh isolates from young (4-7 mo) and aged (22-26 mo) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than do tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase (CS) levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Finally, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production of podocyte mitochondria isolated directly from fresh kidneys. Thus, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than mitochondria-dependent tubules per organelle. Previous studies may not have detected these differences due to reliance on podocyte cell culture conditions, which results in artifactual suppression of mitochondrial function.
    DOI:  https://doi.org/10.1101/2024.11.24.625104
  7. Brain. 2024 Dec 09. pii: awae308. [Epub ahead of print]
    Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease.
    Chiara Pizzamiglio, Renae J Stefanetti, Robert McFarland, Naomi Thomas, George Ransley, Matilda Hugerth, Alvar Grönberg, Sonia Simon Serrano, Eskil Elmér, Michael G Hanna, Magnus J Hansson, Gráinne S Gorman, Robert D S Pitceathly.
      Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design.
    Keywords:  KL1333; clinical trial; phase 1 trial; primary mitochondrial disease; rare diseases
    DOI:  https://doi.org/10.1093/brain/awae308
  8. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00909-2. [Epub ahead of print]84(23): 4612-4628.e13
    Reactive oxygen species control protein degradation at the mitochondrial import gate.
    Rachael McMinimy, Andrew G Manford, Christine L Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y Shih, Christopher M Rose, John Kuriyan, Baris Bingol, Michael Rapé.
      While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.
    Keywords:  FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.004
  9. Genet Med Open. 2024 ;2 100841
    Clinical study of ferredoxin-reductase-related mitochondriopathy: Genotype-phenotype correlation and proposal of ancestry-based carrier screening in the Mexican population.
    Teresa Campbell, Jesse Slone, Hallie Metzger, Wensheng Liu, Stephanie Sacharow, Amy Yang, Mariya Moosajee, Chiara La Morgia, Valerio Carelli, Flavia Palombo, Matthew A Lines, A Micheil Innes, Rebecca J Levy, Derek Neilson, Nicola Longo, Taosheng Huang.
       Purpose: Ferredoxin reductase (FDXR) is a flavoprotein that functions in both iron sulfur cluster biogenesis and steroid biosynthesis pathways in the mitochondria. Not surprisingly, loss of FDXR function causes severe mitochondrial diseases in humans. Although several FDXR-related mitochondriopathy (FRM) cohorts have been reported in the literature, further characterization of the natural history of FRM is warranted.
    Methods: To better understand the spectrum of FRM, a natural history study of FRM was performed. New cases were added to previously reported FRM cases for analysis (n = 62 cases).
    Results: Optic atrophy, movement disorder, and developmental delay were frequent findings. Mortality is high, with 18% of patients, often infants, passing from complications. Notably, 25% of cases were homozygous or compound heterozygous for the previously reported p.Arg386Trp "hotspot" variant. Of the obtained ancestry, all but 1 individual heterozygous for the p.Arg386Trp variant was Hispanic, with many reporting Mexican heritage. Utilizing recent large-scale genome sequencing surveys, the carrier frequency of the p.Arg386Trp variant was estimated as 1 of 185 in the Mexican population.
    Conclusion: Given the high mortality of FRM and carrier frequency of the common variant, consideration of a new approach for population carrier screening and development of therapeutics for affected individuals is needed.
    Keywords:  Carrier screening; FDXR; Ferredoxin reductase; Mexican-Americans; Mitochondrial disease
    DOI:  https://doi.org/10.1016/j.gimo.2023.100841
  10. iScience. 2024 Dec 20. 27(12): 111384
    Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
    Robert Weil, Emmanuel Laplantine, Messaouda Attailia, Anne Oudin, Shannel Curic, Aya Yokota, Elie Banide, Pierre Génin.
      Degradation of damaged mitochondria, a process called mitophagy, plays a role in mitochondrial quality control and its dysfunction has been linked to neurodegenerative pathologies. The PINK1 kinase and the ubiquitin ligase Parkin-mediated mitophagy represents the most common pathway in which specific receptors, including Optineurin (Optn), target ubiquitin-labeled mitochondria to autophagosomes. Here, we show that Protein Kinases D (PKD) are activated and recruited to damaged mitochondria. Subsequently, PKD phosphorylate Optn to promote a complex with Parkin leading to enhancement of its ubiquitin ligase activity. Paradoxically, inhibiting PKD activity enhances the interaction between Optn and LC3, promotes the recruitment of Parkin to mitochondria, and increases the mitophagic function of Optn. This enhancement of mitophagy is characterized by increased production of mitochondrial ROS and a reduction in mitochondrial mass. The PKD kinases may therefore regulate Optn-dependent mitophagy by amplifying the Parkin-mediated degradation signals to improve the cell response against oxidative stress damage.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111384
  11. Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101372
    Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo.
    David V Begelman, Bhavna Dixit, Carly Truong, Christina D King, Mark A Watson, Birgit Schilling, Martin D Brand, Amutha Boominathan.
      Replicative errors, inefficient repair, and proximity to sites of reactive oxygen species production make mitochondrial DNA (mtDNA) susceptible to damage with time. We explore in vivo allotopic expression (re-engineering mitochondrial genes and expressing them from the nucleus) as an approach to rescue defects arising from mtDNA mutations. We used a mouse strain C57BL/6J(mtFVB) with a natural polymorphism (m.7778 G>T) in the mitochondrial ATP8 gene that encodes a protein subunit of the ATP synthase. We generated a transgenic mouse with an epitope-tagged recoded mitochondrial-targeted ATP8 gene expressed from the ROSA26 locus in the nucleus and used the C57BL/6J(mtFVB) strain to verify successful incorporation. The allotopically expressed ATP8 protein in transgenic mice was constitutively expressed across all tested tissues, successfully transported into the mitochondria, and incorporated into ATP synthase. The ATP synthase with transgene had similar activity to non-transgenic control, suggesting successful integration and function. Exogenous ATP8 protein had no negative impact on measured mitochondrial function, metabolism, or behavior. Successful allotopic expression of a mitochondrially encoded protein in vivo in a mammal is a step toward utilizing allotopic expression as a gene therapy in humans to repair physiological consequences of mtDNA defects that may accumulate in congenital mitochondrial diseases or with age.
    Keywords:  ATP8 gene; allotopic expression; in vivo gene therapy; mitochondrial DNA mutation; mtDNA; safe harbor expression; transgenic mouse
    DOI:  https://doi.org/10.1016/j.omtm.2024.101372
  12. Neurogenetics. 2024 Nov 28. 26(1): 13
    Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.
    Bao-Guang Li, Wen-Juan Wu, Li-Hui Wang, Xin Wang, Chong Liu, Ya-Kun Du, Bao-Chi Li, Jin-Tong Hu, Su-Zhen Sun.
       BACKGROUND: Leigh syndrome is a common mitochondrial disorder caused by gene mutations in the nucleus and mitochondria. When building mitochondrial complex I, the main subunit ND1 combines with the Q module to form a 273 kDa complex, which then adds Ndufa3, Ndufa8, and Ndufa13 to create an intermediate product of about 283 kDa called Q/Pp-a. Although Ndufa8 and Ndufa13 have been linked to mitochondrial diseases, the role of Ndufa3 in disease development is still not fully understood.
    METHODS: A family suspected of having Leigh syndrome was examined. Subjects (two brothers and a sister) underwent brain imaging, and their clinical symptoms were evaluated. Also, whole exome sequencing and minigene testing were performed by examining peripheral blood samples (2 ml) collected from the proband, his parents, and brothers.
    RESULTS: Three affected children showed early-onset symptoms, including abnormalities in muscle tone and delayed motor and language development. Symptoms were relatively mild. The second child of the second pregnancy experienced worsened muscle tone abnormalities after injury, slow wound healing, and sustained increased muscle tone up to a year after wound closure. His brain scans revealed lesions in the basal ganglia and brainstem, consistent with Leigh syndrome diagnosis. Genetic analysis identified compound heterozygous mutations in the Ndufa3 gene in all affected family members.
    CONCLUSION: This is the first report of a family affected by Leigh syndrome associated with mutations in the Ndufa3 gene. Our analyses of clinical symptoms, radiological scans, and genetic investigations broaden our understanding of Ndufa3 gene mutations and their role in the development of Leigh syndrome.
    Keywords:   Ndufa3 ; Leigh syndrome; Mitochondrial disease
    DOI:  https://doi.org/10.1007/s10048-024-00782-8
  13. bioRxiv. 2024 Nov 26. pii: 2024.11.25.625249. [Epub ahead of print]
    Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
    Arunkumar Venkatesan, Marc Ridilla, Nileyma Castro, J Mario Wolosin, Jessica L Henty-Ridilla, Barry E Knox, Preethi S Ganapathy, Jamin S Brown, Anthony F DeVincentis, Sandra Sieminski, Audrey M Bernstein.
      Exfoliation Syndrome (XFS) is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG), a secondary open-angle glaucoma. XFG is a complex, multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as altered cellular processes with increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from Normal (No Glaucoma) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species (ROS) accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with an increase in mitochondrial localization to lysosomes and slowed mitophagy flux. Mitochondrial dysfunction in the XFG TFs was associated with an increase in the dynamics of the microtubule cytoskeleton, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A, and a mitochondrial biogenesis inducer, NAD + precursor, Nicotinamide Ribose, improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate abnormal mitochondria in XFG TFs and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.
    DOI:  https://doi.org/10.1101/2024.11.25.625249
  14. Mitochondrion. 2024 Dec 09. pii: S1567-7249(24)00158-2. [Epub ahead of print] 102000
    Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.
    Nishad Keethedeth, Rajesh Anantha Shenoi.
      Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.
    Keywords:  Blood brain barrier; Mitochondria targeting; Nanotherapeutics; Neurodegenerative diseases; Triphenyl Phosphonium
    DOI:  https://doi.org/10.1016/j.mito.2024.102000
  15. Nature. 2024 Dec 11.
    A little bird flies high thanks to mighty mitochondria.
      
    Keywords:  Physiology
    DOI:  https://doi.org/10.1038/d41586-024-04010-z
  16. Proteins. 2024 Dec 08.
    Conserved and Unique Mitochondrial Target Sequence of TRPV4 Can Independently Regulate Mitochondrial Functions.
    Tusar Kanta Acharya, Parnasree Mahapatra, Shamit Kumar, Nishant Kumar Dubey, Srujanika Rajalaxmi, Arijit Ghosh, Ashutosh Kumar, Chandan Goswami.
      Though mitochondria have their own genome and protein synthesis machineries, the majority of the mitochondrial proteins are actually encoded by the nuclear genome. Most of these mitochondrial proteins are imported into specific compartments of the mitochondria due to their mitochondrial target sequence (MTS). Unlike the nuclear target sequence, the MTS of most of the mitochondrial localized proteins remain poorly understood, mainly due to their variability, heterogeneity, unconventional modes of action, mitochondrial potential-dependent transport, and other complexities. Recently, we reported that transient receptor potential vanilloid subtype 4 (TRPV4), a thermosensitive cation channel, is physically located at the mitochondria. Here we characterize a small segment (AA 592-630) located at the TM4-loop4-TM5 segment of TRPV4 that acts as a novel MTS. The same region remains highly conserved in all vertebrates and contains a large number of point mutations each of which causes an diverse spectrum of diseases in human. Using confocal and super-resolution microscopy, we show that this MTS of TRPV4 or its mutants localizes to the mitochondria independently and also induces functional and quantitative changes in the mitochondria. By using conformal microscopy, we could detect the presence of the MTS region within the isolated mitochondria. These findings may be important to understand the complexity of MTS and TRPV4-induced channelopathies better.
    Keywords:  Ca2+‐signaling; channelopathy; ion channel; molecular evolution; oxidative potential
    DOI:  https://doi.org/10.1002/prot.26772
  17. Adv Biol Regul. 2024 Dec 05. pii: S2212-4926(24)00058-7. [Epub ahead of print] 101070
    Tissue specific roles of fatty acid oxidation.
    Danielle M Smith, Joseph Choi, Michael J Wolfgang.
      Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.
    DOI:  https://doi.org/10.1016/j.jbior.2024.101070
  18. Angew Chem Int Ed Engl. 2024 Dec 07. e202417804
    Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions.
    Fabian Schuhmann, Kerem Can Akkaya, Dmytro Puchkov, Martin Lehmann, Fan Liu, Weria Pezeshkian.
      Cross-linking mass spectrometry (XL-MS) enables the mapping of protein-protein interactions on the cellular level. When applied to all compartments of mitochondria, the sheer number of cross-links and connections can be overwhelming, rendering simple cluster analyses convoluted and uninformative. To address this limitation, we integrate the XL-MS data, 3D electron microscopy data, and localization annotations with a supra coarse-grained molecular dynamics simulation to sort all data, making clusters more accessible and interpretable. In the context of mitochondria, this method, through a total of 6.9 milliseconds of simulations, successfully identifies known, suggests unknown protein clusters, and reveals the distribution of inner mitochondrial membrane proteins allowing a more precise localization within compartments. Our integrative approach suggests, that two so-far ambigiously placed proteins FAM162A and TMEM126A are localized in the cristae, which is validated through super resolution microscopy. Together, this demonstrates the strong potential of the presented approach.
    Keywords:  3D volumetric imaging; Cross-linking mass spectrometry; Molecular Dynamics; mitochondrial protein distribution; supra coarse-grained
    DOI:  https://doi.org/10.1002/anie.202417804
  19. bioRxiv. 2024 Nov 26. pii: 2024.11.25.625228. [Epub ahead of print]
    Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake.
    Neeraj K Rai, Anthony M Balynas, Melissa Js MacEwen, Ashley R Bratt, Yasemin Sancak, Dipayan Chaudhuri.
      Mitochondrial Ca 2+ levels are regulated to balance stimulating respiration against the harm of Ca 2+ overload. Contributing to this balance, the main channel transporting Ca 2+ into the matrix, the mitochondrial Ca 2+ uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous to the pore-forming subunit MCU, but when present in the pore-lining tetramer, inhibits Ca 2+ transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB-dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N-terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca 2+ uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca 2+ uptake, suggesting the mechanism of inhibition may involve global rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca 2+ influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca 2+ transport is consistent with MCUB retaining the highly-conserved selectivity filter DIME sequence. Finally, we apply live-cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca 2+ transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca 2+ uptake.
    DOI:  https://doi.org/10.1101/2024.11.25.625228
  20. Cell Rep Methods. 2024 Dec 06. pii: S2667-2375(24)00304-7. [Epub ahead of print] 100914
    Ensemble and consensus approaches to prediction of recessive inheritance for missense variants in human disease.
    Ben O Petrazzini, Daniel J Balick, Iain S Forrest, Judy Cho, Ghislain Rocheleau, Daniel M Jordan, Ron Do.
      Mode of inheritance (MOI) is necessary for clinical interpretation of pathogenic variants; however, the majority of variants lack this information. Furthermore, variant effect predictors are fundamentally insensitive to recessive-acting diseases. Here, we present MOI-Pred, a variant pathogenicity prediction tool that accounts for MOI, and ConMOI, a consensus method that integrates variant MOI predictions from three independent tools. MOI-Pred integrates evolutionary and functional annotations to produce variant-level predictions that are sensitive to both dominant-acting and recessive-acting pathogenic variants. Both MOI-Pred and ConMOI show state-of-the-art performance on standard benchmarks. Importantly, dominant and recessive predictions from both tools are enriched in individuals with pathogenic variants for dominant- and recessive-acting diseases, respectively, in a real-world electronic health record (EHR)-based validation approach of 29,981 individuals. ConMOI outperforms its component methods in benchmarking and validation, demonstrating the value of consensus among multiple prediction methods. Predictions for all possible missense variants are provided in the "Data and code availability" section.
    Keywords:  CP: genetics; CP: systems biology; autosomal dominant; autosomal recessive; electronic health records; mode of inheritance; pathogenic variants; variant effect prediction
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100914
  21. J Neurol. 2024 Dec 12. 272(1): 47
    Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study.
    Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.
       BACKGROUND: Stroke-like episode (SLE) is a subacute evolving brain syndrome in patients with primary mitochondrial diseases. Despite previous research, the understanding of the clinical spectrum, treatment, and outcomes of mitochondrial SLEs is far from complete. In this single centre study, we report the clinical symptoms and radiological findings as well as the medical treatment and outcomes of SLEs in patients with mitochondrial disease.
    METHODS: This retrospective, observational study during years 2000-2023 was based on a cohort of patients diagnosed with mitochondrial disease at Turku University Hospital (TUH; Turku, Finland) in the region of Southwest Finland. Data were obtained from the hospital electronic medical record system.
    RESULTS: The investigated cohort consisted of 76 patients (37 men, 39 women) with a diagnosis of mitochondrial disease. Among these, 12 patients had a history of at least one SLE; the total number of SLEs was 20. The most common genetic aetiology among patients with SLEs was m.3243A > G (N = 7). The mean age at first SLE was 40 years (range: 5-66 years), and the mean interval between episodes was 4.8 years (range: 4 months-10 years). The duration of episodes varied between 1 and 193 days (median 14 days, mean 37 days); 10 patients needed intensive care unit (ICU) treatment. The mean survival time between the first SLE and death was 3.6 years (range: 0-16 years).
    CONCLUSION: Our study highlights the importance of early recognition and prompt management of SLE symptoms, especially epileptic seizures, in this life-threatening entity.
    Keywords:  Epilepsy; Genetics; Mitochondrial DNA; Mitochondrial diseases; Stroke-like episode
    DOI:  https://doi.org/10.1007/s00415-024-12745-y
  22. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01357-3. [Epub ahead of print]43(12): 115006
    Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner.
    Joseph Choi, Danielle M Smith, Susanna Scafidi, Ryan C Riddle, Michael J Wolfgang.
      Mitochondrial fatty acid oxidation is facilitated by the combined activities of carnitine palmitoyltransferase 1 (Cpt1) and Cpt2, which generate and utilize acylcarnitines, respectively. We compare the response of mice with liver-specific deficiencies in the liver-enriched Cpt1a or the ubiquitously expressed Cpt2 and discover that they display unique metabolic, physiological, and molecular phenotypes. The loss of Cpt1a or Cpt2 results in the induction of the muscle-enriched isoenzyme Cpt1b in hepatocytes in a Pparα-dependent manner. However, hepatic Cpt1b does not contribute substantively to hepatic fatty acid oxidation when Cpt1a is absent. Liver-specific double knockout of Cpt1a and Cpt1b or Cpt2 eliminates the mitochondrial oxidation of non-esterified fatty acids. However, Cpt1a/Cpt1b double knockout mice retain fatty acid oxidation by utilizing extracellular long-chain acylcarnitines that are dependent on Cpt2. These data demonstrate the non-cell-autonomous intercellular metabolism of fatty acids in hepatocytes.
    Keywords:  CP: Metabolism; Cpt1; Cpt2; acylcarnitine; biochemistry; fasting; liver; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.115006
  23. Sci Adv. 2024 Dec 13. 10(50): eadp7444
    The adenine nucleotide translocase family underlies cardiac ischemia-reperfusion injury through the mitochondrial permeability pore independently of cyclophilin D.
    Pooja Patel, Arielys Mendoza, Daniel Ramirez, Dexter Robichaux, Jeffery D Molkentin, Jason Karch.
      The mitochondrial permeability transition pore (mPTP) is implicated in cardiac ischemia-reperfusion (I/R) injury. During I/R, elevated mitochondrial Ca2+ triggers mPTP opening, leading to necrotic cell death. Although nonessential regulators of this pore are characterized, the molecular identity of the pore-forming component remains elusive. Two of these genetically verified regulators are cyclophilin D (CypD) and the adenine nucleotide translocase (ANT) family. We investigated the ANT/CypD relationship in mPTP dynamics and I/R injury. Despite lacking all ANT isoforms, Ca2+-dependent mPTP opening persisted in cardiac mitochondria but was desensitized. This desensitization conferred resistance to I/R injury in ANT-deficient mice. CypD is hypothesized to trigger mPTP opening through isomerization of ANTs at proline-62. To test this, we generated mice that expressed a P62A mutated version of ANT1. These mice showed similar mPTP dynamics and I/R sensitivity as the wild type, indicating that P62 is dispensable for CypD regulation. Together, these data indicate that the ANT family contributes to mPTP opening independently of CypD.
    DOI:  https://doi.org/10.1126/sciadv.adp7444
  24. bioRxiv. 2024 Nov 25. pii: 2024.11.24.622516. [Epub ahead of print]
    Cell-specific oxidative metabolism of the renal cortex.
    Kyle Feola, Andrea H Venable, Tatyana Broomfield, Claire B Llamas, Prashant Mishra, Sarah C Huen.
      The metabolic health of the kidney is a primary determinant of the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel kidney functions is limited by the kidney's structural and functional heterogeneity. As the kidney contains many different cell types, we hypothesize that intra-renal mitochondrial heterogeneity contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique to isolate kidney cell-type specific mitochondria. Here, we investigate mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag allele was combined with Slc34a1-CreERT2 , Ggt1-Cre , or Pvalb-Cre alleles to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. Changes with mitochondrial metabolomes induced by fasting suggest that the late PT significantly increases FAO during fasting. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting.
    Translational Statement: While the renal cortex is often considered a single metabolic compartment, we discovered significant diversity of mitochondrial metabolomes and functional capacities across the proximal tubule and the distal convoluted tubule. As mitochondrial dysfunction is a major biochemical pathway related to kidney disease progression, understanding the differences in mitochondrial metabolism across distinct kidney cell populations is thus critical in the development of effective and targeted therapeutic therapies for acute and chronic kidney disease.
    DOI:  https://doi.org/10.1101/2024.11.24.622516
  25. Neurobiol Dis. 2024 Dec 05. pii: S0969-9961(24)00361-9. [Epub ahead of print] 106759
    KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.
    Irune Guerra San Juan, Jessie Brunner, Kevin Eggan, Ruud F Toonen, Matthijs Verhage.
      Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are impacted in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5A null mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons.
    Keywords:  Aging; Axonal injury and repair; Axonal transport; Human neuron development; Human neurons; KIF5A; Kinesins; Mitochondria; Motor neurons; Neurodegeneration; Neurofilaments; RNA granules
    DOI:  https://doi.org/10.1016/j.nbd.2024.106759
  26. Mitochondrial DNA A DNA Mapp Seq Anal. 2024 Dec 12. 1-10
    Detection of single nucleotide variants in the mitochondrial genome of healthy mice and humans.
    Alfredo Varela-Echavarría, Kenya L Contreras-Ramírez, Carlos Lozano-Flores, Maribel Hernández-Rosales.
      Single nucleotide mutations in the mitochondrial genome are linked to aging in humans, primates, and rodents and cause neuromuscular diseases in humans. Load of mitochondrial variants in healthy tissues, however, is little known. Employing an unbiased detection method with no prior enzymatic amplification, we observed that the mitochondrial genome of embryonic, adult, and aged mouse brain from two different strains contains a diversity of single nucleotide variants with no age-related increase in abundance. We also observed de novo variants in single oocytes and adult liver arising at 5x10-5 and 8x10-6 substitutions per base pair per generation, respectively. Moreover, we found variants in human placenta of healthy donors that may reach up to 66% of all mitochondrial genome copies. Increase in the heteroplasmy of the variants observed in healthy mouse and human tissues and of those arisen de novo at high frequency in mice may lead to mitochondrial dysfunction and disease.
    Keywords:  Mexican; Mutation rate; heteroplasmy; mouse
    DOI:  https://doi.org/10.1080/24701394.2024.2439421
  27. Redox Biol. 2024 Dec 03. pii: S2213-2317(24)00432-4. [Epub ahead of print]79 103454
    Coupling of mitochondrial state with active zone plasticity in early brain aging.
    Lu Fei, Yongtian Liang, Ulrich Kintscher, Stephan J Sigrist.
      Neurodegenerative diseases typically emerge after an extended prodromal period, underscoring the critical importance of initiating interventions during the early stages of brain aging to enhance later resilience. Changes in presynaptic active zone proteins ("PreScale") are considered a dynamic, resilience-enhancing form of plasticity in the process of early, still reversible aging of the Drosophila brain. Aging, however, triggers significant changes not only of synapses but also mitochondria. While the two organelles are spaced in close proximity, likely reflecting a direct functional coupling in regard to ATP and Ca2+ homeostasis, the exact modes of coupling in the aging process remain to understood. We here show that genetic manipulations of mitochondrial functional status, which alters brain oxidative phosphorylation, ATP levels, or the production of reactive oxygen species (ROS), can bidirectionally regulate PreScale during early Drosophila brain aging. Conversely, genetic mimicry of PreScale resulted in decreased oxidative phosphorylation and ATP production, potentially due to reduced mitochondrial calcium (Ca2+) import. Our findings indicate the existence of a positive feedback loop where mitochondrial functional state and PreScale are reciprocally coupled to optimize protection during the early stages of brain aging.
    DOI:  https://doi.org/10.1016/j.redox.2024.103454
  28. Genet Med Open. 2024 ;2 101859
    Expanded-access use of elamipretide in a critically ill patient with Barth syndrome.
    Amy C Goldstein, Cassandra Pantano, Mariya Redko, Laura E MacMullen, Katsuhide Maeda, Matthew J O'Connor.
      
    Keywords:  Barth syndrome; Cardiolipin; Cardiomyopathy; Elamipretide; Mitochondria
    DOI:  https://doi.org/10.1016/j.gimo.2024.101859
  29. Front Aging Neurosci. 2024 ;16 1503336
    Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells.
    Helena Borland Madsen, Claudia Navarro, Emilie Gasparini, Jae-Hyeon Park, Zhiquan Li, Deborah L Croteau, Vilhelm A Bohr.
       Introduction: During aging, many cellular processes, such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses, become compromised. Urolithin A (UA) and Nicotinamide Riboside (NR) are two naturally occurring compounds known for their anti-inflammatory and mitochondrial protective properties, yet the effects of these natural substances on microglia cells have not been thoroughly investigated. As both UA and NR are considered safe dietary supplements, it is equally important to understand their function in normal cells and in disease states.
    Methods: This study investigates the effects of UA and NR on immune signaling, mitochondrial function, and microglial activity in a human microglial cell line (HMC3).
    Results: Both UA and NR were shown to reduce DNA damage-induced cellular senescence. However, they differentially regulated gene expression related to neuroinflammation, with UA enhancing cGAS-STING pathway activation and NR displaying broader anti-inflammatory effects. Furthermore, UA and NR differently influenced mitochondrial dynamics, with both compounds improving mitochondrial respiration but exhibiting distinct effects on production of reactive oxygen species and glycolytic function.
    Discussion: These findings underscore the potential of UA and NR as therapeutic agents in managing neuroinflammation and mitochondrial dysfunction in neurodegenerative diseases.
    Keywords:  aging; innate immune signaling; microglia; mitochondrial health; nicotinamide riboside; urolithin A
    DOI:  https://doi.org/10.3389/fnagi.2024.1503336
  30. J Bioenerg Biomembr. 2024 Dec 13.
    Acute CCl4-induced intoxication reduces complex I, but not complex II-based mitochondrial bioenergetics - protective role of succinate.
    Fozila R Ikromova, Feruzbek A Khasanov, Malika J Saidova, Ravshan K Shokirov, Shakhlo Gazieva, Abdukhakim M Khadjibaev, Davron B Tulyaganov, Rustam N Akalaev, Yulia V Levitskaya, Amir A Stopnitskiy, Artyom Y Baev.
      The main therapeutic strategy for the treatment of patients with toxic liver failure is the elimination of the toxic agent in combination with the targeted mitigation of pathological processes that have been initiated due to the toxicant. In the current research we evaluated the strategy of metabolic supplementation to improve mitochondrial bioenergetics during acute liver intoxication. In our study, we have shown that acute CCl4-induced intoxication negatively affects Complex I (in the presence of glutamate-malate as energy substrates) based respiration, generation of mitochondrial membrane potential (ΔΨm), mitochondrial NAD(P)H pool and NADH redox index, mitochondrial calcium retention capacity (CRC) and structure and functions of the liver. Boosting of mitochondrial bioenergetics through the complex II, using succinate as metabolic substrate in vitro, significantly improved mitochondrial respiration and generation of ΔΨm, but not mitochondrial CRC. Co-application of rotenone along with succinate, to prevent possible reverse electron flow, didn't show significant differences compared to the effects of succinate alone. Treatment of animals with acute liver failure, using a metabolic supplement containing succinate, inosine, methionine and nicotinamide improved Complex I based respiration, generation of ΔΨm, mitochondrial NAD(P)H pool and NADH redox index, mitochondrial CRC and slightly decreased the level of oxidative stress. These changes resulted in averting destructive and dystrophic changes in the structure of rat liver tissue caused by CCl4 intoxication, concomitantly enhancing hepatic functionality. Thus, we propose that metabolic supplementation targeting complex II could serve as a potential adjunctive therapy in the management of acute liver intoxication.
    Keywords:  Acute liver failure; CCl4 intoxication; Complex I-based respiration; Mitochondria; Succinate
    DOI:  https://doi.org/10.1007/s10863-024-10047-6
  31. Nat Commun. 2024 Dec 13. 15(1): 10681
    Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.
    Xue Pan, Yun Zhao, Yucong Li, Jiajia Chen, Wenya Zhang, Ling Yang, Yuanyi Zhou Xiong, Yuqing Ying, Hao Xu, Yuhong Zhang, Chong Gao, Yuhan Sun, Nan Li, Liangyi Chen, Zhixing Chen, Kai Lei.
      Tissue regeneration is a complex process involving large changes in cell proliferation, fate determination, and differentiation. Mitochondrial dynamics and metabolism play a crucial role in development and wound repair, but their function in large-scale regeneration remains poorly understood. Planarians offer an excellent model to investigate this process due to their remarkable regenerative abilities. In this study, we examine mitochondrial dynamics during planarian regeneration. We find that knockdown of the mitochondrial fusion gene, opa1, impairs both tissue regeneration and stem cell pluripotency. Interestingly, the regeneration defects caused by opa1 knockdown are rescued by simultaneous knockdown of the mitochondrial fission gene, drp1, which partially restores mitochondrial dynamics. Furthermore, we discover that Mitolow stem cells exhibit an enrichment of pluripotency due to their fate choices at earlier stages. Transcriptomic analysis reveals the delicate mitonuclear balance in metabolism and mitochondrial proteins in regeneration, controlled by mitochondrial dynamics. These findings highlight the importance of maintaining mitochondrial dynamics in large-scale tissue regeneration and suggest the potential for manipulating these dynamics to enhance stem cell functionality and regenerative processes.
    DOI:  https://doi.org/10.1038/s41467-024-54720-1
  32. Pediatr Nephrol. 2024 Dec 10.
    PDSS1 mutations-associated steroid-resistant nephrotic syndrome: case report and review of literature.
    Clair Habib, Galit Tal, Karin Weiss, Daniella Magen, Shirley Pollack.
      PDSS1 mutations hamper Coenzyme Q10 biosynthesis and cause a rare multisystem mitochondrial disease characterized by diverse clinical features and limited treatment options. To date, renal involvement has been reported in only one patient. We report a new female patient with compound heterozygous PDSS1 mutations and the clinical outcome following a trial of Coenzyme Q10 therapy. Our patient presented with developmental delay and regression at age three, which progressed to steroid-resistant nephrotic syndrome at age six, leading to stage 5 chronic kidney disease. Whole exome sequencing identified two pathogenic variants in the PDSS1 gene. High doses of Coenzyme Q10 therapy had no effect at this advanced stage of disease. Coenzyme Q10 treatment did not appear to improve the clinical outcome in this patient. Further data is needed to better understand the phenotypic spectrum of PDSS1-associated disruption, and the potential benefit of early Coenzyme Q10 therapy.
    Keywords:  CoQ10 deficiency; Mitochondrial respiratory chain; Neuro-developmental delay; Steroid-resistant nephrotic syndrome
    DOI:  https://doi.org/10.1007/s00467-024-06596-y
  33. J Inherit Metab Dis. 2024 Dec 09.
    Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders.
    Apolline Imbard, Hortense de Calbiac, Edouard Le Guillou, Pascal Laforêt, Manuel Schiff, Anaïs Brassier, Elise Thevenet, Clément Pontoizeau, Bertrand Lefrère, Chris Ottolenghi, Elise Lebigot, Pauline Gaignard, Stéphanie Gobin, Cécile Acquaviva-Bourdain, Jean-François Benoist, Caroline Tuchmann-Durand, Antoine Legendre, Pascale de Lonlay.
      Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO2) during incremental exercise (dQ/dVO2) provides an indirect surrogate of mitochondrial function. A high dQ/dVO2 slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO2 as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (n = 10), CPT2 (n = 6), VLCAD (n = 7), or MADD (n = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO2. In these patients, dQ/dVO2 was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO2 was significantly associated with the severity score (B = 0.831, p = 0.008) and triheptanoin treatment (B = -0.547, p = 0.025). dQ/dVO2 and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.
    Keywords:  acylcarnitine; cardiac output; exercise test; fatty acid beta‐oxidation disorder; oxygen consumption; triheptanoin
    DOI:  https://doi.org/10.1002/jimd.12819
  34. Autophagy. 2024 Dec 12. 1-16
    Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
    Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen.
      Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A1 or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.Abbreviation: ΔΨm: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.
    Keywords:  PI3K-AKT-MTORC1; m.3243A>G; mitochondria; mitophagy; mtDNA mutations; nutrient signaling
    DOI:  https://doi.org/10.1080/15548627.2024.2437908
  35. Front Endocrinol (Lausanne). 2024 ;15 1443737
    Association of mitochondrial haplogroup H with reduced risk of type 2 Diabetes among Gulf Region Arabs.
    Mohammed Dashti, Naser M Ali, Hussain Alsaleh, Sumi Elsa John, Rasheeba Nizam, Thangavel Alphonse Thanaraj, Fahd Al-Mulla.
       Background: Numerous studies have linked mitochondrial dysfunction to the development of type 2 diabetes (T2D) by affecting glucose-stimulated insulin secretion in pancreatic beta cells and reducing oxidative phosphorylation in insulin-responsive tissues. Given the strong genetic underpinnings of T2D, research has explored the connection between mitochondrial DNA haplogroups, specific variants, and the risk and comorbidities of T2D. For example, haplogroups F, D, M9, and N9a have been linked to an elevated risk of T2D across various populations. Additionally, specific mitochondrial DNA variants, such as the rare mtDNA 3243 A>G and the more prevalent mtDNA 16189 T>C, have also been implicated in heightened T2D risk. Notably, these associations vary among different populations. Given the high incidence of T2D in the Gulf Cooperation Council countries, this study investigates the correlation between T2D and mitochondrial haplogroups and variants in Arab populations from the Gulf region.
    Methods: This analysis involved mitochondrial haplogroup and variant testing in a cohort of 1,112 native Kuwaiti and Qatari individuals, comprising 685 T2D patients and 427 controls. Complete mitochondrial genomes were derived from whole exome sequencing data to examine the associations between T2D and haplogroups and mitochondrial DNA variants.
    Results: The analysis revealed a significant protective effect of haplogroup H against T2D (odds ratio [OR] = 0.65; P = 0.022). This protective association persisted when adjusted for age, sex, body mass index (BMI) and population group, with an OR of 0.607 (P = 0.021). Furthermore, specific mitochondrial variants showed significant associations with T2D risk after adjustment for relevant covariates, and some variants were exclusively found in T2D patients.
    Conclusion: Our findings confirm that the maternal haplogroup H, previously identified as protective against obesity in Kuwaiti Arabs, also serves as a protective factor against T2D in Arabs from the Gulf region. The study also identifies mitochondrial DNA variants that either increase or decrease the risk of T2D, underscoring their role in cellular energy metabolism.
    Keywords:  Arab; haplogroups; mitochondria; mtDNA variants; type 2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2024.1443737
  36. Adv Mater. 2024 Dec 11. e2413371
    Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling.
    Shengjie Ge, Aidong Sun, Xinyu Zhou, Ping Niu, Yong Chen, Xiaotao Bao, Meng Yu, Zhenhua Zhong, Jingwu Sun, Guang Li.
      Mitochondrial dysfunction, which is the primary mechanism underlying cisplatin-induced hearing loss, can potentially be mitigated by modulating the redox balance and reprogramming the energy metabolism to remodel mitochondrial homeostasis. Herein, N-acetyl-l-cysteine-derived carbonized polymer dots (NAC CPDs) are embedded into manganese porphyrin-doped metal-organic frameworks and encapsulated using a polydopamine (PDA) coating and gelatin methacryloyl (GelMA) hydrogel to afford functionalized nanozyme microcapsules. Owing to their injectability and adhesion properties, these microcapsules exhibit the advantages of prolonged retention in the middle ear and sustained release in the inner ear. The synergy between the manganese porphyrin and polymer dots results in excellent antioxidant properties. The developed nanozymes activate the PI3K-AKT pathway, reprogramming the energy supply mechanism, and inhibiting the oligomerization of BAX in mitochondria to prevent the leakage of mitochondrial DNA and cytochrome c. Therapeutic efficacy and related mechanisms are validated in vivo. Thus, this study on mitochondrial homeostasis remodeling by nanozyme microcapsules opens a new chapter in the treatment of hearing loss.
    Keywords:  MOF; cisplatin; hearing loss; mitochondria; nanozymes
    DOI:  https://doi.org/10.1002/adma.202413371
  37. MAbs. 2024 Jan-Dec;16(1):16(1): 2436102
    Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation.
    Dale O Starkie, Charles Arber, Terry Baker, Daniel J Lightwood, Selina Wray.
      Microtubule-associated protein tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3 R- and 4 R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is associated with diseases such as progressive supranuclear palsy and frontotemporal dementia. The mechanisms by which increased 4 R results in neuronal dysfunction and neurodegeneration are not fully understood, and progress has been limited partly by a lack of suitable tools to investigate tau isoform imbalance. This work generated novel 3 R- and 4 R-specific antibody tools and 4 R-tau degrading intracellular antibody fragment "degrabodies". These were used to probe the molecular mechanisms of excess 4 R-tau in disease-mutant induced pluripotent stem cell-derived neurons. For the first time, we demonstrate a causative link between excess 4 R-tau and mitochondrial membrane hyperpolarization with wide-ranging potential for elucidating novel therapeutic approaches to treat neurodegenerative disease.
    Keywords:  Antibody Discovery; degrabodies; degrading antibody fragments; iPSC-derrived neurons; intracellular antibody technologies; targeted protein degradation; tau
    DOI:  https://doi.org/10.1080/19420862.2024.2436102
  38. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2024 Dec 10. 41(12): 1463-1468
    [A case of neonatal Mitochondrial DNA depletion syndrome type 13 caused by FBXL4 gene mutation].
    Yuanyuan Zhu, Chenhong Wang, Junjin Chen, Xiaohong Wang, Xiaolu Ma.
       OBJECTIVE: To explore the clinical phenotypes and genetic variant in a neonatal case of Mitochondrial DNA depletion syndrome type 13 (MTDPS13).
    METHODS: Clinical data and results of genetic testing of a neonate admitted to the Children's Hospital of Zhejiang University School of Medicine in January 2023 was retrospectively analyzed. The study was approved by the Medical Ethics Committee of the Children's Hospital of Zhejiang University.
    RESULTS: The male infant was admitted to the NICU due to tachypnea and persistent lactic acidosis 6 hours after birth. At admission, distinctive facial features were noted. Laboratory tests showed elevated lactic acid (< 30 mmol/L). Whole-exome sequencing revealed that he has harbored homozygous c.141del frameshift mutation of FBXL4 gene, which was unreported previously. The mutation was inherited from both of his parents and classified as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).
    CONCLUSION: The clinical phenotypes of this case of MTDPS13 is characterized by lactic acidosis, distinctive facial features, growth retardation and developmental delay, for which the homozygous c.141del variant of the FBXL4 gene may be accountable.
    DOI:  https://doi.org/10.3760/cma.j.cn511374-20240630-00360
  39. Pathology. 2024 Nov 13. pii: S0031-3025(24)00292-7. [Epub ahead of print]
    Clinicopathological collaboration in adult muscle disease: a pragmatic pathway to approach diagnostic dilemmas.
    Monika Hofer, Stefen Brady.
      The role of muscle biopsy in the investigation of neuromuscular disease remains firmly established but has evolved. Expertise in diagnostic myopathology remains relevant and supports clinical practice. Neuromuscular disease is rare; thus clinicopathological correlation, or better, collaboration is important. The process starts in the clinic with the identification of patients for whom muscle biopsy will be beneficial for diagnosis and management in a multidisciplinary neuromuscular care setting. In this review article, we describe the current use of muscle biopsy in our adult practice and discuss several carefully selected real cases [e.g., asymmetric hand weakness, dysphagia and proximal weakness, subacute weakness with raised creatine kinase (CK), non-specific presentation], where biopsy and collaboration have been instrumental in achieving the correct diagnosis for the patient. We discuss areas of diagnostic difficulty, such as fairly common starting scenarios leading to unusual entities, atypical presentations of common diseases and novel pathological findings. We will focus on the idiopathic inflammatory myopathies (IIMs), the most common indication for adult muscle biopsies in many diagnostic settings, whereby the use of an integrated clinical-serological-pathological classification is now firmly established. We will also explore the evolving role for and continuing need of muscle biopsy in the genomic era, particularly with assessing the potential pathogenicity of reported genetic variants of uncertain significance (VUS). We describe a pragmatic approach to detecting the more common disorders, which also enables us to distinguish 'the horses from the zebras' and manage diagnostic uncertainty.
    Keywords:  adult muscle pathology; approach to muscle biopsy; clinicopathological collaboration; clinicopathological correlation; integrated diagnosis; muscle biopsy; muscle biopsy diagnosis; muscle biopsy interpretation; muscle biopsy selection; myositis
    DOI:  https://doi.org/10.1016/j.pathol.2024.10.004
  40. PNAS Nexus. 2024 Dec;3(12): pgae499
    Disagreement on foundational principles of biological aging.
    Vadim N Gladyshev, Benjamin Anderson, Hanna Barlit, Benjamin Barré, Samuel Beck, Bahareh Behrouz, Daniel W Belsky, Amandine Chaix, Manish Chamoli, Brian H Chen, Kaiyang Cheng, Jane Chuprin, Gary A Churchill, Andrea Cipriano, Alex Colville, Joris Deelen, Yuri Deigin, KeHuan K Edmonds, Bradley W English, Ruogu Fang, Michael Florea, Iosif M Gershteyn, Diljeet Gill, Laura H Goetz, Vera Gorbunova, Patrick T Griffin, Steve Horvath, Martin Borch Jensen, Xin Jin, Sara Jovanovska, Kathrin M Kajderowicz, Tomoko Kasahara, Csaba Kerepesi, Subhash Kulkarni, Vyacheslav M Labunskyy, Morgan E Levine, Sergiy Libert, J Yuyang Lu, Yuancheng Ryan Lu, Riccardo E Marioni, Brianah M McCoy, Wayne Mitchell, Mahdi Moqri, Farzaneh Nasirian, Peter Niimi, Hamilton Se-Hwee Oh, Brian Okundaye, Andrey A Parkhitko, Leonid Peshkin, Mia Petljak, Jesse R Poganik, Glen Pridham, Daniel E L Promislow, Weronika Prusisz, Margaux Quiniou, Ken Raj, Daniel Richard, Jose Luis Ricon, Jarod Rutledge, Morten Scheibye-Knudsen, Nicholas J Schork, Andrei Seluanov, Michael Shadpour, Anastasia V Shindyapina, Steven R Shuken, Sruthi Sivakumar, Thomas Stoeger, Ayumu Sugiura, Nadia R Sutton, Alexander Suvorov, Andrei E Tarkhov, Emma C Teeling, Alexandre Trapp, Alexander Tyshkovskiy, Maximilian Unfried, Cavin K Ward-Caviness, Sun Hee Yim, Kejun Ying, Jeffrey Yunes, Bohan Zhang, Alex Zhavoronkov.
      To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.
    DOI:  https://doi.org/10.1093/pnasnexus/pgae499
  41. Nature. 2024 Dec;636(8042): 322-331
    π-HuB: the proteomic navigator of the human body.
    π-HuB Consortium
      The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body at unprecedented resolution and scale. Here we introduce a big-science endeavour called π-HuB (proteomic navigator of the human body). The aim of the π-HuB project is to (1) generate and harness multimodality proteomic datasets to enhance our understanding of human biology; (2) facilitate disease risk assessment and diagnosis; (3) uncover new drug targets; (4) optimize appropriate therapeutic strategies; and (5) enable intelligent healthcare, thereby ushering in a new era of proteomics-driven phronesis medicine. This ambitious mission will be implemented by an international collaborative force of multidisciplinary research teams worldwide across academic, industrial and government sectors.
    DOI:  https://doi.org/10.1038/s41586-024-08280-5
  42. Clin Genet. 2024 Dec 12.
    Diagnostic Use of Genome Sequencing in Patients With 11p15.5 Imprinting Disorder Features: A Pilot Study.
    Luise Kessler, Jeremias Krause, Florian Kraft, Asmaa K Amin, Gyorgy Fekete, Anna Lengyel, Eva Pinti, Arpad Kovacs, Annette Lischka, Katja Eggermann, Ingo Kurth, Cordula Knopp, Miriam Elbracht, Matthias Begemann, Thomas Eggermann.
      To assess the suitability of genome sequencing (GS) as the second step in the diagnostics of patients with the features of 11p15.5-associated imprinting disorders (ImpDis: Silver-Russell syndrome [SRS], Beckwith-Wiedemann syndrome [BWS]), we performed short-read GS in patients negatively tested for imprinting disturbances. Obtaining a genetic diagnosis for patients with the features of these syndromes is challenging due to the clinical and molecular heterogeneity and overlap, and many patients remain undiagnosed after the currently suggested stepwise diagnostic workup. GS was conducted in 48 patients (SRS features: n = 37 and BWS features: n = 11). The detection rate differed markedly between the ImpDis: although a genetic cause could be identified in 51% of patients referred with SRS features, no pathogenic variants were detected in patients with BWS features. Thus, GS substantially improves the diagnostic yield and broadens the spectrum of overlapping disorders with SRS features. Obtaining a precise molecular diagnosis provides the basis for a personalized clinical management. Our findings support the use of GS as a second-tier diagnostic tool for patients with growth disturbances, as it addresses all currently known variant types and shortens the diagnostic odyssey.
    Keywords:  Beckwith–Wiedemann syndrome; Silver–Russell syndrome; diagnostic yield; genome sequencing
    DOI:  https://doi.org/10.1111/cge.14649
  43. J Neurol. 2024 Dec 12. 272(1): 17
    A rare cause of autosomal recessive ataxia with very late diagnosis and prolonged disease course.
    Shakya Bhattacharjee, Eva Lenassi, Robert W Taylor, Andrew M Schaefer, John Ealing, Christopher Kobylecki.
      
    DOI:  https://doi.org/10.1007/s00415-024-12778-3
  44. Genet Med Open. 2024 ;2 101881
    Using genomic databases to determine the frequency and population-based heterogeneity of autosomal recessive conditions.
    William B Hannah, Mitchell L Drumm, Keith Nykamp, Tiziano Pramparo, Robert D Steiner, Steven J Schrodi.
      
    Keywords:  Disease prevalence; Genetic epidemiology; Mendelian disorders; Recessive; Sequence database
    DOI:  https://doi.org/10.1016/j.gimo.2024.101881
  45. Sci Adv. 2024 Dec 13. 10(50): eadp1980
    Synergistic label-free fluorescence imaging and miRNA studies reveal dynamic human neuron-glial metabolic interactions following injury.
    Yang Zhang, Maria Savvidou, Volha Liaudanskaya, Pramesh Singh, Yuhang Fu, Amreen Nasreen, Marly Coe, Marilyn Kelly, Dustin Snapper, Chelsea Wagner, Jessica Gill, Aviva Symes, Abani Patra, David L Kaplan, Afshin Beheshti, Irene Georgakoudi.
      Neuron-glial cell interactions following traumatic brain injury (TBI) determine the propagation of damage and long-term neurodegeneration. Spatiotemporally heterogeneous cytosolic and mitochondrial metabolic pathways are involved, leading to challenges in developing effective diagnostics and treatments. An engineered three-dimensional brain tissue model comprising human neurons, astrocytes, and microglia is used in combination with label-free, two-photon imaging and microRNA studies to characterize metabolic interactions between glial and neuronal cells over 72 hours following impact injury. We interpret multiparametric, quantitative, optical metabolic assessments in the context of microRNA gene set analysis and identify distinct metabolic changes in neurons and glial cells. Glycolysis, nicotinamide adenine dinucleotide phosphate (reduced form) and glutathione synthesis, fatty acid synthesis, and oxidation are mobilized within glial cells to mitigate the impacts of initial enhancements in oxidative phosphorylation and fatty acid oxidation within neurons, which lack robust antioxidant defenses. This platform enables enhanced understanding of mechanisms that may be targeted to improve TBI diagnosis and treatment.
    DOI:  https://doi.org/10.1126/sciadv.adp1980
  46. Nature. 2024 Dec;636(8042): 512
    Bad bar charts are pervasive across biology.
    Amanda Heidt.
      
    Keywords:  Publishing; Research data; Technology
    DOI:  https://doi.org/10.1038/d41586-024-03996-w
  47. PLoS One. 2024 ;19(12): e0312352
    Mitochondrial fission is required for thermogenesis in brown adipose tissue.
    Yuta Ibayashi, Nao Hasuzawa, Seiji Nomura, Masaharu Kabashima, Ayako Nagayama, Shimpei Iwata, Miyuki Kitamura, Kenji Ashida, Yoshinori Moriyama, Ken Yamamoto, Masatoshi Nomura, Lixiang Wang.
      Brown adipose tissue (BAT) thermogenesis is pivotal for maintaining body temperature and energy balance. Mitochondrial morphology is dynamically controlled by a balance between fusion and fission, which is crucial for cell differentiation, response to metabolic insults, and heat production. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. This study investigates the role of Drp1 in BAT development and thermogenesis by generating Drp1-deficient mice. These mice were created by crossing Drp1 floxed mice with fatty acid-binding protein 4-Cre (aP2-Cre) transgenic mice, resulting in aP2-Cre+/-Drp1flox/flox (aP2-Drp1f/f) mice. The aP2-Drp1f/f mice exhibited severe BAT and brain hypoplasia, with the majority dying within 48 hours postnatally, highlighting Drp1's crucial role in neonatal survival. Impaired thermogenic responses were observed in aP2-Drp1f/f mice, characterized by significantly decreased expression of thermogenic and lipogenic genes in BAT. Ultrastructural analysis revealed disrupted mitochondrial morphology and reduced lipid droplet content in BAT. The few surviving adult aP2-Drp1f/f mice also showed impaired BAT and brain development, along with BAT thermogenesis dysfunction during cold exposure. Our findings underscore the essential role of Drp1-mediated mitochondrial fission in BAT thermogenesis and neonatal survival, providing insights into potential therapeutic approaches for metabolic disorders.
    DOI:  https://doi.org/10.1371/journal.pone.0312352
  48. Aging (Albany NY). 2024 Dec 12. null
    Arginase-II gene deficiency reduces skeletal muscle aging in mice.
    Matteo Caretti, Duilio Michele Potenza, Guillaume Ajalbert, Urs Albrecht, Xiu-Fen Ming, Andrea Brenna, Zhihong Yang.
      Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males. The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.
    Keywords:  aging; arginase-II; cellular senescence; fibrosis; physical activity; skeletal muscle
    DOI:  https://doi.org/10.18632/aging.206173
  49. Genet Med Open. 2024 ;2 101838
    Loss of function in NSD2 causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome.
    Tomoko Kawai, Shiori Kinoshita, Yuka Takayama, Eriko Ohnishi, Hiromi Kamura, Kazuaki Kojima, Hiroki Kikuchi, Miho Terao, Tohru Sugawara, Ohsuke Migita, Masayo Kagami, Tsuyoshi Isojima, Yu Yamaguchi, Keiko Wakui, Hirofumi Ohashi, Kenji Shimizu, Seiji Mizuno, Nobuhiko Okamoto, Yoshimitsu Fukushima, Fumio Takada, Kenjiro Kosaki, Shuji Takada, Hidenori Akutsu, Kiyoe Ura, Kazuhiko Nakabayashi, Kenichiro Hata.
       Purpose: Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by heterozygous deletions of the distal short arm of chromosome 4 that includes NSD2, reportedly causes specific DNA methylation signatures in peripheral blood cells. However, the genomic loci responsible for these signatures have not been elucidated. The present study aims to define the loci underlying WHS-related DNA methylation signatures and explore the role of NSD2 in these signatures.
    Methods: We conducted genome-wide methylation analysis of individuals with WHS or NSD2 variants using an array method. We studied genome-edited knockin mice and induced pluripotent stem cells to explore the function of NSD2 variants.
    Results: Three undiagnosed cases with NSD2 variants showed WHS-related DNA methylation signatures. In patient-derived induced pluripotent stem cells and genome-edited knockin mice, these variants cause NSD2 loss of function, respectively. The p.Pro905Leu variant caused decreased Nsd2 protein levels and altered histone H3-lysine 36 dimethylation levels similarly to what was observed in Nsd2 knockout mice. Nsd2 knockout and p.Pro905Leu knockin mice exhibited common DNA methylation changes.
    Conclusion: These results revealed that WHS-related DNA methylation signatures are dependent on NSD2 dysfunction and could be useful in identifying NSD2 variants of uncertain significance.
    Keywords:  DNA methylation signature; Histone H3-lysine 36 dimethylation; NSD2; Peripheral blood cells; Wolf-Hirschhorn syndrome
    DOI:  https://doi.org/10.1016/j.gimo.2024.101838
  50. Cell. 2024 Dec 12. pii: S0092-8674(24)01332-1. [Epub ahead of print]187(25): 7045-7063
    How to build the virtual cell with artificial intelligence: Priorities and opportunities.
    Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B Burkhardt, Andrea Califano, Jonah Cool, Abby F Dernburg, Kirsty Ewing, Emily B Fox, Matthias Haury, Amy E Herr, Eric Horvitz, Patrick D Hsu, Viren Jain, Gregory R Johnson, Thomas Kalil, David R Kelley, Shana O Kelley, Anna Kreshuk, Tim Mitchison, Stephani Otte, Jay Shendure, Nicholas J Sofroniew, Fabian Theis, Christina V Theodoris, Srigokul Upadhyayula, Marc Valer, Bo Wang, Eric Xing, Serena Yeung-Levy, Marinka Zitnik, Theofanis Karaletsos, Aviv Regev, Emma Lundberg, Jure Leskovec, Stephen R Quake.
      Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.
    Keywords:  AI; ML; cell biology; virtual cell
    DOI:  https://doi.org/10.1016/j.cell.2024.11.015
  51. Pathology. 2024 Nov 14. pii: S0031-3025(24)00297-6. [Epub ahead of print]
    Current concepts and molecular pathology of neurodegenerative diseases.
    Shelley L Forrest, Gabor G Kovacs.
      Neurodegenerative diseases are a pathologically, clinically and genetically diverse group of diseases characterised by selective dysfunction, loss of synaptic connectivity and neurodegeneration, ​and are associated with the deposition of misfolded proteins in neurons and/or glia. Molecular studies have highlighted the role of conformationally altered proteins in the pathogenesis of neurodegenerative diseases and have paved the way for developing disease-specific biomarkers that capture and differentiate the main type/s of protein abnormality responsible for neurodegenerative diseases, some of which are currently used in clinical practice. These proteins follow sequential patterns of anatomical involvement and disease spread in the brain and may also be detected in peripheral organs. Recent studies suggest that glia are likely to have an important role in pathological spread throughout the brain and even follow distinct progression patterns from neurons. In addition to morphological and molecular approaches to the classification of these disorders, a further new stratification level incorporates the structure of protein filaments detected by cryogenic electron microscopy. Rather than occurring in isolation, combined deposition of tau, amyloid-β, α-synuclein and TDP-43 are frequently observed in neurodegenerative diseases and in the ageing brain. These can be overlooked, and their clinicopathological relevance is difficult to interpret. This review provides an overview of disease pathogenesis and diagnostic implications, recent molecular and ultrastructural classification of neurodegenerative diseases, how to approach ageing-related and mixed pathologies, ​and the importance of the protein-based classification system for practising neuropathologists and clinicians. This review also informs general pathologists about the relevance of ongoing full body autopsy studies to understand the spectrum and pathogenesis of neurodegenerative diseases.
    Keywords:  disease classification; mixed pathology; neurodegenerative disease; proteinopathy
    DOI:  https://doi.org/10.1016/j.pathol.2024.10.006
  52. Neural Regen Res. 2024 Dec 07.
    Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease.
    Ling-Xiao Yi, Hui Ren Woon, Genevieve Saw, Li Zeng, Eng King Tan, Zhi Dong Zhou.
      The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease, the second most common human neurodegenerative disease. Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear, the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy. The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons, which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies. The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells. The benefits of induced pluripotent stem cell-based research are highlighted. Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared. The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated. Finally, limitations, challenges, and future directions of induced pluripotent stem cell- based approaches are analyzed and proposed, which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-00771
  53. Apoptosis. 2024 Dec 07.
    Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    Tomasz Wenta, Guanpeng Wang, Tessa Van Buren, Michal Zolkiewski, Anna Zolkiewska.
      Loss-of-function mutations in the CLPB gene lead to congenital neutropenia due to impaired neutrophil differentiation. CLPB, a member of the AAA+ family of proteins, resides in the intermembrane space of mitochondria. The mechanism by which a loss of CLPB elicits defects in the differentiation program of neutrophil precursor cells is not understood. Here, we used 32D clone 3 (32Dcl3) cells, an interleukin-3 (IL-3)-dependent mouse myeloblastic cell line model, to investigate the effects of CLPB knockout on myeloblast-to-neutrophil differentiation in vitro. We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells. Despite those abnormalities, CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF). CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells. Moreover, we found that increased apoptosis of CLPB-deficient cells is linked to production of reactive oxygen species (ROS). N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation. The protective effect of citrate was abolished by inhibition of ATP-citrate lyase (ACLY), an enzyme that converts cytosolic citrate into acetyl-CoA, a substrate for protein acetylation. We propose that citrate supplementation may help mitigate the effects of CLPB loss by facilitating ACLY-dependent ROS detoxification in granulocytic precursor cells.
    Keywords:  Apoptosis; Mitochondria; Neutropenia; Neutrophil differentiation; Promyeloblast; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s10495-024-02053-1
  54. Bioinformatics. 2024 Nov 28. pii: btae714. [Epub ahead of print]40(12):
    OpenVariant: a toolkit to parse and operate multiple input file formats.
    David Martínez-Millán, Federica Brando, Miguel L Grau, Mònica Sánchez-Guixé, Carlos López-Elorduy, Iker Reyes-Salazar, Jordi Deu-Pons, Núria López-Bigas, Abel González-Pérez.
       SUMMARY: Advances in high-throughput DNA sequencing technologies and decreasing costs have fueled the identification of small genetic variants (such as single nucleotide variants and indels) across tumors. Despite efforts to standardize variant formats and vocabularies, many sources of variability persist across databases and computational tools that annotate variants, hindering their integration within cancer genomic analyses. In this context, we present OpenVariant, an easily extendable Python package that facilitates seamless reading, parsing and refinement of diverse input file formats in a customizable structure, all within a single process.
    AVAILABILITY AND IMPLEMENTATION: OpenVariant is an open-source package available at https://github.com/bbglab/openvariant. Documentation may be found at https://openvariant.readthedocs.io.
    DOI:  https://doi.org/10.1093/bioinformatics/btae714
  55. Int J Pharm. 2024 Dec 07. pii: S0378-5173(24)01292-4. [Epub ahead of print]669 125058
    Targeting hyperactive mitochondria in activated HSCs and inhibition of liver fibrogenesis in mice using sorafenib complex micelles.
    Li Xiang, Yuting Qin, Lei Li, Xianjing Xiang, Wenhui Zhang, Qiangqiang Jiao, Yaru Shao, Xinqiong Huang, Meichun Wu, Tianle Zhou, Yukang Lin, Yuping Chen.
      Liver fibrosis is a pathological condition marked by the excessive buildup of extracellular matrix primarily resulting from the transformation of quiescent hepatic stellate cells (HSCs) to myofibroblastic (MF) phenotype and their resultant over-expansion. Activated HSCs completely rely on their hyperactive mitochondria to supply the energy and biomass for their rapid proliferation and collagen secretion, so an intervention targeting their mitochondria can effectively restrict their pathological amplification and contribution to liver fibrosis. Here we tried sorafenib, a drug that plays anticancer roles by inducing the disruption and loss of mitochondrial functions, to reach an antifibrotic goal. And a complex micellar system, VA-PEG-PCL/TPGS (VPP/TPGS), was specifically designed and fabricated to encapsulate and deliver sorafenib selectively to activated HSCs to overcome its application limitations in bioavailability, toxicity and intracellular stay, and eventually maximize its induction of mitochondrial dysfunction and therapeutically antifibrotic efficacy. The prepared sorafenib complex micelles not only exhibited a suitable particle size, uniform morphology, and nice stability, but also performed excellently in the biosafety and HSCs-targetability in vitro and in vivo. In human active HSC cell lines, they markedly attenuated mitochondrial hyperactivity, induced apoptosis, and downregulated fibrosis markers as expected; while in a CCl4-induced murine model of hepatic fibrosis, they effectively restricted the expansion of MF-HSCs, reduced collagen deposition, and promoted the healing of liver damage, showing a good potential in fibrosis curation. Collectively, our VPP/TPGS complex micelles provide an ideal drug delivery platform that has the potential to revolutionize the treatment of liver fibrosis via addressing its cellular and metabolic underpinnings and thus improve patient outcomes.
    Keywords:  Complex micelles; D-α-tocopheryl polyethylene glycol succinate; Hepatic stellate cell; Liver fibrosis; Mitochondria; Sorafenib
    DOI:  https://doi.org/10.1016/j.ijpharm.2024.125058
  56. PLoS One. 2024 ;19(12): e0310626
    Modeling the consequences of age-linked rDNA hypermethylation with dCas9-directed DNA methylation in human cells.
    Yana Blokhina, Abigail Buchwalter.
      Ribosomal DNA (rDNA) genes encode the structural RNAs of the ribosome and are present in hundreds of copies in mammalian genomes. Age-linked DNA hypermethylation throughout the rDNA constitutes a robust "methylation clock" that accurately reports age, yet the consequences of hypermethylation on rDNA function are unknown. We confirmed that pervasive hypermethylation of rDNA occurs during mammalian aging and senescence while rDNA copy number remains stable. We found that DNA methylation is exclusively found on the promoters and gene bodies of inactive rDNA. To model the effects of age-linked methylation on rDNA function, we directed de novo DNA methylation to the rDNA promoter or gene body with a nuclease-dead Cas9 (dCas9)-DNA methyltransferase fusion enzyme in human cells. Hypermethylation at each target site had no detectable effect on rRNA transcription, nucleolar morphology, or cellular growth rate. Instead, human UBF and Pol I remain bound to rDNA promoters in the presence of increased DNA methylation. These data suggest that promoter methylation is not sufficient to impair transcription of the human rDNA and imply that the human rDNA transcription machinery may be resilient to age-linked rDNA hypermethylation.
    DOI:  https://doi.org/10.1371/journal.pone.0310626
  57. Biochemistry (Mosc). 2024 Nov;89(11): 2028-2036
    Vimentin and Desmin Intermediate Filaments Maintain Mitochondrial Membrane Potential.
    Alexander A Dayal, Olga I Parfenteva, Wang Huiying, Anton S Shakhov, Irina B Alieva, Alexander A Minin.
      Intermediate filaments (IFs) represented by a diverse range of proteins, are one of the three main cytoskeleton components in different types of animal cells. IFs provide mechanical strength to cells and help position the nucleus and organelles in the cell. Desmin is an IF protein typical of muscle cells, while vimentin, which has a similar structure, is expressed in many mesenchymal cells. Both proteins are synthesized during myogenesis and regeneration of damaged muscle tissue and form a mixed IF network. Both desmin and vimentin regulate mitochondrial activity, including mitochondrial localization and maintenance of mitochondrial membrane potential, in the corresponding cells, but the role of mixed IFs in the control of mitochondrial functions remains unclear. To investigate how a simultaneous presence of these proteins affects mitochondrial membrane potential, we used BHK21 cells expressing both vimentin and desmin IFs. Expression of vimentin or desmin individually or both proteins simultaneously was suppressed using gene knockout and/or RNA interference. It was found that disruption of biosynthesis of either vimentin or desmin did not affect the mitochondrial membrane potential, which remained unchanged compared to cells expressing both proteins. Simultaneous abolishment of both proteins resulted in a 20% reduction in the mitochondrial membrane potential, indicating that both vimentin and desmin play an equally important role in its maintenance.
    Keywords:  desmin; mitochondria; mitochondrial membrane potential; vimentin
    DOI:  https://doi.org/10.1134/S0006297924110154
  58. Genet Med Open. 2024 ;2 101834
    Copy-number analysis from genome sequencing data of 11,754 rare-disease parent-child trios: A model for identifying autosomal recessive human gene knockouts including a novel gene for autosomal recessive retinopathy.
    Genomics England Research Consortium
       Purpose: In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders.
    Methods: We developed a copy-number variations analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies.
    Results: Autosomal recessive (AR) modeling detected 34 distinct rare deletions that were homozygous in the proband and heterozygous in both parents. These inherited biallelic deletions were only detected in 52 trios. These "knockout" regions included 37 genes, having among them 8 with an Online Mendelian Inheritance in Man AR annotation. Deletions of NPHP1, followed by OTOA, both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous NPHP1 deletions were detected in 0.3%-0.5% of controls. We reviewed "knockout" patients for the remaining 29 genes without disease associations and identified SLC66A1 as a likely novel cause for AR rod-cone dystrophy in 4 families.
    Conclusion: A tailored copy-number variations analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with NPHP1 biallelic deletions causing nephronophthisis the leading finding. We propose SLC66A1 as a novel cause for AR retinopathy.
    Keywords:  CNV analysis; Genome sequencing; NPHP1; Retinopathy; SLC66A1
    DOI:  https://doi.org/10.1016/j.gimo.2024.101834
  59. Brain. 2024 Dec 09. pii: awae398. [Epub ahead of print]
    Genome-wide epistasis analysis reveals significant epistatic signals associated with Parkinson's disease risk.
    Alejandro Cisterna-Garcia, Bernabe I Bustos, Sara Bandres-Ciga, Thiago P Leal, Elif I Sarihan, Christie Jok, Dimitri Krainc, Ignacio F Mata, Steven J Lubbe, Juan A Botia.
      Genome-wide association studies (GWAS) have increased our understanding of Parkinson's disease (PD) genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis, the statistical interaction between two or more genetic variants. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called Variant-variant interaction through variable thresholds (VARI3) and applied it to diverse PD GWAS cohorts. We used 14 cohorts of European ancestry (14,671 cases and 17,667 controls) as a discovery stage, identifying 14 significant candidate variant-variant interactions. We then used four independent cohorts (13,377 cases and 413,789 controls) as replication stage, successfully replicating three epistasis signals located nearby SNCA and within MAPT and WNT3. Admixture analysis showed that the epistatic effect on PD of those variants at these loci was observed in both European ancestry and Native American ancestry individuals. We assessed the functional impact of the epistasis signals across a range of functional/-omics datasets identifying significant single-variant eQTLs across brain tissues, epistasis eQTL signals in whole-blood, PD-relevant pathways and ontologies, and chromatin interactions between the regions of the interacting SNPs. In conclusion, we identified and replicated novel epistatic signals associated with PD risk across multiple diverse genetic ancestry cohorts, highlighting their enrichment in pathways relevant to Parkinson's disease.
    Keywords:   MAPT ; SNCA ; VARI3 ; WNT3 ; Parkinson’s; epistasis
    DOI:  https://doi.org/10.1093/brain/awae398
  60. Nat Methods. 2024 Dec 09.
    ProHap enables human proteomic database generation accounting for population diversity.
    Jakub Vašíček, Ksenia G Kuznetsova, Dafni Skiadopoulou, Lucas Unger, Simona Chera, Luiza M Ghila, Nuno Bandeira, Pål R Njølstad, Stefan Johansson, Stefan Bruckner, Lukas Käll, Marc Vaudel.
      Amid the advances in genomics, the availability of large reference panels of human haplotypes is key to account for human diversity within and across populations. However, mass spectrometry-based proteomics does not benefit from this information. To address this gap, we introduce ProHap, a Python-based tool that constructs protein sequence databases from phased genotypes of reference panels. ProHap enables researchers to account for haplotype diversity in proteomic searches.
    DOI:  https://doi.org/10.1038/s41592-024-02506-0
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