bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024‒06‒09
58 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.
  2. Cardiolipin clustering promotes mitochondrial membrane dynamics.
  3. A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function.
  4. Mitochondrial ribosome biogenesis and redox sensing.
  5. Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.
  6. Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.
  7. Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism.
  8. Structural basis for human mitochondrial tRNA maturation.
  9. Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI.
  10. Redox regulation of UPR signalling and mitochondrial ER contact sites.
  11. Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
  12. Energy substrate supplementation increases ATP levels and is protective to PD neurons.
  13. Skeletal Muscle Mitochondrial Morphology Negatively Affected in Mice Lacking Xin.
  14. Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.
  15. Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.
  16. Structure prediction analysis of human core TIM23 complex reveals conservation of the protein translocation mechanism.
  17. Liver mitochondrial coupling efficiency and its relationship to oxidative capacity and adenine nucleotide translocase content: A comparative study among crocodiles, birds and mammals.
  18. Quantitative Assessment of Morphological Changes in Lipid Droplets and Lipid-Mito Interactions with Aging in Brown Adipose.
  19. Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
  20. TANGO2 deficiency disease is predominantly caused by a lipid imbalance.
  21. Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.
  22. Impact of genome build on RNA-seq interpretation and diagnostics.
  23. Application of long read sequencing in rare diseases: The longer, the better?
  24. ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation.
  25. LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1.
  26. Genotype and Phenotype Characteristics of 58 Cases of Mitochondrial Epilepsy with Nuclear DNA Mutations in Children.
  27. Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
  28. A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype.
  29. Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice.
  30. Maculopapillary Bundle Degeneration in Optic Neuropathies.
  31. Dysarthria and dysphagia in patients with mitochondrial diseases.
  32. Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease.
  33. Heterogeneous distribution of mitochondria and succinate dehydrogenase activity in human airway smooth muscle cells.
  34. Mitophagy in relation to chronic inflammation/ROS in aging.
  35. Mitochondrial lipidomes are tissue specific - low cholesterol contents relate to UCP1 activity.
  36. Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease.
  37. Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
  38. Diagnostic genomic sequencing in critically ill children.
  39. Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.
  40. Addressing Diagnostic Gaps and Priorities of the Global Rare Diseases Community: Recommendations from the IRDiRC Diagnostics Scientific Committee.
  41. Revisiting Cardiac Biology in the Era of Single Cell and Spatial Omics.
  42. SPNS1 ablation drives skeletal muscle atrophy by disrupting mitophagy, mitochondrial function, and apoptosis in mice.
  43. Genome Sequencing for Diagnosing Rare Diseases.
  44. Editorial - Diagnostic genome sequencing in rare disorders.
  45. TRABD modulates mitochondrial homeostasis and tissue integrity.
  46. The mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism.
  47. The future role of facial image analysis in ACMG classification guidelines.
  48. Status epilepticus in POLG disease: a large multinational study.
  49. Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
  50. Senescent glia link mitochondrial dysfunction and lipid accumulation.
  51. Polygenic risk scores in epilepsy.
  52. Lighting Up Nucleolus To Report Mitochondria Damage Using a Mitochondria-to-Nucleolus Migration Probe.
  53. Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.
  54. The lipid side of unfolded protein response.
  55. An interactive atlas of genomic, proteomic, and metabolomic biomarkers promotes the potential of proteins to predict complex diseases.
  56. Rare codon recoding for efficient noncanonical amino acid incorporation in mammalian cells.
  57. Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.
  58. Cardiomyocyte βII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function.
  1. Mol Cell Biol. 2024 Jun 03. 1-19
    Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.
    Jordan J Crameri, Catherine S Palmer, Tegan Stait, Thomas D Jackson, Matthew Lynch, Adriane Sinclair, Leah E Frajman, Alison G Compton, David Coman, David R Thorburn, Ann E Frazier, Diana Stojanovski.
      TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.
    Keywords:  Mitochondria; TIM23 complex; TIMM50; mitochondrial disease; mitochondrial protein import
    DOI:  https://doi.org/10.1080/10985549.2024.2353652
  2. bioRxiv. 2024 May 23. pii: 2024.05.21.595226. [Epub ahead of print]
    Cardiolipin clustering promotes mitochondrial membrane dynamics.
    Kelly E Zuccaro, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.
      Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.Teaser: This study reveals how CL modulates the activity of OPA1 and how MLCL impacts its ability to govern mitochondrial function.
    DOI:  https://doi.org/10.1101/2024.05.21.595226
  3. J Genet Genomics. 2024 May 31. pii: S1673-8527(24)00122-X. [Epub ahead of print]
    A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function.
    Ting Li, Tursunjan Aziz, Guangyuan Li, Lin Zhang, Jihua Yao, Shunji Jia.
      Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy. Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4 (COXPD4), a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain (MRC) complexes. The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management. In this study, we construct a zebrafish tufm-/- mutant that closely resembles the COXPD4 syndrome, exhibiting compromised mitochondrial protein translation, dysfunctional mitochondria with oxidative phosphorylation (OXPHOS) defects, and significant metabolic suppression of the tricarboxylic acid (TCA) cycle. Leveraging this COXPD4 zebrafish model, we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4. Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.
    Keywords:  COXPD4; Disease model; Mitochondria; Tufm; Zebrafish
    DOI:  https://doi.org/10.1016/j.jgg.2024.05.009
  4. FEBS Open Bio. 2024 Jun 07.
    Mitochondrial ribosome biogenesis and redox sensing.
    Michele Brischigliaro, Ana Sierra-Magro, Ahram Ahn, Antoni Barrientos.
      Mitoribosome biogenesis is a complex process involving RNA elements encoded in the mitochondrial genome and mitoribosomal proteins typically encoded in the nuclear genome. This process is orchestrated by extra-ribosomal proteins, nucleus-encoded assembly factors, which play roles across all assembly stages to coordinate ribosomal RNA processing and maturation with the sequential association of ribosomal proteins. Both biochemical studies and recent cryo-EM structures of mammalian mitoribosomes have provided insights into their assembly process. In this article, we will briefly outline the current understanding of mammalian mitoribosome biogenesis pathways and the factors involved. Special attention is devoted to the recent identification of iron-sulfur clusters as structural components of the mitoribosome and a small subunit assembly factor, the existence of redox-sensitive cysteines in mitoribosome proteins and assembly factors, and the role they may play as redox sensor units to regulate mitochondrial translation under stress.
    Keywords:  iron–sulfur cluster; mitochondrial disease; mitochondrial ribosome; mitochondrial translation; mitoribosome assembly; redox sensing
    DOI:  https://doi.org/10.1002/2211-5463.13844
  5. Adv Drug Deliv Rev. 2024 Jun 05. pii: S0169-409X(24)00177-7. [Epub ahead of print] 115355
    Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.
    Yi Wang, Jing-Song Yang, Min Zhao, Jia-Qi Chen, Hai-Xin Xie, Hao-Yuan Yu, Na-Hui Liu, Zi-Juan Yi, Hui-Lin Liang, Lei Xing, Hu-Lin Jiang.
      Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summary mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involving in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing detail on the design of mitochondria-targeted delivery systems and limitations regarding the varying technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.
    Keywords:  Drug delivery system; Gene delivery; Mitochondrial endogenous transport; Mitochondrial genome; Nanomaterials
    DOI:  https://doi.org/10.1016/j.addr.2024.115355
  6. EMBO J. 2024 Jun 05.
    Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.
    Nanami Senoo, Dinesh K Chinthapalli, Matthew G Baile, Vinaya K Golla, Bodhisattwa Saha, Abraham O Oluwole, Oluwaseun B Ogunbona, James A Saba, Teona Munteanu, Yllka Valdez, Kevin Whited, Macie S Sheridan, Dror Chorev, Nathan N Alder, Eric R May, Carol V Robinson, Steven M Claypool.
      Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS). In the inner mitochondrial membrane, the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) exchanges ADP and ATP, enabling OXPHOS. AAC/ANT contains three tightly bound CLs, and these interactions are evolutionarily conserved. Here, we investigated the role of these buried CLs in AAC/ANT using a combination of biochemical approaches, native mass spectrometry, and molecular dynamics simulations. We introduced negatively charged mutations into each CL-binding site of yeast Aac2 and established experimentally that the mutations disrupted the CL interactions. While all mutations destabilized Aac2 tertiary structure, transport activity was impaired in a binding site-specific manner. Additionally, we determined that a disease-associated missense mutation in one CL-binding site in human ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.
    Keywords:  Cardiolipin; Lipid–Protein Interaction; Membrane Transport; Mitochondria; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1038/s44318-024-00132-2
  7. bioRxiv. 2024 May 21. pii: 2024.05.20.594820. [Epub ahead of print]
    Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism.
    James P Held, Nadir H Dbouk, Adrianna M Strozak, Lantana K Grub, Hayeon Ryou, Samantha H Schaffner, Maulik R Patel.
      Reproductive status, such as pregnancy and menopause in women, profoundly influences metabolism of the body. Mitochondria likely orchestrate many of these metabolic changes. However, the influence of reproductive status on somatic mitochondria and the underlying mechanisms remain largely unexplored. We demonstrate that reproductive signals modulate mitochondria in the Caenorhabditis elegans soma. We show that the germline acts via an RNA endonuclease, HOE-1, which despite its housekeeping role in tRNA maturation, selectively regulates the mitochondrial unfolded protein response (UPRmt). Mechanistically, we uncover a fatty acid metabolism pathway acting upstream of HOE-1 to convey germline status. Furthermore, we link vitamin B12's dietary intake to the germline's regulatory impact on HOE-1-driven UPRmt. Combined, our study uncovers a germline-somatic mitochondrial connection, reveals the underlying mechanism, and highlights the importance of micronutrients in modulating this connection. Our findings provide insights into the interplay between reproductive biology and metabolic regulation.
    DOI:  https://doi.org/10.1101/2024.05.20.594820
  8. Nat Commun. 2024 Jun 01. 15(1): 4683
    Structural basis for human mitochondrial tRNA maturation.
    Vincent Meynier, Steven W Hardwick, Marjorie Catala, Johann J Roske, Stephanie Oerum, Dimitri Y Chirgadze, Pierre Barraud, Wyatt W Yue, Ben F Luisi, Carine Tisné.
      The human mitochondrial genome is transcribed into two RNAs, containing mRNAs, rRNAs and tRNAs, all dedicated to produce essential proteins of the respiratory chain. The precise excision of tRNAs by the mitochondrial endoribonucleases (mt-RNase), P and Z, releases all RNA species from the two RNA transcripts. The tRNAs then undergo 3'-CCA addition. In metazoan mitochondria, RNase P is a multi-enzyme assembly that comprises the endoribonuclease PRORP and a tRNA methyltransferase subcomplex. The requirement for this tRNA methyltransferase subcomplex for mt-RNase P cleavage activity, as well as the mechanisms of pre-tRNA 3'-cleavage and 3'-CCA addition, are still poorly understood. Here, we report cryo-EM structures that visualise four steps of mitochondrial tRNA maturation: 5' and 3' tRNA-end processing, methylation and 3'-CCA addition, and explain the defined sequential order of the tRNA processing steps. The methyltransferase subcomplex recognises the pre-tRNA in a distinct mode that can support tRNA-end processing and 3'-CCA addition, likely resulting from an evolutionary adaptation of mitochondrial tRNA maturation complexes to the structurally-fragile mitochondrial tRNAs. This subcomplex can also ensure a tRNA-folding quality-control checkpoint before the sequential docking of the maturation enzymes. Altogether, our study provides detailed molecular insight into RNA-transcript processing and tRNA maturation in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-024-49132-0
  9. J Virol. 2024 Jun 05. e0035624
    Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI.
    Erik Schubert, Kwangchol Mun, Mårten Larsson, Styliani Panagiotou, Olof Idevall-Hagren, Catharina Svensson, Tanel Punga.
      The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-β) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-β gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-β gene expression. Overall, we assign a new mitochondria and IFN-β signaling-modulating function to the HAdV-C5 minor capsid protein VI.IMPORTANCE: Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics.
    Keywords:  adenovirus; cGAS; immune system; mitochondria
    DOI:  https://doi.org/10.1128/jvi.00356-24
  10. Cell Mol Life Sci. 2024 Jun 07. 81(1): 250
    Redox regulation of UPR signalling and mitochondrial ER contact sites.
    Jose C Casas-Martinez, Afshin Samali, Brian McDonagh.
      Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.
    Keywords:   C. elegans ; Contact-sites; Hormesis; Mitochondrial dynamics; Redox signalling; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00018-024-05286-0
  11. Sci Adv. 2024 Jun 07. 10(23): eadn7191
    Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
    Olawale G Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M Lange, Cristian Polo Rivera, Tom D Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P M Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, Miratul M K Muqit.
      Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.
    DOI:  https://doi.org/10.1126/sciadv.adn7191
  12. Curr Res Pharmacol Drug Discov. 2024 ;6 100187
    Energy substrate supplementation increases ATP levels and is protective to PD neurons.
    Andrey Y Vinokurov, Marina Y Pogonyalova, Larisa Andreeva, Andrey Y Abramov, Plamena R Angelova.
      Alteration of mitochondrial metabolism by various mutations or toxins leads to various neurological conditions. Age-related changes in energy metabolism could also play the role of a trigger for neurodegenerative disorders. Nonetheless, it is not clear if restoration of ATP production or supplementation of brain cells with substrates for energy production could be neuroprotective. Using primary neurons and astrocytes, and neurons with familial forms of neurodegenerative disorders we studied whether various substrates of energy metabolism could improve mitochondrial metabolism and stimulate ATP production, and whether increased ATP levels could protect cells against glutamate excitotoxicity and neurodegeneration. We found that supplementation of neurons with several substrates, or combination thereof, for the TCA cycle and cellular respiration, and oxidative phosphorylation resulted in an increase in mitochondrial NADH level and in mitochondrial membrane potential and led to an increased level of ATP in neurons and astrocytes. Subsequently, these cells were protected against energy deprivation during ischemia or glutamate excitotoxicity. Provision of substrates for energy metabolism to cells with familial forms of Parkinson's disease also prevented triggering of cell death. Thus, restoration of energy metabolism and increase of ATP production can play neuroprotective role in neurodegeneration. A combination of a succinate salt of choline and nicotinamide provided the best results.
    Keywords:  Ageing; Brain energy metabolism; Neurodegeneration; Parkinson's disease; Substrate supplementation
    DOI:  https://doi.org/10.1016/j.crphar.2024.100187
  13. Biochem Cell Biol. 2024 Jun 06.
    Skeletal Muscle Mitochondrial Morphology Negatively Affected in Mice Lacking Xin.
    Grace Martin, Dhuha Al-Sajee, Molly Gingrich, Rimsha Chattha, Michael Akcan, Cynthia M F Monaco, Meghan C Hughes, Christopher G R Perry, Irena A Rebalka, Mark A Tarnopolsky, Thomas James Hawke.
      Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins are known to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated mitochondrial alterations in mice lacking the cytoskeletal adapter protein, XIN (XIN-/-). XIN-/- and wild-type littermate male and female mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before analyses of their skeletal muscles was conducted. Immuno-electron microscopy (EM) and immunofluorescence staining revealed XIN in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed XIN-/- mice were notably different from wild-type (large, and/or swollen in appearance). Succinate Dehydrogenase and Cytochrome Oxidase IV staining indicated greater evidence of mitochondrial enzyme activity in XIN-/- mice. No difference in body mass gains or glucose handling was observed between cohorts with HFD. However, EM revealed significantly greater mitochondrial density with evident structural abnormalities (swelling, reduced cristae density) in XIN-/- mice. Absolute Complex I and II-supported respiration was not different between groups, but relative to mitochondrial density, was significantly lower in XIN-/-. These results provide the first evidence for a role of XIN in maintaining mitochondrial morphology and function.
    DOI:  https://doi.org/10.1139/bcb-2024-0034
  14. bioRxiv. 2024 May 20. pii: 2024.05.20.594480. [Epub ahead of print]
    Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.
    Eyal Paz, Sahil Jain, Irit Gottfried, Orna Staretz-Chacham, Muhammad Mahajnah, Pritha Bagchi, Nicholas T Seyfried, Uri Ashery, Abdussalam Azem.
      TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a TIMM50 disease causing mutation in human fibroblasts, and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its substrates, challenging the currently accepted import dogma of the essential general import role of TIM23 and suggesting that fully functioning TIM23 complex is not essential for maintaining the steady state level of the majority of mitochondrial proteins. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients' epileptic phenotype.
    DOI:  https://doi.org/10.1101/2024.05.20.594480
  15. Ann Med Surg (Lond). 2024 Jun;86(6): 3753-3756
    Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.
    Azita Tavasoli, Maryam Kachuei, Saeed Talebi, Shayan Eghdami.
      Introduction and importance: Cytochrome C oxidase (COX) deficiency is an uncommon inherited metabolic disorder. It is identified by a lack of the COX, also known as Complex IV. This enzyme plays a crucial role in the rate-limiting and oxygen-accepting step of the respiratory chain within the subcellular structures called mitochondria. The deficiency of COX can either be restricted to skeletal muscle tissues or can impact multiple tissues throughout the body.Case presentation: A 3-year-old girl was admitted due to muscle weakness and a decline in developmental milestones 7 days after a significant stressor. Leukodystrophy was observed in the brain magnetic resonance imaging, and genome sequencing identified a homozygous mutation in exon 1 and 7 of chromosome 17. This mutation led to a deficiency in COX10, which is a component of mitochondrial complex IV.
    Clinical discussion: In the medical field, inherited metabolic disorders can be complex to diagnose due to overlapping symptoms with other conditions. Mitochondria's oxidative phosphorylation system, including the COX enzyme complex, plays a crucial role in energy production. Mitochondrial disorders, including COX deficiency, can present at various stages of life with diverse symptoms. Treatment options focus on supportive care and potential benefits from supplements like coenzyme-Q10 and small-molecule therapies targeting mitochondrial function. Identifying genetic mutations is key for advancing treatments in this area.
    Conclusion: This report presents a unique case of developmental regression and muscle weakness in a paediatric patient, which can be attributed to a rare occurrence of type 3 nuclear mitochondrial complex IV deficiency.
    Keywords:  COX10; case report; cytochrome c oxidase deficiency; mitochondrial complex IV; mitochondrial disorder
    DOI:  https://doi.org/10.1097/MS9.0000000000002096
  16. FEBS Open Bio. 2024 Jun 04.
    Structure prediction analysis of human core TIM23 complex reveals conservation of the protein translocation mechanism.
    Klaudia K Maruszczak, Piotr Draczkowski, Artur Wnorowski, Agnieszka Chacinska.
      The majority of mitochondrial proteins are encoded in the nucleus, translated on cytosolic ribosomes, and subsequently targeted to the mitochondrial surface. Their further import into the organelle is facilitated by highly specialized protein translocases. Mitochondrial precursor proteins that are destined to the mitochondrial matrix and, to some extent, the inner membrane, utilize translocase of the inner membrane (TIM23). This indispensable import machinery has been extensively studied in yeast. The translocating unit of the TIM23 complex in yeast consists of two membrane proteins, Tim17 and Tim23. In contrast to previous findings, recent reports demonstrate the primary role of Tim17, rather than Tim23, in the translocation of newly synthesized proteins. Very little is known about human TIM23 translocase. Human cells have two orthologs of yeast Tim17, TIMM17A and TIMM17B. Here, using computational tools, we present the architecture of human core TIM23 variants with either TIMM17A or TIMM17B, forming two populations of highly similar complexes. The structures reveal high conservation of the core TIM23 complex between human and yeast. Interestingly, both TIMM17A and TIMM17B variants interact with TIMM23 and reactive oxygen species modulator 1 (ROMO1); a homolog of yeast Mgr2, a protein that can create a channel-like structure with Tim17. The high structural conservation of proteins that form the core TIM23 complex in yeast and humans raises an interesting question about mechanistic and functional differences that justify existence of the two variants of TIM23 in higher eukaryotes.
    Keywords:  TIM23 complex; TIM23 structure prediction; mitochondria; mitochondrial import
    DOI:  https://doi.org/10.1002/2211-5463.13840
  17. Mitochondrion. 2024 Jun 04. pii: S1567-7249(24)00067-9. [Epub ahead of print] 101909
    Liver mitochondrial coupling efficiency and its relationship to oxidative capacity and adenine nucleotide translocase content: A comparative study among crocodiles, birds and mammals.
    Damien Roussel, Nathan Roussel, Yann Voituron, Benjamin Rey.
      The primary objective of this study was to assess whether adenine nucleotide translocase (ANT) content could be associated with phylogenetic disparities in mitochondrial coupling efficiency, within liver mitochondria obtained from rats, crocodiles, and ducklings. Our measurements included mitochondrial membrane conductance, ANT content, and oxidative phosphorylation fluxes at various steady-state rates. We observed significant variations in liver mitochondrial coupling efficiency across the three species. These variations correlated with interspecific differences in mitochondrial oxidative capacity and, to a lesser extent, the ANT content of liver mitochondria. These findings expand upon previous research by highlighting the pivotal role of oxidative capacity and ANT in modulating mitochondrial efficiency on an interspecific scale.
    Keywords:  Adenine nucleotide translocase (ANT); Archosaurs; Liver; Oxidative phosphorylation; Proton leak
    DOI:  https://doi.org/10.1016/j.mito.2024.101909
  18. bioRxiv. 2024 May 21. pii: 2023.09.23.559135. [Epub ahead of print]
    Quantitative Assessment of Morphological Changes in Lipid Droplets and Lipid-Mito Interactions with Aging in Brown Adipose.
    Amber Crabtree, Kit Neikirk, Julia Pinette, Aaron Whiteside, Bryanna Shao, Jessica McKenzie, Zer Vue, Larry Vang, Han Le, Mert Dermici, Taseer Ahmad, Trinity Celeste Owens, Ashton Oliver, Faben Zeleke, Heather K Beasley, Edgar Garza Lopez, Estevão Scudese, Taylor Rodman, Kinuthia Kabugi, Alice Koh, Suzanne Navarro, Jacob Lam, Ben Kirk, Margaret Mungai, Mariya Sweetwyne, Ho-Jin Koh, Elma Zaganjor, Steven M Damo, Jennifer A Gaddy, Annet Kirabo, Sandra A Murray, Anthonya Cooper, Clintoria Williams, Melanie R McReynolds, Andrea G Marshall, Antentor Hinton.
      The physical characteristics of brown adipose tissue (BAT) are defined by the presence of multilocular lipid droplets (LD) within the brown adipocytes and a high abundance of iron-containing mitochondria, which give it its characteristic color. Normal mitochondrial function is, in part, regulated by organelle-to-organelle contacts. Particularly, the contact sites that mediate mitochondria-LD interactions are thought to have various physiological roles, such as the synthesis and metabolism of lipids. Aging is associated with mitochondrial dysfunction, and previous studies show that there are changes in mitochondrial structure and proteins that modulate organelle contact sites. However, how mitochondria-LD interactions change with aging has yet to be fully clarified. Therefore, we sought to define age-related changes in LD morphology and mitochondria-lipid interactions in BAT. We examined the three-dimensional morphology of mitochondria and LDs in young (3-month) and aged (2-year) murine BAT using serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. Analysis showed reductions in LD volume, area, and perimeter in aged samples compared to young samples. Additionally, we observed changes in LD appearance and type in aged samples compared to young samples. Notably, we found differences in mitochondrial interactions with LDs, which could implicate that these contacts may be important for energetics in aging. Upon further investigation, we also found changes in mitochondrial and cristae structure for mitochondria interacting with LD lipids. Overall, these data define the nature of LD morphology and organelle-organelle contacts during aging and provide insight into LD contact site changes that interconnect biogerontology and mitochondrial functionality, metabolism, and bioactivity in aged BAT.Abstract Figure:
    DOI:  https://doi.org/10.1101/2023.09.23.559135
  19. bioRxiv. 2024 May 26. pii: 2024.05.22.595374. [Epub ahead of print]
    Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
    Takuya Karasawa, Ran Hee Choi, Cesar A Meza, J Alan Maschek, James E Cox, Katsuhiko Funai.
      Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency.Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria.
    Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria.
    Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.
    Keywords:  exercise; mitochondria; phospholipids; skeletal muscle
    DOI:  https://doi.org/10.1101/2024.05.22.595374
  20. Dis Model Mech. 2024 Jun 01. pii: dmm050662. [Epub ahead of print]17(6):
    TANGO2 deficiency disease is predominantly caused by a lipid imbalance.
    Michael Sacher, Jay DeLoriea, Mahsa Mehranfar, Cody Casey, Aaliya Naaz, Chiara Gamberi.
      TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.
    Keywords:  Lipid imbalance; Metabolic crises; Neurodevelopmental disease; TANGO2 deficiency disease
    DOI:  https://doi.org/10.1242/dmm.050662
  21. NPJ Syst Biol Appl. 2024 Jun 03. 10(1): 64
    Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.
    Safal Shrestha, Rahil Taujale, Samiksha Katiyar, Natarajan Kannan.
      Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the Tree of Life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) HepG2 cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), and carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3K and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. Our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance and NAD-dependent metabolic processes are altered.
    DOI:  https://doi.org/10.1038/s41540-024-00390-0
  22. Am J Hum Genet. 2024 May 31. pii: S0002-9297(24)00168-X. [Epub ahead of print]
    Impact of genome build on RNA-seq interpretation and diagnostics.
    Undiagnosed Diseases Network
      Transcriptomics is a powerful tool for unraveling the molecular effects of genetic variants and disease diagnosis. Prior studies have demonstrated that choice of genome build impacts variant interpretation and diagnostic yield for genomic analyses. To identify the extent genome build also impacts transcriptomics analyses, we studied the effect of the hg19, hg38, and CHM13 genome builds on expression quantification and outlier detection in 386 rare disease and familial control samples from both the Undiagnosed Diseases Network and Genomics Research to Elucidate the Genetics of Rare Disease Consortium. Across six routinely collected biospecimens, 61% of quantified genes were not influenced by genome build. However, we identified 1,492 genes with build-dependent quantification, 3,377 genes with build-exclusive expression, and 9,077 genes with annotation-specific expression across six routinely collected biospecimens, including 566 clinically relevant and 512 known OMIM genes. Further, we demonstrate that between builds for a given gene, a larger difference in quantification is well correlated with a larger change in expression outlier calling. Combined, we provide a database of genes impacted by build choice and recommend that transcriptomics-guided analyses and diagnoses are cross referenced with these data for robustness.
    Keywords:  RNA-seq; genome build; rare disease
    DOI:  https://doi.org/10.1016/j.ajhg.2024.05.005
  23. Eur J Med Genet. 2023 Dec;pii: S1769-7212(23)00177-5. [Epub ahead of print]66(12): 104871
    Application of long read sequencing in rare diseases: The longer, the better?
    Si-Yan Yu, Yu-Lin Xi, Fu-Qiang Xu, Jian Zhang, Yan-Shan Liu.
      Rare diseases encompass a diverse group of genetic disorders that affect a small proportion of the population. Identifying the underlying genetic causes of these conditions presents significant challenges due to their genetic heterogeneity and complexity. Conventional short-read sequencing (SRS) techniques have been widely used in diagnosing and investigating of rare diseases, with limitations due to the nature of short-read lengths. In recent years, long read sequencing (LRS) technologies have emerged as a valuable tool in overcoming these limitations. This minireview provides a concise overview of the applications of LRS in rare disease research and diagnosis, including the identification of disease-causing tandem repeat expansions, structural variations, and comprehensive analysis of pathogenic variants with LRS.
    Keywords:  Comprehensive analysis; Long-read sequencing; Rare diseases; Structural variations; Tandem repeats
    DOI:  https://doi.org/10.1016/j.ejmg.2023.104871
  24. Redox Biol. 2024 May 31. pii: S2213-2317(24)00190-3. [Epub ahead of print]73 103212
    ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation.
    Yena Cho, Yong Kee Kim.
      The dynamic regulation of mitochondria through fission and fusion is essential for maintaining cellular homeostasis. In this study, we discovered a role of coactivator-associated arginine methyltransferase 1 (CARM1) in mitochondrial dynamics. CARM1 methylates specific residues (R403 and R634) on dynamin-related protein 1 (DRP1). Methylated DRP1 interacts with mitochondrial fission factor (Mff) and forms self-assembly on the outer mitochondrial membrane, thereby triggering fission, reducing oxygen consumption, and increasing reactive oxygen species (ROS) production. This sets in motion a feedback loop that facilitates the translocation of CARM1 from the nucleus to the cytoplasm, enhancing DRP1 methylation and ROS production through mitochondrial fragmentation. Consequently, ROS reinforces the CARM1-DRP1-ROS axis, resulting in cellular senescence. Depletion of CARM1 or DRP1 impedes cellular senescence by reducing ROS accumulation. The uncovering of the above-described mechanism fills a missing piece in the vicious cycle of ROS-induced senescence and contributes to a better understanding of the aging process.
    Keywords:  CARM1; DRP1; Methylation; Mitochondrial dynamics; ROS; Senescence
    DOI:  https://doi.org/10.1016/j.redox.2024.103212
  25. Circulation. 2024 Jun 06.
    LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1.
    Hengzhi Du, Yanru Zhao, Jianpei Wen, Beibei Dai, Guo Hu, Yufei Zhou, Zhongwei Yin, Nan Ding, Huaping Li, Jiahui Fan, Xiang Nie, Feng Wang, Qian Liu, Zheng Wen, Gang Xu, Dao Wen Wang, Chen Chen.
      BACKGROUND: Dilated cardiomyopathy is characterized by left ventricular dilation and continuous systolic dysfunction. Mitochondrial impairment is critical in dilated cardiomyopathy; however, the underlying mechanisms remain unclear. Here, we explored the cardioprotective role of a heart-enriched long noncoding RNA, the dilated cardiomyopathy repressive transcript (DCRT), in maintaining mitochondrial function.METHODS: The DCRT knockout (DCRT-/-) mice and DCRT knockout cells were developed using CRISPR-Cas9 technology. Cardiac-specific DCRT transgenic mice were generated using α-myosin heavy chain promoter. Chromatin coimmunoprecipitation, RNA immunoprecipitation, Western blot, and isoform sequencing were performed to investigate the underlying mechanisms.
    RESULTS: We found that the long noncoding RNA DCRT was highly enriched in the normal heart tissues and that its expression was significantly downregulated in the myocardium of patients with dilated cardiomyopathy. DCRT-/- mice spontaneously developed cardiac dysfunction and enlargement with mitochondrial impairment. DCRT transgene or overexpression with the recombinant adeno-associated virus system in mice attenuated cardiac dysfunction induced by transverse aortic constriction treatment. Mechanistically, DCRT inhibited the third exon skipping of NDUFS2 (NADH dehydrogenase ubiquinone iron-sulfur protein 2) by directly binding to PTBP1 (polypyrimidine tract binding protein 1) in the nucleus of cardiomyocytes. Skipping of the third exon of NDUFS2 induced mitochondrial dysfunction by competitively inhibiting mitochondrial complex I activity and binding to PRDX5 (peroxiredoxin 5) and suppressing its antioxidant activity. Furthermore, coenzyme Q10 partially alleviated mitochondrial dysfunction in cardiomyocytes caused by DCRT reduction.
    CONCLUSIONS: Our study revealed that the loss of DCRT contributed to PTBP1-mediated exon skipping of NDUFS2, thereby inducing cardiac mitochondrial dysfunction during dilated cardiomyopathy development, which could be partially treated with coenzyme Q10 supplementation.
    Keywords:  NDUFS2 protein, human; PTBP1 protein, human; RNA, long, noncoding; cardiomyopathy, dilated; exons; mitochondria
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067861
  26. Neurol Sci. 2024 Jun 04.
    Genotype and Phenotype Characteristics of 58 Cases of Mitochondrial Epilepsy with Nuclear DNA Mutations in Children.
    Xiaodi Han, Hua Li, Jie Deng, Xiuwei Zhuo, Zhimei Liu, Manting Xu, Weixing Feng, Shuhua Chen, Fang Fang.
      OBJECTIVE: Identify the genotype and clinical characteristics of mitochondrial epilepsy caused by nDNA mutations in Chinese children and explore the treatment and prognosis of the condition.STUDY DESIGN: This is a retrospective cohort study conducted at a single center, including patients diagnosed with an established nDNA mutation-associated primary mitochondrial disease between October 2012 and March 2023 who also met the practical clinical definition of epilepsy published by the ILAE in 2014.
    RESULTS: Of the 58 patients identified, 74.1% had an onset before the age of 1 year and 63.8% had seizures as their initial symptom. Developmental and epileptic encephalopathy (DEE) (31%) are the most common phenotypes. The most frequently observed MRI abnormalities include abnormal signal asymmetry in the bilateral basal ganglia and/or brainstem (34.7%), as well as brain atrophy, myelin sheath dysplasia, and corpus callosum dysplasia (32.7%). Of the 40 patients followed, seizure treatment was effective in 18 of the cases, while it was ineffective in 22. The mitochondrial DNA depletion syndrome (MDS) was found to be more difficult to control seizures than other phenotypes (P < 0.05). Additionally, the MDS was associated with a significantly higher mortality rate compared to alternative phenotypes (P < 0.05).
    CONCLUSIONS: The onset of mitochondrial epilepsy due to nDNA mutations is early and seizures are the most common initial symptom. DEE is the most common phenotype. Characteristic MRI abnormalities in the brain may be helpful in the diagnosis of primary mitochondrial disease. People with MDS typically face challenges in seizure control and have a poor prognosis.
    Keywords:  Children; Epilepsy; Nuclear DNA; Primary mitochondrial disease
    DOI:  https://doi.org/10.1007/s10072-024-07586-6
  27. Dev Cell. 2024 Jun 04. pii: S1534-5807(24)00325-3. [Epub ahead of print]
    Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
    Seungyoon B Yu, Haoming Wang, Richard G Sanchez, Natasha M Carlson, Khanh Nguyen, Andrew Zhang, Zachary D Papich, Ahmed A Abushawish, Zachary Whiddon, Weronika Matysik, Jie Zhang, Thomas C Whisenant, Majid Ghassemian, John N Koberstein, Melissa L Stewart, Samuel A Myers, Gulcin Pekkurnaz.
      Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.
    Keywords:  ATP synthesis; O-GlcNAc transferase; O-GlcNAcylation; glycosylation; mitochondria; neuronal metabolism; synaptic activity
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.008
  28. Am J Med Genet A. 2024 Jun 06. e63783
    A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype.
    E Jennions, M Olsson-Engman, K Visuttijai, Å Wiksell, N Fluriach Dominguez, G Kollberg, A Oldfors, C Hedberg-Oldfors.
      Cytochrome c oxidase (COX) deficiency is a phenotypically diverse group of diseases caused by variants in over 30 genes. Biallelic pathogenic variants in COX6B1 have been described in four patients to date with varying disease manifestations. We describe the clinical features and follow-up of a patient with a novel homozygous pathogenic variant in COX6B1 who presented acutely with severe encephalomyopathy associated with an infection. New findings include ophthalmological evaluation and follow-up of neuroradiological investigations. The novel p.Trp31Arg variant was predicted to be pathogenic in silico, and further functional analyses with biochemical analysis of mitochondrial function showed isolated COX deficiency. Muscle biopsy showed a specific lack of COX6B1 protein together with complex IV deficiency on western blot, enzyme histochemistry, and immuno-histochemistry.
    Keywords:  COX deficiency; COX6B1; cavitating leukoencephalopathy
    DOI:  https://doi.org/10.1002/ajmg.a.63783
  29. iScience. 2024 Jun 21. 27(6): 109991
    Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice.
    Taolin Yuan, Surinder Kumar, Mary E Skinner, Ryan Victor-Joseph, Majd Abuaita, Jaap Keijer, Jessica Zhang, Thaddeus J Kunkel, Yanghan Liu, Elyse M Petrunak, Thomas L Saunders, Andrew P Lieberman, Jeanne A Stuckey, Nouri Neamati, Fathiya Al-Murshedi, Majid Alfadhel, Johannes N Spelbrink, Richard Rodenburg, Vincent C J de Boer, David B Lombard.
      SIRT5 is a sirtuin deacylase that removes negatively charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal conditions, the phenotypes of SIRT5 deficiency are quite subtle. Here, we identify two homozygous SIRT5 variants in patients suspected to have mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generated a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology, or other gross phenotypes. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, but are likely not by themselves the primary pathogenic cause of the neuropathology observed in the patients.
    Keywords:  biochemistry; health sciences; molecular biology; neuroscience; physiology; structural biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109991
  30. Curr Neurol Neurosci Rep. 2024 Jun 04.
    Maculopapillary Bundle Degeneration in Optic Neuropathies.
    Darius W Lambiri, Leonard A Levin.
      PURPOSE OF REVIEW: Degeneration of the maculopapillary bundle (MPB) is a prominent feature in a spectrum of optic neuropathies. MPB-selective degeneration is seen in specific conditions, such as nutritional and toxic optic neuropathies, Leber hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA). Despite their distinct etiologies and clinical presentations, which encompass variations in age of incidence and monocular or binocular onset, these disorders share a core molecular mechanism: compromised mitochondrial homeostasis. This disruption is characterized by dysfunctions in mitochondrial metabolism, biogenesis, and protein synthesis. This article provides a comprehensive understanding of the MPB's role in optic neuropathies, emphasizing the importance of mitochondrial mechanisms in the pathogenesis of these conditions.RECENT FINDINGS: Optical coherence tomography studies have characterized the retinal nerve fiber layer changes accompanying mitochondrial-affiliated optic neuropathies. Selective thinning of the temporal optic nerve head is preceded by thickening in early stages of these disorders which correlates with reductions in macular ganglion cell layer thinning and vascular atrophy. A recently proposed mechanism underpinning the selective atrophy of the MPB involves the positive feedback of reactive oxygen species generation as a common consequence of mitochondrial dysfunction. Additionally, new research has revealed that the MPB can undergo degeneration in the early stages of glaucoma, challenging the historically held belief that this area was not involved in this common optic neuropathy. A variety of anatomical risk factors influence the propensity of glaucomatous MPB degeneration, and cases present distinct patterns of ganglion cell degeneration that are distinct from those observed in mitochondria-associated diseases. This review synthesizes clinical and molecular research on primary MPB disorders, highlighting the commonalities and differences in their pathogenesis.
    KEY POINTS (BOX): 1. Temporal degeneration of optic nerve fibers accompanied by cecocentral scotoma is a hallmark of maculopapillary bundle (MPB) degeneration. 2. Mechanisms of MPB degeneration commonly implicate mitochondrial dysfunction. 3. Recent research challenges the traditional belief that the MPB is uninvolved in glaucoma by showing degeneration in the early stages of this common optic neuropathy, yet with features distinct from other MPB-selective neuropathies. 4. Reactive oxygen species generation is a mechanism linking mitochondrial mechanisms of MPB-selective optic neuropathies, but in-vivo and in-vitro studies are needed to validate this hypothesis.
    Keywords:  Dominant optic atrophy; Glaucoma; Leber hereditary optic neuropathy; Maculopapillary bundle; Mitochondrial dysfunction; Optic neuropathies
    DOI:  https://doi.org/10.1007/s11910-024-01343-0
  31. Mol Genet Metab. 2024 Jun 01. pii: S1096-7192(24)00394-9. [Epub ahead of print]142(3): 108510
    Dysarthria and dysphagia in patients with mitochondrial diseases.
    R E M Kuin, J T Groothuis, P Buit, M C H Janssen, S Knuijt.
      BACKGROUND: Information about dysarthria and dysphagia in mitochondrial diseases (MD) is scarce. However, this knowledge is needed to identify speech and swallowing problems early, to monitor the disease course, and to develop and offer optimal treatment and support. This study therefore aims to examine the prevalence and severity of dysarthria and dysphagia in patients with MD and its relation to clinical phenotype and disease severity. Secondary aim is to determine clinically relevant outcome measures for natural history studies and clinical trials.METHODS: This retrospective cross-sectional medical record study includes adults (age ≥ 18 years) diagnosed with genetically confirmed MD who participated in a multidisciplinary admission within the Radboud center for mitochondrial medicine between January 2015 and April 2023. Dysarthria and dysphagia were examined by administering the Radboud dysarthria assessment, swallowing speed, dysphagia limit, test of mastication and swallowing solids (TOMASS), and 6-min mastication test (6MMT). The disease severity was assessed using the Newcastle mitochondrial disease scale for adults (NMDAS).
    RESULTS: The study included 224 patients with MD with a median age of 42 years of whom 37.5% were male. The pooled prevalence of dysarthria was 33.8% and of dysphagia 35%. Patients with MD showed a negative deviation from the norm on swallowing speed, TOMASS (total time) and the 6MMT. Furthermore, a significant moderate relation was found between the presence of dysarthria and the clinical phenotypes. There was a statistically significant difference in total time on the TOMASS between the clinical phenotypes. Finally, disease severity showed a significant moderate relation with the severity of dysarthria and a significant weak relation with the severity of dysphagia.
    CONCLUSION: Dysarthria and dysphagia occur in about one-third of patients with MD. It is important for treating physicians to pay attention to this subject because of the influence of both disorders on social participation and wellbeing. Referral to a speech and language therapist should therefore be considered, especially in patients with a more severe clinical phenotype. The swallowing speed, TOMASS and 6MMT are the most clinically relevant tests to administer.
    Keywords:  Adults; Dysarthria; Dysphagia; Mitochondrial diseases; Speech and language therapy
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108510
  32. Int J Cardiol. 2024 Jun 04. pii: S0167-5273(24)00849-0. [Epub ahead of print] 132227
    Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease.
    Fatemeh Baharvand, Mehryar Habibi Roudkenar, Zahra Pourmohammadi-Bejarpasi, Nima Najafi Ghalehlou, Alireza Feizkhah, Somaye Bashiri Aliabadi, Arsalan Salari, Amaneh Mohammadi Roushandeh.
      BACKGROUND: Acute ST-elevation myocardial infarction (STEMI) remains a globally significant health challenge in spite of improvement in management strategy. Being aware that mitochondrial dysfunction plays a crucial role in ischaemia-reperfusion injury (IRI) modulation, empirical evidence suggests functional mitochondrial transplantation strikes as a reliable therapeutic approach for patients with acute myocardial infarction.METHODS AND RESULTS: We conducted a prospective, triple-blinded, parallel-group, blocked randomised clinical trial to investigate the therapeutic effects and clinical outcomes of platelet-derived mitochondrial transplantation in 30 patients with acute STEMI, such that the 15 subjects in the control group were given standard of care treatment, whereas the subjects in the intervention group received autologous platelet-derived mitochondria through the intracoronary injection. We observed that within 40 days, the intervention group had a slightly greater improvement in the left ventricular ejection fraction (LVEF) compared to the control group and experienced a significant enhancement in the exercise capacity (p < 0.001). Moreover, major adverse cardiac events (MACE), arrhythmia, fever, and tachycardia were compared between the groups and lack of significant difference marks the safety of mitochondrial transplantation (p > 0.05). Furthermore, the two groups were not significantly distinct as regards the average length of stay for a hospitalisation (p > 0.05).
    CONCLUSION: We suggest platelet-derived mitochondrial transplantation appears as a beneficial and highly promising therapeutic option for patients of ischaemic heart disease (IHD); however, we are aware that further in-depth studies with larger sample sizes along with longer follow-up periods are necessary for validating the clinical implications of our findings.
    Keywords:  Acute ST-elevation myocardial infarction; Acute myocardial infarction; Ischaemia-reperfusion injury; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.ijcard.2024.132227
  33. FASEB Bioadv. 2024 Jun;6(6): 159-176
    Heterogeneous distribution of mitochondria and succinate dehydrogenase activity in human airway smooth muscle cells.
    Sanjana Mahadev Bhat, Gary C Sieck.
      Succinate dehydrogenase (SDH) is a key mitochondrial enzyme involved in the tricarboxylic acid cycle, where it facilitates the oxidation of succinate to fumarate, and is coupled to the reduction of ubiquinone in the electron transport chain as Complex II. Previously, we developed a confocal-based quantitative histochemical technique to determine the maximum velocity of the SDH reaction (SDHmax) in single cells and observed that SDHmax corresponds with mitochondrial volume density. In addition, mitochondrial volume and motility varied within different compartments of human airway smooth muscle (hASM) cells. Therefore, we hypothesize that the SDH activity varies relative to the intracellular mitochondrial volume within hASM cells. Using 3D confocal imaging of labeled mitochondria and a concentric shell method for analysis, we quantified mitochondrial volume density, mitochondrial complexity index, and SDHmax relative to the distance from the nuclear membrane. The mitochondria within individual hASM cells were more filamentous in the immediate perinuclear region and were more fragmented in the distal parts of the cell. Within each shell, SDHmax also corresponded to mitochondrial volume density, where both peaked in the perinuclear region and decreased in more distal parts of the cell. Additionally, when normalized to mitochondrial volume, SDHmax was lower in the perinuclear region when compared to the distal parts of the cell. In summary, our results demonstrate that SDHmax measures differences in SDH activity within different cellular compartments. Importantly, our data indicate that mitochondria within individual cells are morphologically heterogeneous, and their distribution varies substantially within different cellular compartments, with distinct functional properties.
    Keywords:  airway smooth muscle; confocal microscope; intracellular distribution; mitochondria; succinate dehydrogenase
    DOI:  https://doi.org/10.1096/fba.2024-00047
  34. Mol Cell Biochem. 2024 Jun 04.
    Mitophagy in relation to chronic inflammation/ROS in aging.
    Liang Kong, Shuhao Li, Yu Fu, Qinyun Cai, Xinyun Du, Jingyan Liang, Tan Ma.
      Various assaults on mitochondria occur during the human aging process, contributing to mitochondrial dysfunction. This mitochondrial dysfunction is intricately connected with aging and diseases associated with it. In vivo, the accumulation of defective mitochondria can precipitate inflammatory and oxidative stress, thereby accelerating aging. Mitophagy, an essential selective autophagy process, plays a crucial role in managing mitochondrial quality control and homeostasis. It is a highly specialized mechanism that systematically removes damaged or impaired mitochondria from cells, ensuring their optimal functioning and survival. By engaging in mitophagy, cells are able to maintain a balanced and stable environment, free from the potentially harmful effects of dysfunctional mitochondria. An ever-growing body of research highlights the significance of mitophagy in both aging and age-related diseases. Nonetheless, the association between mitophagy and inflammation or oxidative stress induced by mitochondrial dysfunction remains ambiguous. We review the fundamental mechanisms of mitophagy in this paper, delve into its relationship with age-related stress, and propose suggestions for future research directions.
    Keywords:  Aging; Chronic inflammation; Mitophagy; ROS
    DOI:  https://doi.org/10.1007/s11010-024-05042-9
  35. Life Sci Alliance. 2024 Aug;pii: e202402828. [Epub ahead of print]7(8):
    Mitochondrial lipidomes are tissue specific - low cholesterol contents relate to UCP1 activity.
    Sarah Brunner, Marcus Höring, Gerhard Liebisch, Sabine Schweizer, Josef Scheiber, Piero Giansanti, Maria Hidrobo, Sven Hermeling, Josef Oeckl, Natalia Prudente de Mello, Fabiana Perocchi, Claudine Seeliger, Akim Strohmeyer, Martin Klingenspor, Johannes Plagge, Bernhard Küster, Ralph Burkhardt, Klaus-Peter Janssen, Josef Ecker.
      Lipid composition is conserved within sub-cellular compartments to maintain cell function. Lipidomic analyses of liver, muscle, white and brown adipose tissue (BAT) mitochondria revealed substantial differences in their glycerophospholipid (GPL) and free cholesterol (FC) contents. The GPL to FC ratio was 50-fold higher in brown than white adipose tissue mitochondria. Their purity was verified by comparison of proteomes with ER and mitochondria-associated membranes. A lipid signature containing PC and FC, calculated from the lipidomic profiles, allowed differentiation of mitochondria from BAT of mice housed at different temperatures. Elevating FC in BAT mitochondria prevented uncoupling protein (UCP) 1 function, whereas increasing GPL boosted it. Similarly, STARD3 overexpression facilitating mitochondrial FC import inhibited UCP1 function in primary brown adipocytes, whereas a knockdown promoted it. We conclude that the mitochondrial GPL/FC ratio is key for BAT function and propose that targeting it might be a promising strategy to promote UCP1 activity.
    DOI:  https://doi.org/10.26508/lsa.202402828
  36. Med Genet. 2022 Jun;34(2): 103-116
    Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease.
    Joanne Trinh, Emma L Schymanski, Semra Smajic, Meike Kasten, Esther Sammler, Anne Grünewald.
      Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson's disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.
    Keywords:  LRRK2; Parkinson’s disease; Rab signalling; environment; genetic modifiers; mitochondria; penetrance; toxin exposure
    DOI:  https://doi.org/10.1515/medgen-2022-2127
  37. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00178-5. [Epub ahead of print]36(6): 1394-1410.e12
    Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
    Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R Keshari.
      A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.
    Keywords:  brain; glucose; imaging; ketogenic diet; metabolism; propionate; pyruvate; pyruvate dehydrogenase deficiency
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.002
  38. Med Genet. 2023 Jun;35(2): 105-112
    Diagnostic genomic sequencing in critically ill children.
    Bernd Auber, Gunnar Schmidt, Chen Du, Sandra von Hardenberg.
      Rare genetic diseases are a major cause of severe illnesses and deaths in new-borns and infants. Disease manifestation in critically ill children may be atypical or incomplete, making a monogenetic disease difficult to diagnose clinically. Rapid exome or genome ("genomic") sequencing in critically ill children demonstrated profound diagnostic and clinical value, and there is growing evidence that the faster a molecular diagnosis is established in such children, the more likely clinical management is influenced positively. An early molecular diagnosis enables treatment of critically ill children with precision medicine, has the potential to improve patient outcome and leads to healthcare cost savings. In this review, we outline the status quo of rapid genomic sequencing and possible future implications.
    Keywords:  clinical utility, precision medicine, OPS 1-944.11, diagnostic odyssey; rapid whole genome sequencing
    DOI:  https://doi.org/10.1515/medgen-2023-2015
  39. Metab Brain Dis. 2024 Jun 04.
    Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.
    Diane Rizkallah, Rose T Daher, Laith Haddad, Pascale E Karam.
      Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is an extremely rare disorder of urea cycle, with few patients reported worldwide. Despite hyperammonemia control, the long-term outcome remains poor with progressive neurological deterioration. We report the clinical, biochemical, and molecular features of two Lebanese siblings diagnosed with this disorder and followed for 8 and 15 years, respectively. Variable clinical manifestations and neurological outcome were observed. The patient with earlier onset of symptoms had a severe neurological deterioration while the other developed a milder form of the disease at an older age. Diagnosis was challenging in the absence of the complete biochemical triad and the non-specific clinical presentations. Whole exome sequencing revealed a homozygous variant, p.Phe188del, in the SLC25A15 gene, a French- Canadian founder mutation previously unreported in Arab patients. Hyperammonemia was controlled in both patients but hyperonithinemia persisted. Frequent hyperalaninemia spikes and lactic acidosis occured concomitantly with the onset of seizures in one of the siblings. Variable neurological deterioration and outcome were observed within the same family. This is the first report from the Arab population of the long-term outcome of this devastating neurometabolic disorder.
    Keywords:  Encephalopathy; Hyperornithinemia-hyperammonemia-homocitrullinuria; Neurometabolic; SLC25A15 gene; Urea cycle
    DOI:  https://doi.org/10.1007/s11011-024-01366-z
  40. Eur J Med Genet. 2024 Jun 05. pii: S1769-7212(24)00043-0. [Epub ahead of print] 104951
    Addressing Diagnostic Gaps and Priorities of the Global Rare Diseases Community: Recommendations from the IRDiRC Diagnostics Scientific Committee.
    members of the IRDiRC Diagnostic Scientific Committee
      The International Rare Diseases Research Consortium (IRDiRC) Diagnostic Scientific Committee (DSC) is charged with discussion and contribution to progress on diagnostic aspects of the IRDiRC core mission. Specifically, IRDiRC goals include timely diagnosis, use of globally coordinated diagnostic pipelines, and assessing the impact of rare diseases on affected individuals. As part of this mission, the DSC endeavored to create a list of research priorities to achieve these goals. We present a discussion of those priorities along with aspects of current, global rare disease needs and opportunities that support our prioritization. In support of this discussion, we also provide clinical vignettes illustrating real-world examples of diagnostic challenges.
    DOI:  https://doi.org/10.1016/j.ejmg.2024.104951
  41. Circ Res. 2024 Jun 07. 134(12): 1681-1702
    Revisiting Cardiac Biology in the Era of Single Cell and Spatial Omics.
    Jack A Palmer, Nadia Rosenthal, Sarah A Teichmann, Monika Litvinukova.
      Throughout our lifetime, each beat of the heart requires the coordinated action of multiple cardiac cell types. Understanding cardiac cell biology, its intricate microenvironments, and the mechanisms that govern their function in health and disease are crucial to designing novel therapeutical and behavioral interventions. Recent advances in single-cell and spatial omics technologies have significantly propelled this understanding, offering novel insights into the cellular diversity and function and the complex interactions of cardiac tissue. This review provides a comprehensive overview of the cellular landscape of the heart, bridging the gap between suspension-based and emerging in situ approaches, focusing on the experimental and computational challenges, comparative analyses of mouse and human cardiac systems, and the rising contextualization of cardiac cells within their niches. As we explore the heart at this unprecedented resolution, integrating insights from both mouse and human studies will pave the way for novel diagnostic tools and therapeutic interventions, ultimately improving outcomes for patients with cardiovascular diseases.
    Keywords:  cardiovascular diseases; genomics; heart; human; single-cell analysis; spatial analysis
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.323672
  42. Genes Dis. 2024 Sep;11(5): 101083
    SPNS1 ablation drives skeletal muscle atrophy by disrupting mitophagy, mitochondrial function, and apoptosis in mice.
    Xianzhong Zhang, Fengmin Zhang, Haofan Wu, Zhen Yu, Chengle Zhuang.
      
    DOI:  https://doi.org/10.1016/j.gendis.2023.101083
  43. N Engl J Med. 2024 Jun 06. 390(21): 1985-1997
    Genome Sequencing for Diagnosing Rare Diseases.
    Monica H Wojcik, Gabrielle Lemire, Eva Berger, Maha S Zaki, Mariel Wissmann, Wathone Win, Susan M White, Ben Weisburd, Dagmar Wieczorek, Leigh B Waddell, Jeffrey M Verboon, Grace E VanNoy, Ana Töpf, Tiong Yang Tan, Steffen Syrbe, Vincent Strehlow, Volker Straub, Sarah L Stenton, Hana Snow, Moriel Singer-Berk, Josh Silver, Shirlee Shril, Eleanor G Seaby, Ronen Schneider, Vijay G Sankaran, Alba Sanchis-Juan, Kathryn A Russell, Karit Reinson, Gianina Ravenscroft, Maximilian Radtke, Denny Popp, Tilman Polster, Konrad Platzer, Eric A Pierce, Emily M Place, Sander Pajusalu, Lynn Pais, Katrin Õunap, Ikeoluwa Osei-Owusu, Henry Opperman, Volkan Okur, Kaisa Teele Oja, Melanie O'Leary, Emily O'Heir, Chantal F Morel, Andreas Merkenschlager, Rhett G Marchant, Brian E Mangilog, Jill A Madden, Daniel MacArthur, Alysia Lovgren, Jordan P Lerner-Ellis, Jasmine Lin, Nigel Laing, Friedhelm Hildebrandt, Julia Hentschel, Emily Groopman, Julia Goodrich, Joseph G Gleeson, Roula Ghaoui, Casie A Genetti, Janina Gburek-Augustat, Hanna T Gazda, Vijay S Ganesh, Mythily Ganapathi, Lyndon Gallacher, Jack M Fu, Emily Evangelista, Eleina England, Sandra Donkervoort, Stephanie DiTroia, Sandra T Cooper, Wendy K Chung, John Christodoulou, Katherine R Chao, Liam D Cato, Kinga M Bujakowska, Samantha J Bryen, Harrison Brand, Carsten G Bönnemann, Alan H Beggs, Samantha M Baxter, Tobias Bartolomaeus, Pankaj B Agrawal, Michael Talkowski, Christina Austin-Tse, Rami Abou Jamra, Heidi L Rehm, Anne O'Donnell-Luria.
      BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.
    RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.
    CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2314761
  44. Med Genet. 2023 Jun;35(2): 89
    Editorial - Diagnostic genome sequencing in rare disorders.
    Peter Krawitz, Tobias B Haack.
      
    DOI:  https://doi.org/10.1515/medgen-2023-2029
  45. Cell Rep. 2024 Jun 05. pii: S2211-1247(24)00632-6. [Epub ahead of print]43(6): 114304
    TRABD modulates mitochondrial homeostasis and tissue integrity.
    Caixia Zhou, Zhirong Li, Yawen Li, Yaoyao Li, Wei Wang, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      High TRABD expression is associated with tau pathology in patients with Alzheimer's disease; however, the function of TRABD is unknown. Human TRABD encodes a mitochondrial outer-membrane protein. The loss of TRABD resulted in mitochondrial fragmentation, and TRABD overexpression led to mitochondrial clustering and fusion. The C-terminal tail of the TRABD anchored to the mitochondrial outer membrane and the TraB domain could form homocomplexes. Additionally, TRABD forms complexes with MFN2, MIGA2, and PLD6 to facilitate mitochondrial fusion. Flies lacking dTRABD are viable and have normal lifespans. However, aging flies exhibit reduced climbing ability and abnormal mitochondrial morphology in their muscles. The expression of dTRABD is increased in aged flies. dTRABD overexpression leads to neurodegeneration and enhances tau toxicity in fly eyes. The overexpression of dTRABD also increased reactive oxygen species (ROS), ATP production, and protein turnover in the mitochondria. This study suggested that TRABD-induced mitochondrial malfunctions contribute to age-related neurodegeneration.
    Keywords:  CP: Cell biology; Drosophila; mitochondria; mitochondria fusion; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2024.114304
  46. Redox Biol. 2024 May 21. pii: S2213-2317(24)00181-2. [Epub ahead of print]73 103203
    The mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism.
    Felipe Paredes, Holly C Williams, Xuesong Liu, Claire Holden, Bethany Bogan, Yu Wang, Kathryn M Crotty, Samantha M Yeligar, Alvaro A Elorza, Zhiyong Lin, Amir Rezvan, Alejandra San Martin.
      Vascular smooth muscle cells (VSMCs), known for their remarkable lifelong phenotypic plasticity, play a pivotal role in vascular pathologies through their ability to transition between different phenotypes. Our group discovered that the deficiency of the mitochondrial protein Poldip2 induces VSMC differentiation both in vivo and in vitro. Further comprehensive biochemical investigations revealed Poldip2's specific interaction with the mitochondrial ATPase caseinolytic protease chaperone subunit X (CLPX), which is the regulatory subunit for the caseinolytic protease proteolytic subunit (ClpP) that forms part of the ClpXP complex - a proteasome-like protease evolutionarily conserved from bacteria to humans. This interaction limits the protease's activity, and reduced Poldip2 levels lead to ClpXP complex activation. This finding prompted the hypothesis that ClpXP complex activity within the mitochondria may regulate the VSMC phenotype. Employing gain-of-function and loss-of-function strategies, we demonstrated that ClpXP activity significantly influences the VSMC phenotype. Notably, both genetic and pharmacological activation of ClpXP inhibits VSMC plasticity and fosters a quiescent, differentiated, and anti-inflammatory VSMC phenotype. The pharmacological activation of ClpP using TIC10, currently in phase III clinical trials for cancer, successfully replicates this phenotype both in vitro and in vivo and markedly reduces aneurysm development in a mouse model of elastase-induced aortic aneurysms. Our mechanistic exploration indicates that ClpP activation regulates the VSMC phenotype by modifying the cellular NAD+/NADH ratio and activating Sirtuin 1. Our findings reveal the crucial role of mitochondrial proteostasis in the regulation of the VSMC phenotype and propose the ClpP protease as a novel, actionable target for manipulating the VSMC phenotype.
    Keywords:  Aneurysms; ClpXP complex; Clpp; Metabolism; Mitochondria; NAD(+); Sirtuin 1; TIC10; VSMC; Vascular smooth mucle cell; Vasculature
    DOI:  https://doi.org/10.1016/j.redox.2024.103203
  47. Med Genet. 2023 Jun;35(2): 115-121
    The future role of facial image analysis in ACMG classification guidelines.
    Hellen Lesmann, Hannah Klinkhammer, Prof Dr Med Dipl Phys Peter M Krawitz.
      The use of next-generation sequencing (NGS) has dramatically improved the diagnosis of rare diseases. However, the analysis of genomic data has become complex with the increasing detection of variants by exome and genome sequencing. The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed a 5-tier classification scheme in 2015 for variant interpretation, that has since been widely adopted. Despite efforts to minimise discrepancies in the application of these criteria, inconsistencies still occur. Further specifications for individual genes were developed by Variant Curation Expert Panels (VCEPs) of the Clinical Genome Resource (ClinGen) consortium, that also take into consideration gene or disease specific features. For instance, in disorders with a highly characerstic facial gestalt a "phenotypic match" (PP4) has higher pathogenic evidence than e.g. in a non-syndromic form of intellectual disability. With computational approaches for quantifying the similarity of dysmorphic features results of such analysis can now be used in a refined Bayesian framework for the ACMG/AMP criteria.
    Keywords:  Bayesian statistics,; next-generation phenotyping; next-generation sequencing; phenotypic score; variant classification
    DOI:  https://doi.org/10.1515/medgen-2023-2014
  48. J Neurol. 2024 Jun 01.
    Status epilepticus in POLG disease: a large multinational study.
    Omar Hikmat, Karin Naess, Martin Engvall, Claus Klingenberg, Magnhild Rasmussen, Eylert Brodtkorb, Elsebet Ostergaard, Irenaeus de Coo, Leticia Pias-Peleteiro, Pirjo Isohanni, Johanna Uusimaa, Kari Majamaa, Mikko Kärppä, Juan Dario Ortigoza-Escobar, Trine Tangeraas, Siren Berland, Emma Harrison, Heather Biggs, Rita Horvath, Niklas Darin, Shamima Rahman, Laurence A Bindoff.
      We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.
    Keywords:   POLG ; Epilepsy; Mitochondrial disease; Refractory status epilepticus
    DOI:  https://doi.org/10.1007/s00415-024-12463-5
  49. Nat Commun. 2024 Jun 03. 15(1): 4700
    Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
    Shashank Dadsena, Rodrigo Cuevas Arenas, Gonçalo Vieira, Susanne Brodesser, Manuel N Melo, Ana J García-Sáez.
      BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.
    DOI:  https://doi.org/10.1038/s41467-024-49067-6
  50. Nature. 2024 Jun 05.
    Senescent glia link mitochondrial dysfunction and lipid accumulation.
    China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.
      Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.
    DOI:  https://doi.org/10.1038/s41586-024-07516-8
  51. Med Genet. 2022 Oct;34(3): 225-230
    Polygenic risk scores in epilepsy.
    Henrike O Heyne.
      An epilepsy diagnosis has large consequences for an individual but is often difficult to make in clinical practice. Novel biomarkers are thus greatly needed. Here, we give an overview of how thousands of common genetic factors that increase the risk for epilepsy can be summarized as epilepsy polygenic risk scores (PRS). We discuss the current state of research on how epilepsy PRS can serve as a biomarker for the risk for epilepsy. The high heritability of common forms of epilepsy, particularly genetic generalized epilepsy, indicates a promising potential for epilepsy PRS in diagnosis and risk prediction. Small sample sizes and low ancestral diversity of current epilepsy genome-wide association studies show, however, a need for larger and more diverse studies before epilepsy PRS could be properly implemented in the clinic.
    Keywords:  complex disease; epilepsy; genome-wide association study; polygenic score; risk prediction
    DOI:  https://doi.org/10.1515/medgen-2022-2146
  52. Anal Chem. 2024 Jun 04.
    Lighting Up Nucleolus To Report Mitochondria Damage Using a Mitochondria-to-Nucleolus Migration Probe.
    Yumeng Wang, Qiaowen Lin, Yang Liu, Chi Li, Zhiqiang Liu, Xiaoqiang Yu, Kang-Nan Wang.
      Visualization of the mitochondrial state is crucial for tracking cell life processes and diagnosing disease, while fluorescent probes that can accurately assess mitochondrial status are currently scarce. Herein, a fluorescent probe named "SYN" was designed and prepared, which can target mitochondria via the mitochondrial membrane potential. Upon pathology or external stimulation, SYN can be released from the mitochondria and accumulate in the nucleolus to monitor the status of mitochondria. During this process, the brightness of the nucleolus can then serve as an indicator of mitochondrial damage. SYN has demonstrated excellent photostability in live cells as well as an extremely inert fluorescence response to bioactive molecules and the physiological pH environment of live cells. Spectroscopic titration and molecular docking studies have revealed that SYN can be lit up in nucleoli due to the high viscosity of the nucleus and the strong electrostatic interaction with the phosphate backbone of RNA. This probe is expected to be an exceptional tool based on its excellent imaging properties for tracking mitochondrial state in live cells.
    DOI:  https://doi.org/10.1021/acs.analchem.3c05629
  53. Pharmacol Res. 2024 Jun 02. pii: S1043-6618(24)00192-0. [Epub ahead of print]205 107247
    Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.
    Christian Griñán-Ferré, Aina Bellver-Sanchis, Ana Guerrero, Mercè Pallàs.
      About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.
    Keywords:  Alzheimer´s disease; Amyotrophic lateral sclerosis; Epigenetics; Huntington's disease; Multiple sclerosis; Neurodegenerative disorders; Parkinson’s disease; Personalized medicine; Pharmacoepigenetics; Pharmacoepigenomics
    DOI:  https://doi.org/10.1016/j.phrs.2024.107247
  54. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jun 04. pii: S1388-1981(24)00065-9. [Epub ahead of print] 159515
    The lipid side of unfolded protein response.
    Wojciech Białek, Anita Hryniewicz-Jankowska, Paulina Czechowicz, Jakub Sławski, James F Collawn, Aleksander Czogalla, Rafał Bartoszewski.
      Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival. Lipid dysregulation is known to activate many aspects of the UPR, but the complexity of this crosstalk remains a major research barrier. ER lipid disequilibrium and lipotoxicity are known to be important contributors to numerous human pathologies, including insulin resistance, liver disease, cardiovascular diseases, neurodegenerative diseases, and cancer. Despite their medical significance and continuous research, however, the molecular mechanisms that modulate lipid synthesis during ER stress conditions, and their impact on cell fate decisions, remain poorly understood. Here we summarize the current view on crosstalk and connections between altered lipid metabolism, ER stress, and the UPR.
    Keywords:  ER stress; Lipid membrane homeostasis; Lipid metabolism
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159515
  55. Sci Rep. 2024 06 03. 14(1): 12710
    An interactive atlas of genomic, proteomic, and metabolomic biomarkers promotes the potential of proteins to predict complex diseases.
    Martin Smelik, Yelin Zhao, Xinxiu Li, Joseph Loscalzo, Oleg Sysoev, Firoj Mahmud, Dina Mansour Aly, Mikael Benson.
      Multiomics analyses have identified multiple potential biomarkers of the incidence and prevalence of complex diseases. However, it is not known which type of biomarker is optimal for clinical purposes. Here, we make a systematic comparison of 90 million genetic variants, 1453 proteins, and 325 metabolites from 500,000 individuals with complex diseases from the UK Biobank. A machine learning pipeline consisting of data cleaning, data imputation, feature selection, and model training using cross-validation and comparison of the results on holdout test sets showed that proteins were most predictive, followed by metabolites, and genetic variants. Only five proteins per disease resulted in median (min-max) areas under the receiver operating characteristic curves for incidence of 0.79 (0.65-0.86) and 0.84 (0.70-0.91) for prevalence. In summary, our work suggests the potential of predicting complex diseases based on a limited number of proteins. We provide an interactive atlas (macd.shinyapps.io/ShinyApp/) to find genomic, proteomic, or metabolomic biomarkers for different complex diseases.
    DOI:  https://doi.org/10.1038/s41598-024-63399-9
  56. Science. 2024 Jun 07. 384(6700): 1134-1142
    Rare codon recoding for efficient noncanonical amino acid incorporation in mammalian cells.
    Wenlong Ding, Wei Yu, Yulin Chen, Lihui Lao, Yu Fang, Chengzhu Fang, Hongxia Zhao, Bo Yang, Shixian Lin.
      The ability to genetically encode noncanonical amino acids (ncAAs) has empowered proteins with improved or previously unknown properties. However, existing strategies in mammalian cells rely on the introduction of a blank codon to incorporate ncAAs, which is inefficient and limits their widespread applications. In this study, we developed a rare codon recoding strategy that takes advantage of the relative rarity of the TCG codon to achieve highly selective and efficient ncAA incorporation through systematic engineering and big data-model predictions. We highlight the broad utility of this strategy for the incorporation of dozens of ncAAs into various functional proteins at the wild-type protein expression levels, as well as the synthesis of proteins with up to six-site ncAAs or four distinct ncAAs in mammalian cells for downstream applications.
    DOI:  https://doi.org/10.1126/science.adm8143
  57. iScience. 2024 Jun 21. 27(6): 109796
    Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.
    Hua Qu, Xiufei Liu, Jiaran Zhu, Niexia He, Qingshan He, Linlin Zhang, Yuren Wang, Xiaoli Gong, Xin Xiong, Jinbo Liu, Chuan Wang, Gangyi Yang, Qingwu Yang, Gang Luo, Zhiming Zhu, Yi Zheng, Hongting Zheng.
      Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.
    Keywords:  biological sciences; cell biology; cellular physiology; diabetology; endocrinology; natural sciences; pathophysiology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109796
  58. Cardiovasc Res. 2024 Jun 04. pii: cvae116. [Epub ahead of print]
    Cardiomyocyte βII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function.
    Rongjin Yang, Banjun Ruan, Rutao Wang, Xiaomeng Zhang, Pingping Xing, Congye Li, Yunyun Zhang, Xiaoqian Chang, Haifeng Song, Shun Zhang, Huishou Zhao, Feiyu Zhang, Tao Yin, Tingting Qi, Wenjun Yan, Fuyang Zhang, Guangyu Hu, Shan Wang, Ling Tao.
      AIMS: βII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of βII spectrin in cardiac contractile function and pathological post-myocardial infarction remodeling remain unclear. Here, we investigated whether and how βII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischemia/reperfusion (I/R) injury.METHODS AND RESULTS: We observed that the levels of serum βII spectrin breakdown products (βII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, βII spectrin was degraded into βII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific βII spectrin knockout mice, we found that deletion of βII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific βII spectrin knockout mice had not developed, deletion of βII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of βII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that βII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, βII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability.
    CONCLUSION: βII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in βII spectrin exacerbate cardiac I/R injury.
    Keywords:  Cardiac function; Cytoskeleton; Mitochondria; Mitochondrial complex I; βII spectrin
    DOI:  https://doi.org/10.1093/cvr/cvae116
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