bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–04–28
fifty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
  2. Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.
  3. Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
  4. Regulation of mitochondrial fission by fatty acyl-coenzyme A.
  5. Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
  6. Geranylgeranylated-SCF FBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.
  7. mRNA therapy for a rare childhood disease.
  8. Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.
  9. Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
  10. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST.
  11. The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.
  12. Mitochondrial sites of contact with the nucleus.
  13. Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.
  14. Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.
  15. OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
  16. Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.
  17. Repurposing a diabetes drug to treat Parkinson's disease.
  18. Extracellular vesicle encapsulated nicotinamide delivered via a trans-scleral route provides retinal ganglion cell neuroprotection.
  19. Inflammation and mitophagy are mitochondrial checkpoints to aging.
  20. Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation.
  21. Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review.
  22. Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.
  23. Primary Coenzyme Q10 Deficiency-Related Ataxias.
  24. Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration.
  25. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
  26. Unraveling the Pathogenetic Mechanisms Underlying the Association between Specific Mitochondrial DNA Haplogroups and Parkinson's Disease.
  27. De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.
  28. A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.
  29. Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.
  30. BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
  31. Spaced training activates Miro/Milton-dependent mitochondrial dynamics in neuronal axons to sustain long-term memory.
  32. Presenting metabolomics analyses: what is in a number?
  33. Deciphering missense coding variants with AlphaMissense.
  34. Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.
  35. Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
  36. Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
  37. A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
  38. Eye movement function captured via an electronic tablet informs on cognition and disease severity in Parkinson's disease.
  39. The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
  40. Insights into conformational changes in cytochrome b during the early steps of its maturation.
  41. The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.
  42. Integrative machine learning approaches for predicting disease risk using multi-omics data from the UK Biobank.
  43. Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.
  44. CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.
  45. Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.
  46. An AlphaFold Structure Analysis of COQ2 as Key a Component of the Coenzyme Q Synthesis Complex.
  47. Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
  48. Micro-and mesoscale aspects of neurodegeneration in engineered human neural networks carrying the LRRK2 G2019S mutation.
  49. Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue.
  50. Mitochondrial Venus is more likely to have a lower birthweight.
  51. SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.
  52. Redox signaling and skeletal muscle adaptation during aerobic exercise.
  53. Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.
  54. Emerging therapies for childhood-onset movement disorders.
  55. Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.
  56. Genome-first evaluation with exome sequence and clinical data uncovers underdiagnosed genetic disorders in a large healthcare system.
  1. Cell Death Dis. 2024 Apr 20. 15(4): 281
    Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
    Raquel Brañas Casas, Alessandro Zuppardo, Giovanni Risato, Alberto Dinarello, Rudy Celeghin, Camilla Fontana, Eleonora Grelloni, Alexandru Ionut Gilea, Carlo Viscomi, Andrea Rasola, Luisa Dalla Valle, Tiziana Lodi, Enrico Baruffini, Nicola Facchinello, Francesco Argenton, Natascia Tiso.
      The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.
    DOI:  https://doi.org/10.1038/s41419-024-06622-9
  2. Am J Med Genet A. 2024 Apr 24. e63643
    Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.
    Aynur Küçükcongar Yavaş, Hacer Basan, Serpil Dinçer, Berrak Bilginer Gürbüz, Çiğdem Seher Kasapkara.
      The mitochondrial phosphate carrier is critical for adenosine triphosphate synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. Variants in the SLC25A3 gene coding mitochondrial phosphate carrier lead to failure in inorganic phosphate transport across mitochondria. The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases. The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene. Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency.
    Keywords:  adenosine triphosphate synthesis; cardiomyopathy; elevated creatinine kinase; muscular hypotonia
    DOI:  https://doi.org/10.1002/ajmg.a.63643
  3. Genes (Basel). 2024 Apr 17. pii: 500. [Epub ahead of print]15(4):
    Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
    Doriana Misceo, Petter Strømme, Fatemeh Bitarafan, Maninder Singh Chawla, Ying Sheng, Sandra Monica Bach de Courtade, Lars Eide, Eirik Frengen.
      Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called "primary mitochondrial disorders" (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient's fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.
    Keywords:  Alu element; COX; Complex IV; Leigh syndrome; NDUFA4/COXFA4; WGS; encephalopathy; structural variant (SV)
    DOI:  https://doi.org/10.3390/genes15040500
  4. Nat Cell Biol. 2024 Apr 23.
    Regulation of mitochondrial fission by fatty acyl-coenzyme A.
      
    DOI:  https://doi.org/10.1038/s41556-024-01406-x
  5. J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]
    Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
    Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.
      Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.
    Keywords:  Metabolism; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI167371
  6. bioRxiv. 2024 Apr 16. pii: 2024.04.16.589745. [Epub ahead of print]
    Geranylgeranylated-SCF FBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.
    Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Anish Gudur, Hagar Ismail, Ritika Adhikari, Avantika Dhabaria, Beatrix Ueberheide, Shafi Kuchay.
      E3-ubiquitin ligases (E3s) are main components of the ubiquitin-proteasome system (UPS), as they determine substrate specificity in response to internal and external cues to regulate protein homeostasis. However, the regulation of membrane protein ubiquitination by E3s within distinct cell membrane compartments or organelles is not well understood. We show that FBXO10, the interchangeable component of the SKP1/CUL1/F-box ubiquitin ligase complex (SCF-E3), undergoes lipid-modification with geranylgeranyl isoprenoid at Cysteine953 (C953), facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide does not contain a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and the interaction with two cytosolic factors, PDE6δ (a prenyl group-binding protein), and HSP90 (a mitochondrial chaperone) orchestrate specific OMM targeting of prenyl-FBXO10 across diverse membrane compartments. The geranylgeranylation-deficient FBXO10(C953S) mutant redistributes away from the OMM, leading to impaired mitochondrial ATP production, decreased mitochondrial membrane potential, and increased mitochondrial fragmentation. Phosphoglycerate mutase 5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative mass spectrometry analyses of enriched mitochondria (LFQ-MS/MS), leveraging the redistribution of FBXO10(C953S). FBXO10, but not FBXO10(C953S), promoted polyubiquitylation and degradation of PGAM5. Examination of the role of this pathway in a physiological context revealed that the loss of FBXO10 or expression of prenylation-deficient-FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human iPSCs and murine myoblasts. Our studies identify a mechanism for selective E3-ligase mediated regulation of mitochondrial membrane proteostasis and metabolic health, potentially amenable to therapeutic intervention.
    DOI:  https://doi.org/10.1101/2024.04.16.589745
  7. Nat Med. 2024 Apr 22.
    mRNA therapy for a rare childhood disease.
    Karen O'Leary.
      
    Keywords:  Clinical trials; Metabolic disorders; RNA nanotechnology
    DOI:  https://doi.org/10.1038/d41591-024-00027-z
  8. Front Cell Dev Biol. 2024 ;12 1260496
    Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.
    Eszter Dombi, Tony Marinaki, Paolo Spingardi, Val Millar, Nastasia Hadjichristou, Janet Carver, Iain G Johnston, Carl Fratter, Joanna Poulton.
      Introduction: In mitochondrial DNA (mtDNA) depletion syndrome (MDS), patients cannot maintain sufficient mtDNA for their energy needs. MDS presentations range from infantile encephalopathy with hepatopathy (Alpers syndrome) to adult chronic progressive external ophthalmoplegia. Most are caused by nucleotide imbalance or by defects in the mtDNA replisome. There is currently no curative treatment available. Nucleoside therapy is a promising experimental treatment for TK2 deficiency, where patients are supplemented with exogenous deoxypyrimidines. We aimed to explore the benefits of nucleoside supplementation in POLG and TWNK deficient fibroblasts. Methods: We used high-content fluorescence microscopy with software-based image analysis to assay mtDNA content and membrane potential quantitatively, using vital dyes PicoGreen and MitoTracker Red CMXRos respectively. We tested the effect of 15 combinations (A, T, G, C, AT, AC, AG, CT, CG, GT, ATC, ATG, AGC, TGC, ATGC) of deoxynucleoside supplements on mtDNA content of fibroblasts derived from four patients with MDS (POLG1, POLG2, DGUOK, TWNK) in both a replicating (10% dialysed FCS) and quiescent (0.1% dialysed FCS) state. We used qPCR to measure mtDNA content of supplemented and non-supplemented fibroblasts following mtDNA depletion using 20 µM ddC and after 14- and 21-day recovery in a quiescent state. Results: Nucleoside treatments at 200 µM that significantly increased mtDNA content also significantly reduced the number of cells remaining in culture after 7 days of treatment, as well as mitochondrial membrane potential. These toxic effects were abolished by reducing the concentration of nucleosides to 50 µM. In POLG1 and TWNK cells the combination of ATGC treatment increased mtDNA content the most after 7 days in non-replicating cells. ATGC nucleoside combination significantly increased the rate of mtDNA recovery in quiescent POLG1 cells following mtDNA depletion by ddC. Conclusion: High-content imaging enabled us to link mtDNA copy number with key read-outs linked to patient wellbeing. Elevated G increased mtDNA copy number but severely impaired fibroblast growth, potentially by inhibiting purine synthesis and/or causing replication stress. Combinations of nucleosides ATGC, T, or TC, benefited growth of cells harbouring POLG mutations. These combinations, one of which reflects a commercially available preparation, could be explored further for treatment of POLG patients.
    Keywords:  POLG; TWNK; alpers syndrome; heavy isotope labelling mass spectroscopy; high-content imaging; mitochondrial DNA; mitochondrial DNA depletion syndrome; nucleoside bypass therapy
    DOI:  https://doi.org/10.3389/fcell.2024.1260496
  9. PLoS Biol. 2024 Apr 26. 22(4): e3002602
    Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
    Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.
      Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.
    DOI:  https://doi.org/10.1371/journal.pbio.3002602
  10. bioRxiv. 2024 Apr 10. pii: 2024.04.10.588849. [Epub ahead of print]
    Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST.
    Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.
      Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
    DOI:  https://doi.org/10.1101/2024.04.10.588849
  11. Mitochondrion. 2024 Apr 21. pii: S1567-7249(24)00043-6. [Epub ahead of print]76 101885
    The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.
    Priyanka Biswal, Manas Ranjan Sahu, Mir Hilal Ahmad, Amal Chandra Mondal.
      Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.
    Keywords:  Apoptosis; Hippo signaling; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.mito.2024.101885
  12. J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):
    Mitochondrial sites of contact with the nucleus.
    Michelangelo Campanella, Brindha Kannan.
      Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.
    DOI:  https://doi.org/10.1083/jcb.202305010
  13. Eur J Clin Invest. 2024 Apr 21. e14217
    Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.
    Kevin Aguilar, Patrycja Jakubek, Antonio Zorzano, Mariusz R Wieckowski.
       OBJECTIVES AND SCOPE: Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient-derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation.
    INSIGHTS: The central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments.
    SUMMARY: In summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression.
    Keywords:  ETC; OXPHOS; bioenergetics; metabolism; mitochondria; mtDNA; nDNA; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.1111/eci.14217
  14. Acta Physiol (Oxf). 2024 Apr 26. e14150
    Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.
    Charlotte A Hoogstraten, Tom J J Schirris, Frans G M Russel.
      A disturbed mitochondrial function contributes to the pathology of many common diseases. These organelles are therefore important therapeutic targets. On the contrary, many adverse effects of drugs can be explained by a mitochondrial off-target effect, in particular, due to an interaction with carrier proteins in the inner membrane. Yet this class of transport proteins remains underappreciated and understudied. The aim of this review is to provide a deeper understanding of the role of mitochondrial carriers in health and disease and their significance as drug targets. We present literature-based evidence that mitochondrial carrier proteins are associated with prevalent diseases and emphasize their potential as drug (off-)target sites by summarizing known mitochondrial drug-transporter interactions. Studying these carriers will enhance our knowledge of mitochondrial drug on- and off-targets and provide opportunities to further improve the efficacy and safety of drugs.
    Keywords:  carrier proteins; drugs; efficacy and safety; inner mitochondrial membrane; mitochondria; on‐ and off‐target
    DOI:  https://doi.org/10.1111/apha.14150
  15. Int J Mol Sci. 2024 Apr 22. pii: 4566. [Epub ahead of print]25(8):
    OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
    Robert Gilkerson, Harpreet Kaur, Omar Carrillo, Isaiah Ramos.
      In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities.
    Keywords:  DRP1; OMA1; OPA1; apoptosis; autophagy; bioenergetics; cristae; fission; fusion; integrated stress response; mitochondria; transmembrane potential
    DOI:  https://doi.org/10.3390/ijms25084566
  16. Life Sci Alliance. 2024 Jul;pii: e202302473. [Epub ahead of print]7(7):
    Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.
    Rita Soares, Diogo M Lourenço, Isa F Mota, Ana M Sebastião, Sara Xapelli, Vanessa A Morais.
      Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.
    DOI:  https://doi.org/10.26508/lsa.202302473
  17. Nat Med. 2024 Apr 20.
    Repurposing a diabetes drug to treat Parkinson's disease.
    Sonia Muliyil.
      
    Keywords:  Clinical trials; Diabetes; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41591-024-00026-0
  18. Acta Neuropathol Commun. 2024 Apr 22. 12(1): 65
    Extracellular vesicle encapsulated nicotinamide delivered via a trans-scleral route provides retinal ganglion cell neuroprotection.
    Myungjin Kim, Jun Yong Kim, Won-Kyu Rhim, Gloria Cimaglia, Andrew Want, James E Morgan, Pete A Williams, Chun Gwon Park, Dong Keun Han, Seungsoo Rho.
      The progressive and irreversible degeneration of retinal ganglion cells (RGCs) and their axons is the major characteristic of glaucoma, a leading cause of irreversible blindness worldwide. Nicotinamide adenine dinucleotide (NAD) is a cofactor and metabolite of redox reaction critical for neuronal survival. Supplementation with nicotinamide (NAM), a precursor of NAD, can confer neuroprotective effects against glaucomatous damage caused by an age-related decline of NAD or mitochondrial dysfunction, reflecting the high metabolic activity of RGCs. However, oral supplementation of drug is relatively less efficient in terms of transmissibility to RGCs compared to direct delivery methods such as intraocular injection or delivery using subconjunctival depots. Neither method is ideal, given the risks of infection and subconjunctival scarring without novel techniques. By contrast, extracellular vesicles (EVs) have advantages as a drug delivery system with low immunogeneity and tissue interactions. We have evaluated the EV delivery of NAM as an RGC protective agent using a quantitative assessment of dendritic integrity using DiOlistics, which is confirmed to be a more sensitive measure of neuronal health in our mouse glaucoma model than the evaluation of somatic loss via the immunostaining method. NAM or NAM-loaded EVs showed a significant neuroprotective effect in the mouse retinal explant model. Furthermore, NAM-loaded EVs can penetrate the sclera once deployed in the subconjunctival space. These results confirm the feasibility of using subconjunctival injection of EVs to deliver NAM to intraocular targets.
    Keywords:  Extracellular vesicle; Glaucoma; Neuroprotection; Nicotinamide; Retinal ganglion cell; Trans-scleral route
    DOI:  https://doi.org/10.1186/s40478-024-01777-0
  19. Nat Commun. 2024 Apr 20. 15(1): 3375
    Inflammation and mitophagy are mitochondrial checkpoints to aging.
    Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.
      
    DOI:  https://doi.org/10.1038/s41467-024-47840-1
  20. bioRxiv. 2024 Apr 13. pii: 2024.04.09.588624. [Epub ahead of print]
    Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation.
    Tara A Saleh, Jeremy Whitson, Phoebe Keiser, Praveena Prasad, Brenita C Jenkins, Tori Sodeinde, Carolyn N Mann, Peter S Rabinovitch, Melanie R McReynolds, Mariya T Sweetwyne.
      The mitochondrial-rich renal tubule cells are key regulators of blood homeostasis via excretion and reabsorption of metabolic waste. With age, tubules are subject to increasing mitochondrial dysfunction and declining nicotinamide adenine dinucleotide (NAD+) levels, both hampering ATP production efficiency. We tested two mitochondrial interventions in young (6-mo) and aged (26-mo) adult male mice: elamipretide (ELAM), a tetrapeptide in clinical trials that improves mitochondrial structure and function, and nicotinamide mononucleotide (NMN), an NAD+ intermediate and commercially available oral supplement. Kidneys were analyzed from young and aged mice after eight weeks of treatment with ELAM (3 mg/kg/day), NMN (300 mg/kg/day), or from aged mice treated with the two interventions combined (ELAM+NMN). We hypothesized that combining pharmacologic treatments to ameliorate mitochondrial dysfunction and boost NAD+ levels, would more effectively reduce kidney aging than either intervention alone. Unexpectedly, in aged kidneys, NMN increased expression of genetic markers of inflammation (IL-1β and Ccl2) and tubule injury (Kim-1). Metabolomics of endpoint sera showed that NMN-treated aged mice had higher circulating levels of uremic toxins than either aged controls or young NMN-treated mice. ELAM+NMN-treated aged mice accumulated uremic toxins like NMN-only aged mice, but reduced IL-1β and Ccl2 kidney mRNA. This suggests that pre-existing mitochondrial dysfunction in aged kidney underlies susceptibility to inflammatory signaling with NMN supplementation in aged, but not young, mice. These findings demonstrate age and tissue dependent effects on downstream metabolic accumulation from NMN and highlight the need for targeted analysis of aged kidneys to assess the safety of anti-aging supplements in older populations.
    Keywords:  elamipretide; inflammation; kidney; metabolites; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1101/2024.04.09.588624
  21. Int J Neonatal Screen. 2024 Mar 30. pii: 29. [Epub ahead of print]10(2):
    Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review.
    Maria Al Bandari, Laura Nagy, Vivian Cruz, Stacy Hewson, Alomgir Hossain, Michal Inbar-Feigenberg.
      Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare genetic condition affecting the mitochondrial beta-oxidation of long-chain fatty acids. This study reports on the clinical outcomes of patients diagnosed by newborn screening with VLCAD deficiency comparing metabolic parameters, enzyme activities, molecular results, and clinical management. It is a single-center retrospective chart review of VLCAD deficiency patients who met the inclusion criteria between January 2002 and February 2020. The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%. The Pearson correlation between enzyme activity and the C14:1 level at newborn screening showed a p-value of 0.0003, and the correlation between enzyme activity and the C14:1 level at diagnosis had a p-value of 0.0295. There was no clear correlation between the number of documented admissions and the enzyme activity level. Patients who had a high C14:1 value at diagnosis were started on a diet with a lower percentage of energy from long-chain triglycerides. The C14:1 result at diagnosis is the value that has been guiding our initial clinical management in asymptomatic diagnosed newborns. However, the newborn screening C14:1 value is the most sensitive predictor of low enzyme activity and may help guide dietary management.
    Keywords:  newborn screening; residual enzyme activity; very long-chain acyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.3390/ijns10020029
  22. bioRxiv. 2024 Apr 21. pii: 2024.04.19.590241. [Epub ahead of print]
    Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.
    Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Rachel Haahr, Jack Devine, Cynthia C Liu, Catherine Kelly, Elizabeth Thompson, Mangesh Kurade, Jeremy Michelson, Evan D Shaulson, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Faris M Zuraikat, Marie-Pierre St-Onge, Brett A Kaufman, Richard Sloan, Robert-Paul Juster, Anna L Marsland, Gilles Gouspillou, Michio Hirano, Martin Picard.
      GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Plasma and saliva GDF15 levels are not correlated. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychological stress increases plasma (+3.4-5.3%) and saliva GDF15 (+45%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ∼42-92% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish the dynamic properties of saliva GDF15, reveal it as a stress-sensitive, and as a clinically relevant marker of mitochondrial diseases. These findings point to a shared psychobiological pathway integrating metabolic and mental stress.
    DOI:  https://doi.org/10.1101/2024.04.19.590241
  23. J Clin Med. 2024 Apr 19. pii: 2391. [Epub ahead of print]13(8):
    Primary Coenzyme Q10 Deficiency-Related Ataxias.
    Piervito Lopriore, Marco Vista, Alessandra Tessa, Martina Giuntini, Elena Caldarazzo Ienco, Michelangelo Mancuso, Gabriele Siciliano, Filippo Maria Santorelli, Daniele Orsucci.
      Cerebellar ataxia is a neurological syndrome characterized by the imbalance (e.g., truncal ataxia, gait ataxia) and incoordination of limbs while executing a task (dysmetria), caused by the dysfunction of the cerebellum or its connections. It is frequently associated with other signs of cerebellar dysfunction, including abnormal eye movements, dysmetria, kinetic tremor, dysarthria, and/or dysphagia. Among the so-termed mitochondrial ataxias, variants in genes encoding steps of the coenzyme Q10 biosynthetic pathway represent a common cause of autosomal recessive primary coenzyme Q10 deficiencies (PCoQD)s. PCoQD is a potentially treatable condition; therefore, a correct and timely diagnosis is essential. After a brief presentation of the illustrative case of an Italian woman with this condition (due to a novel homozygous nonsense mutation in COQ8A), this article will review ataxias due to PCoQD.
    Keywords:  ataxia; cerebellum; coenzyme Q10; mitochondrial diseases; primary coenzyme Q10 deficiencies
    DOI:  https://doi.org/10.3390/jcm13082391
  24. bioRxiv. 2024 Apr 20. pii: 2024.04.16.589775. [Epub ahead of print]
    Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration.
    Agustian Surya, Blythe Marie Bolton, Reed Rothe, Raquel Mejia-Trujillo, Qiuxia Zhao, Amanda Leonita, Yue Liu, Rekha Rangan, Yasash Gorusu, Pamela Nguyen, Can Cenik, Elif Sarinay Cenik.
      The interplay between ribosomal protein composition and mitochondrial function is essential for sustaining energy homeostasis. Precise stoichiometric production of ribosomal proteins is crucial to maximize protein synthesis efficiency while reducing the energy costs to the cell. However, the impact of this balance on mitochondrial ATP generation, morphology and function remains unclear. Particularly, the loss of a single copy ribosomal protein gene is observed in Mendelian disorders like Diamond Blackfan Anemia and is common in somatic tumors, yet the implications of this imbalance on mitochondrial function and energy dynamics are still unclear. In this study, we investigated the impact of haploinsufficiency for four ribosomal protein genes implicated in ribosomopathy disorders ( rps-10, rpl-5, rpl-33, rps-23 ) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Our findings uncover significant, albeit variably penetrant, mitochondrial morphological differences across these mutants, alongside an upregulation of glutathione transferases, and SKN-1 dependent increase in oxidative stress resistance, indicative of increased ROS production. Specifically, loss of a single copy of rps-10 in C. elegans led to decreased mitochondrial activity, characterized by lower energy levels and reduced oxygen consumption. A similar reduction in mitochondrial activity and energy levels was observed in human leukemia cells with a 50% reduction in RPS10 transcript levels. Importantly, we also observed alterations in the translation efficiency of nuclear and mitochondrial electron transport chain components in response to reductions in ribosomal protein genes' expression in both C. elegans and human cells. This suggests a conserved mechanism whereby the synthesis of components vital for mitochondrial function are adjusted in the face of compromised ribosomal machinery. Finally, mitochondrial membrane and cytosolic ribosomal components exhibited significant covariation at the RNA and translation efficiency level in lymphoblastoid cells across a diverse group of individuals, emphasizing the interplay between the protein synthesis machinery and mitochondrial energy production. By uncovering the impact of ribosomal protein haploinsufficiency on the translation efficiency of electron transport chain components, mitochondrial physiology, and the adaptive stress responses, we provide evidence for an evolutionarily conserved strategy to safeguard cellular functionality under genetic stress.
    DOI:  https://doi.org/10.1101/2024.04.16.589775
  25. EMBO J. 2024 Apr 22.
    SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
    Weiwei Yan, Chengmei Xie, Sijun Sun, Quan Zheng, Jingyi Wang, Zihao Wang, Cheuk-Him Man, Haiyan Wang, Yunfan Yang, Tianshi Wang, Leilei Shi, Shengjie Zhang, Chen Huang, Shuangnian Xu, Yi-Ping Wang.
      Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.
    Keywords:  FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase
    DOI:  https://doi.org/10.1038/s44318-024-00101-9
  26. Cells. 2024 Apr 17. pii: 694. [Epub ahead of print]13(8):
    Unraveling the Pathogenetic Mechanisms Underlying the Association between Specific Mitochondrial DNA Haplogroups and Parkinson's Disease.
    Min-Yu Lan, Tsu-Kung Lin, Baiba Lace, Algirdas Utkus, Birute Burnyte, Kristina Grigalioniene, Yu-Han Lin, Inna Inashkina, Chia-Wei Liou.
      Variants of mitochondrial DNA (mtDNA) have been identified as risk factors for the development of Parkinson's disease (PD). However, the underlying pathogenetic mechanisms remain unclear. Cybrid models carrying various genotypes of mtDNA variants were tested for resistance to PD-simulating MPP+ treatment. The most resistant line was selected for transcriptome profiling, revealing specific genes potentially influencing the resistant characteristic. We then conducted protein validation and molecular biological studies to validate the related pathways as the influential factor. Cybrids carrying the W3 mtDNA haplogroup demonstrated the most resistance to the MPP+ treatment. In the transcriptome study, PPP1R15A was identified, while further study noted elevated expressions of the coding protein GADD34 across all cybrids. In the study of GADD34-related mitochondrial unfolding protein response (mtUPR), we found that canonical mtUPR, launched by the phosphate eIF2a, is involved in the resistant characteristic of specific mtDNA to MPP+ treatment. Our study suggests that a lower expression of GADD34 in the late phase of mtUPR may prolong the mtUPR process, thereby benefitting protein homeostasis and facilitating cellular resistance to PD development. We herein demonstrate that GADD34 plays an important role in PD development and should be further investigated as a target for the development of therapies for PD.
    Keywords:  Parkinson’s disease; cybrid; mitochondrial haplogroup; transcriptome; unfolding protein response
    DOI:  https://doi.org/10.3390/cells13080694
  27. medRxiv. 2024 Apr 09. pii: 2024.04.07.24305438. [Epub ahead of print]
    De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.
    Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Sarah L Stenton, Susan Walker, Alicia Ljungdahl, Jenny Lord, Vijay S Ganesh, Jialan Ma, Alexandra C Martin-Geary, Gabrielle Lemire, Elston N D'Souza, Shan Dong, Jamie M Ellingford, David R Adams, Kirsten Allan, Madhura Bakshi, Erin E Baldwin, Seth I Berger, Jonathan A Bernstein, Natasha J Brown, Lindsay C Burrage, Kimberly Chapman, Alison G Compton, Chloe A Cunningham, Precilla D'Souza, Emmanuèle C Délot, Kerith-Rae Dias, Ellen R Elias, Carey-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L Fraser, Lyndon Gallacher, Casie A Genetti, Christina L Grant, Tobias Haack, Alma Kuechler, Seema R Lalani, Elsa Leitão, Anna Le Fevre, Richard J Leventer, Jan E Liebelt, Paul J Lockhart, Alan S Ma, Ellen F Macnamara, Taylor M Maurer, Hector R Mendez, Stephen B Montgomery, Marie-Cécile Nassogne, Serena Neumann, Melanie O'Leary, Elizabeth E Palmer, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L Rehm, Chloe M Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A Rosenfeld, Rani Sachdev, Cas Simons, Sanjay M Sisodiya, Penny Snell, Laura Clair, Zornitza Stark, Tiong Yang Tan, Natalie B Tan, Suzanna El Temple, David R Thorburn, Cynthia J Tifft, Eloise Uebergang, Grace E VanNoy, Eric Vilain, David H Viskochil, Laura Wedd, Matthew T Wheeler, Susan M White, Monica Wojcik, Lynne A Wolfe, Zoe Wolfenson, Changrui Xiao, David Zocche, John L Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M Fica, Diana Baralle, Christel Depienne, Daniel G MacArthur, Joanna Mm Howson, Stephan J Sanders, Anne O'Donnell-Luria, Nicola Whiffin.
      Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.
    DOI:  https://doi.org/10.1101/2024.04.07.24305438
  28. Brain. 2024 Apr 25. pii: awae134. [Epub ahead of print]
    A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.
    Maali Odeh, Clara Sajrawi, Adam Majcher, Salman Zubedat, Lihi Shaulov, Alex Radzishevsky, Liron Mizrahi, Wendy K Chung, Avi Avital, Thorsten Hornemann, Daniel J Liebl, Inna Radzishevsky, Herman Wolosker.
      Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.
    Keywords:  d-serine; mitochondria; mitophagy; serine metabolism; synaptopathy
    DOI:  https://doi.org/10.1093/brain/awae134
  29. Diabetes. 2024 Apr 24. pii: db230432. [Epub ahead of print]
    Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.
    Soyoung Park, Hye-Na Cha, Min-Gyeong Shin, Sanghee Park, Yeongmin Kim, Min-Seob Kim, Kyung-Hoon Shin, Themis Thoudam, Eun Ju Lee, Robert R Wolfe, Jinmyoung Dan, Jin-Ho Koh, Il-Young Kim, Inho Choi, In-Kyu Lee, Hoon-Ki Sung, So-Young Park.
      Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.
    DOI:  https://doi.org/10.2337/db23-0432
  30. Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]
    BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
    Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.
    Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis
    DOI:  https://doi.org/10.1016/j.cell.2024.03.030
  31. Curr Biol. 2024 Apr 17. pii: S0960-9822(24)00390-7. [Epub ahead of print]
    Spaced training activates Miro/Milton-dependent mitochondrial dynamics in neuronal axons to sustain long-term memory.
    Alice Pavlowsky, Typhaine Comyn, Julia Minatchy, David Geny, Philippe Bun, Lydia Danglot, Thomas Preat, Pierre-Yves Plaçais.
      Neurons have differential and fluctuating energy needs across distinct cellular compartments, shaped by brain electrochemical activity associated with cognition. In vitro studies show that mitochondria transport from soma to axons is key to maintaining neuronal energy homeostasis. Nevertheless, whether the spatial distribution of neuronal mitochondria is dynamically adjusted in vivo in an experience-dependent manner remains unknown. In Drosophila, associative long-term memory (LTM) formation is initiated by an early and persistent upregulation of mitochondrial pyruvate flux in the axonal compartment of neurons in the mushroom body (MB). Through behavior experiments, super-resolution analysis of mitochondria morphology in the neuronal soma and in vivo mitochondrial fluorescence recovery after photobleaching (FRAP) measurements in the axons, we show that LTM induction, contrary to shorter-lived memories, is sustained by the departure of some mitochondria from MB neuronal soma and increased mitochondrial dynamics in the axonal compartment. Accordingly, impairing mitochondrial dynamics abolished the increased pyruvate consumption, specifically after spaced training and in the MB axonal compartment, thereby preventing LTM formation. Our results thus promote reorganization of the mitochondrial network in neurons as an integral step in elaborating high-order cognitive processes.
    Keywords:  3D-STED microscopy; Drosophila; brain energy metabolism; long-term memory; mitochondria motility; mushroom body
    DOI:  https://doi.org/10.1016/j.cub.2024.03.050
  32. EMBO J. 2024 Apr 25.
    Presenting metabolomics analyses: what is in a number?
    Johannes Meiser, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s44318-024-00098-1
  33. Kidney Int. 2024 Apr 10. pii: S0085-2538(24)00190-X. [Epub ahead of print]
    Deciphering missense coding variants with AlphaMissense.
    Zhicheng Pan, Chandra L Theesfeld.
      
    Keywords:  machine learning; missense variant; protein structure
    DOI:  https://doi.org/10.1016/j.kint.2024.02.022
  34. Biomolecules. 2024 Mar 28. pii: 415. [Epub ahead of print]14(4):
    Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.
    Emanuele Marzetti, Biliana Lozanoska-Ochser, Riccardo Calvani, Francesco Landi, Hélio José Coelho-Júnior, Anna Picca.
      Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia-reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.
    Keywords:  aging; cytokines; inflammation; mitochondrial dysfunction; mitochondrial-derived vesicles; muscle fibrosis; muscle injury; muscle satellite cells; muscle wasting; skeletal muscle fibers
    DOI:  https://doi.org/10.3390/biom14040415
  35. Nature. 2024 Apr 24.
    Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
    Anna V Kotrys, Timothy J Durham, Xiaoyan A Guo, Venkata R Vantaku, Sareh Parangi, Vamsi K Mootha.
      Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.
    DOI:  https://doi.org/10.1038/s41586-024-07332-0
  36. Science. 2024 Apr 26. 384(6694): 438-446
    Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
    Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.
      Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.
    DOI:  https://doi.org/10.1126/science.adk1005
  37. J Mater Chem B. 2024 Apr 23.
    A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
    Deeksha Rajput, Nachiket Pradhan, Shabnam Mansuri, Virupakshi Soppina, Sriram Kanvah.
      This paper explores the use of a di-cationic fluorophore for visualizing mitochondria in live cells independent of membrane potential. Through the synthesized di-cationic fluorophore, we investigate the monitoring of viscosity, ferroptosis, stress-induced mitophagy, and lysosomal uptake of damaged mitochondria. The designed fluorophore is based on DQAsomes, cationic vesicles responsible for transporting drugs and DNA to mitochondria. The symmetric fluorophores possess two charge centres separated by an alkyl chain and are distinguished by a pyridinium group for mitochondrial selectivity, the C-12 alkyl substitution for membrane affinity, and an electron donor-π-acceptor fluorescent scaffold for intramolecular charge transfer. The synthesized fluorophores, PP and NP, emit wavelengths exceeding 600 nm, with a significant Stokes shift (130-211 nm), and NP demonstrates near-infrared emission (∼690 nm). Our study underscores the potential of these fluorophores for live-cell imaging, examining physiological responses such as viscosity and ferroptosis, and highlights their utility in investigating mitophagy damage and lysosomal uptake.
    DOI:  https://doi.org/10.1039/d4tb00293h
  38. Sci Rep. 2024 04 20. 14(1): 9082
    Eye movement function captured via an electronic tablet informs on cognition and disease severity in Parkinson's disease.
    Nils A Koch, Patrice Voss, J Miguel Cisneros-Franco, Alexandre Drouin-Picaro, Fama Tounkara, Simon Ducharme, Daniel Guitton, Étienne de Villers-Sidani.
      Studying the oculomotor system provides a unique window to assess brain health and function in various clinical populations. Although the use of detailed oculomotor parameters in clinical research has been limited due to the scalability of the required equipment, the development of novel tablet-based technologies has created opportunities for fast, easy, cost-effective, and reliable eye tracking. Oculomotor measures captured via a mobile tablet-based technology have previously been shown to reliably discriminate between Parkinson's Disease (PD) patients and healthy controls. Here we further investigate the use of oculomotor measures from tablet-based eye-tracking to inform on various cognitive abilities and disease severity in PD patients. When combined using partial least square regression, the extracted oculomotor parameters can explain up to 71% of the variance in cognitive test scores (e.g. Trail Making Test). Moreover, using a receiver operating characteristics (ROC) analysis we show that eye-tracking parameters can be used in a support vector classifier to discriminate between individuals with mild PD from those with moderate PD (based on UPDRS cut-off scores) with an accuracy of 90%. Taken together, our findings highlight the potential usefulness of mobile tablet-based technology to rapidly scale eye-tracking use and usefulness in both research and clinical settings by informing on disease stage and cognitive outcomes.
    DOI:  https://doi.org/10.1038/s41598-024-59750-9
  39. Cell Mol Biol Lett. 2024 Apr 23. 29(1): 59
    The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
    Yuhang Lei, Mailin Gan, Yanhao Qiu, Qiuyang Chen, Xingyu Wang, Tianci Liao, Mengying Zhao, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Li Zhu, Linyuan Shen.
      Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.
    Keywords:  Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1186/s11658-024-00572-y
  40. FEBS Lett. 2024 Apr 25.
    Insights into conformational changes in cytochrome b during the early steps of its maturation.
    Andreas Carlström, Martin Ott.
      Membrane proteins carrying redox cofactors are key subunits of respiratory chain complexes, yet the exact path of their folding and maturation remains poorly understood. Here, using cryo-EM and structure prediction via Alphafold2, we generated models of early assembly intermediates of cytochrome b (Cytb), a central subunit of complex III. The predicted structure of the first assembly intermediate suggests how the binding of Cytb to the assembly factor Cbp3-Cbp6 imposes an open configuration to facilitate the acquisition of its heme cofactors. Moreover, structure predictions of the second intermediate indicate how hemes get stabilized by binding of the assembly factor Cbp4, with a concomitant weakening of the contact between Cbp3-Cbp6 and Cytb, preparing for the release of the fully hemylated protein from the assembly factors.
    Keywords:  biogenesis; cytochrome b; membrane protein assembly; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1002/1873-3468.14888
  41. Autophagy. 2024 Apr 23. 1-12
    The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.
    Simone Patergnani, Méghane S Bataillard, Alberto Danese, Stacy Alves, Chantal Cazevieille, René Valéro, Lisbeth Tranebjærg, Tangui Maurice, Paolo Pinton, Benjamin Delprat, Elodie M Richard.
      Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.
    Keywords:  Autophagy; WFS1; Wolfram-like syndrome; mitochondria-associated endoplasmic reticulum membrane; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2341588
  42. bioRxiv. 2024 Apr 20. pii: 2024.04.16.589819. [Epub ahead of print]
    Integrative machine learning approaches for predicting disease risk using multi-omics data from the UK Biobank.
    Oscar Aguilar, Cheng Chang, Elsa Bismuth, Manuel A Rivas.
      We train prediction and survival models using multi-omics data for disease risk identification and stratification. Existing work on disease prediction focuses on risk analysis using datasets of individual data types (metabolomic, genomics, demographic), while our study creates an integrated model for disease risk assessment. We compare machine learning models such as Lasso Regression, Multi-Layer Perceptron, XG Boost, and ADA Boost to analyze multi-omics data, incorporating ROC-AUC score comparisons for various diseases and feature combinations. Additionally, we train Cox proportional hazard models for each disease to perform survival analysis. Although the integration of multi-omics data significantly improves risk prediction for 8 diseases, we find that the contribution of metabolomic data is marginal when compared to standard demographic, genetic, and biomarker features. Nonetheless, we see that metabolomics is a useful replacement for the standard biomarker panel when it is not readily available.
    DOI:  https://doi.org/10.1101/2024.04.16.589819
  43. Mol Neurobiol. 2024 Apr 23.
    Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.
    Laura Bierhansl, Lukas Gola, Venu Narayanan, Andre Dik, Sven G Meuth, Heinz Wiendl, Stjepana Kovac.
      Epilepsy is one of the most common neurological disorders in the world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent the emergence of seizures. However, up to a third of the patients suffer from drug-resistant epilepsy, and there is an urgent need to develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics that also might have effects on chronic epilepsy comorbidities such as cognitive decline and depression. The mitochondrial calcium uniporter (MCU) mediates rapid mitochondrial Ca2+ transport through the inner mitochondrial membrane. Ca2+ influx is essential for mitochondrial functions, but longer elevations of intracellular Ca2+ levels are closely associated with seizure-induced neuronal damage, which are underlying mechanisms of cognitive decline and depression. Using neuronal-specific MCU knockout mice (MCU-/-ΔN), we demonstrate that neuronal MCU deficiency reduced hippocampal excitability in vivo. Furthermore, in vitro analyses of hippocampal glioneuronal cells reveal no change in total Ca2+ levels but differences in intracellular Ca2+ handling. MCU-/-ΔN reduces ROS production, declines metabolic fluxes, and consequently prevents glioneuronal cell death. This effect was also observed under pathological conditions, such as the low magnesium culture model of seizure-like activity or excitotoxic glutamate stimulation, whereby MCU-/-ΔN reduces ROS levels and suppresses Ca2+ overload seen in WT cells. This study highlights the importance of MCU at the interface of Ca2+ handling and metabolism as a mediator of stress-related mitochondrial dysfunction, which indicates the modulation of MCU as a potential target for future antiepileptogenic therapy.
    Keywords:  Hyperexcitability; Metabolism; Mitochondrial calcium uniporter (MCU); Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-024-04148-x
  44. J Transl Med. 2024 Apr 26. 22(1): 390
    CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.
    Ping Guo, Shuiqing Hu, Xiaohui Liu, Miaomiao He, Jie Li, Tingqiong Ma, Man Huang, Qin Fang, Yan Wang.
       BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated.
    METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments.
    RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10.
    CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.
    Keywords:  Apoptosis; CAV3; Diabetic cardiomyopathy; Mitochondrial dysfunction; NDUFA10
    DOI:  https://doi.org/10.1186/s12967-024-05223-6
  45. Res Sq. 2024 Apr 10. pii: rs.3.rs-4178088. [Epub ahead of print]
    Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.
    Chunling Chen, Ronald A Merrill, Chian Ju Jong, Stefan Strack.
      Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion ( B β 2 KO) nor fission ( Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.
    DOI:  https://doi.org/10.21203/rs.3.rs-4178088/v1
  46. Antioxidants (Basel). 2024 Apr 21. pii: 496. [Epub ahead of print]13(4):
    An AlphaFold Structure Analysis of COQ2 as Key a Component of the Coenzyme Q Synthesis Complex.
    María de Los Ángeles Vargas-Pérez, Damien Paul Devos, Guillermo López-Lluch.
      Coenzyme Q (CoQ) is a lipidic compound that is widely distributed in nature, with crucial functions in metabolism, protection against oxidative damage and ferroptosis and other processes. CoQ biosynthesis is a conserved and complex pathway involving several proteins. COQ2 is a member of the UbiA family of transmembrane prenyltransferases that catalyzes the condensation of the head and tail precursors of CoQ, which is a key step in the process, because its product is the first intermediate that will be modified in the head by the next components of the synthesis process. Mutations in this protein have been linked to primary CoQ deficiency in humans, a rare disease predominantly affecting organs with a high energy demand. The reaction catalyzed by COQ2 and its mechanism are still unknown. Here, we aimed at clarifying the COQ2 reaction by exploring possible substrate binding sites using a strategy based on homology, comprising the identification of available ligand-bound homologs with solved structures in the Protein Data Bank (PDB) and their subsequent structural superposition in the AlphaFold predicted model for COQ2. The results highlight some residues located on the central cavity or the matrix loops that may be involved in substrate interaction, some of which are mutated in primary CoQ deficiency patients. Furthermore, we analyze the structural modifications introduced by the pathogenic mutations found in humans. These findings shed new light on the understanding of COQ2's function and, thus, CoQ's biosynthesis and the pathogenicity of primary CoQ deficiency.
    Keywords:  antioxidant; coenzyme Q; mitochondria; rare disease; ubiquinol
    DOI:  https://doi.org/10.3390/antiox13040496
  47. Am J Physiol Cell Physiol. 2024 Apr 22.
    Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
    Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.
      We previously showed that the transaminase inhibitor, aminooxyacetic acid, reduced respiration energized at complex II (succinate dehydrogenase, SDH) in mitochondria isolated from mouse hindlimb muscle. The effect required a reduction in membrane potential with resultant accumulation of oxaloacetate (OAA), a potent inhibitor of SDH. To specifically assess the effect of the mitochondrial transaminase, glutamic oxaloacetic transaminase (GOT2) on complex II respiration and to determine the effect in intact cells as well as isolated mitochondria, we performed respiratory and metabolic studies in wildtype (WT) and CRISPR-generated GOT2 knockdown (KD) C2C12 myocytes. Intact cell respiration by GOT2KD cells versus WT was reduced by adding carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to lower potential. In mitochondria of C2C12 KD cells, respiration at low potential generated by 1µM FCCP and energized at complex II by 10mM succinate + 0.5mM glutamate, (but not by complex I substrates) was reduced versus WT mitochondria. Although we could not detect OAA, metabolite data suggested that OAA inhibition of SDH may have contributed to the FCCP effect. C2C12 mitochondria differed from skeletal muscle mitochondria in that the effect of FCCP on complex II respiration was not evident with ADP addition. We also observed that C2C12 cells, unlike skeletal muscle, expressed glutamate dehydrogenase, which competes with GOT2 for glutamate metabolism. In summary, GOT2 KD reduced C2C12 respiration in intact cells at low potential. From differential substrate effects, this occurred largely at complex II. Moreover, C2C12 versus muscle mitochondria differ in complex II sensitivity to ADP and differ markedly in expression of glutamate dehydrogenase.
    Keywords:  aspartate aminotransferase; mitochondria; myocytes; oxaloacetate; succinate dehydrogenase
    DOI:  https://doi.org/10.1152/ajpcell.00576.2023
  48. Front Cell Neurosci. 2024 ;18 1366098
    Micro-and mesoscale aspects of neurodegeneration in engineered human neural networks carrying the LRRK2 G2019S mutation.
    Vibeke Devold Valderhaug, Ola Huse Ramstad, Rosanne van de Wijdeven, Kristine Heiney, Stefano Nichele, Axel Sandvig, Ioanna Sandvig.
      Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been widely linked to Parkinson's disease, where the G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events related to these mutations remain poorly understood. The advancement and availability of tools for neural engineering now enable modeling of selected pathological aspects of neurodegenerative disease in human neural networks in vitro. Our study revealed distinct pathology associated dynamics in engineered human cortical neural networks carrying the LRRK2 G2019S mutation compared to healthy isogenic control neural networks. The neurons carrying the LRRK2 G2019S mutation self-organized into networks with aberrant morphology and mitochondrial dynamics, affecting emerging structure-function relationships both at the micro-and mesoscale. Taken together, the findings of our study points toward an overall heightened metabolic demand in networks carrying the LRRK2 G2019S mutation, as well as a resilience to change in response to perturbation, compared to healthy isogenic controls.
    Keywords:  LRRK2 G2019S mutation; Parkinsons disease (PD); human neural networks; mitochondrial dynamics; neurodegenerative disease model; structure–function
    DOI:  https://doi.org/10.3389/fncel.2024.1366098
  49. Biomolecules. 2024 Mar 28. pii: 411. [Epub ahead of print]14(4):
    Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue.
    Sharon Natasha Cox, Claudio Lo Giudice, Anna Lavecchia, Maria Luana Poeta, Matteo Chiara, Ernesto Picardi, Graziano Pesole.
      Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.
    Keywords:  Amyotrophic Lateral Sclerosis; WES; WGS; bioinformatic pipeline; heteroplasmy; mtDNA; nDNA; variants
    DOI:  https://doi.org/10.3390/biom14040411
  50. Trends Endocrinol Metab. 2024 Apr 24. pii: S1043-2760(24)00094-8. [Epub ahead of print]
    Mitochondrial Venus is more likely to have a lower birthweight.
    Elina Aleksejeva, Masoud Zamani Esteki, Andres Salumets.
      Assisted reproductive technologies (ART) are associated with a moderately higher risk of preterm birth and low birthweight, but the causes are unknown. A recent study by Mertens et al. reveals a link between being born through ART, ovarian stimulation, and an increased incidence of mitochondrial heteroplasmic variants that correlate with lower birthweight.
    Keywords:  assisted reproduction; birthweight; mitochondria; ovarian aging; ovarian stimulation; preterm birth
    DOI:  https://doi.org/10.1016/j.tem.2024.04.011
  51. Circulation. 2024 Apr 25.
    SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.
    Anna Kovilakath, Adolfo G Mauro, Yolander Valentine, Frank Raucci, Maryam Jamil, Christiane Carter, Jeremy Thompson, Qun Chen, Beutner Gisela, Yang Yue, Jeremy Allegood, Xiaoxin X Wang, Jordan Dail, Teja Devarakonda, Komuraiah Myakala, Jolene J Windle, Mark A Subler, David Montefusco, Belinda Willard, Ali Javaheri, Tytus Bernas, Sushil K Mahata, Moshe Levi, Jinze Liu, George A Porter, Edward J Lesnefsky, Fadi N Salloum, L Ashley Cowart.
       BACKGROUND: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3).
    METHODS: The noncanonical (d16) and canonical (d18) sphingolipidome profiles in cardiac tissues of patients with end-stage ischemic cardiomyopathy and in mice with ischemic cardiomyopathy were analyzed by targeted lipidomics. Regulation of SPTLC3 by HIF1α under ischemic conditions was determined with chromatin immunoprecipitation. Transcriptomics, lipidomics, metabolomics, echocardiography, mitochondrial electron transport chain, mitochondrial membrane fluidity, and mitochondrial membrane potential were assessed in the cSPTLC3KO transgenic mice we generated. Furthermore, morphological and functional studies were performed on cSPTLC3KO mice subjected to permanent nonreperfused myocardial infarction.
    RESULTS: Herein, we report that SPTLC3 is induced in both human and mouse models of ischemic cardiomyopathy and leads to production of atypical sphingolipids bearing 16-carbon sphingoid bases, resulting in broad changes in cell sphingolipid composition. This induction is in part attributable to transcriptional regulation by HIF1α under ischemic conditions. Furthermore, cardiomyocyte-specific depletion of SPTLC3 in mice attenuates oxidative stress, fibrosis, and hypertrophy in chronic ischemia, and mice demonstrate improved cardiac function and increased survival along with increased ketone and glucose substrate metabolism utilization. Depletion of SPTLC3 mechanistically alters the membrane environment and subunit composition of mitochondrial complex I of the electron transport chain, decreasing its activity.
    CONCLUSIONS: Our findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.
    Keywords:  cardiomyopathy; electron transport complex I; mitochondria; serine C-palmitoyltransferase; sphingolipids
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066879
  52. iScience. 2024 May 17. 27(5): 109643
    Redox signaling and skeletal muscle adaptation during aerobic exercise.
    Yingsong Zhou, Xuan Zhang, Julien S Baker, Gareth W Davison, Xiaojun Yan.
      Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.
    Keywords:  Biological sciences; Cell biology; Cellular physiology; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109643
  53. Front Bioeng Biotechnol. 2024 ;12 1372211
    Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.
    Jiaxin Qiu, Haibo Wu, Qin Xie, Yuxiao Zhou, Yining Gao, Junbo Liu, Xueyi Jiang, Lun Suo, Yanping Kuang.
      Introduction: Mitochondrial diseases caused by mtDNA have no effective cures. Recently developed DddA-derived cytosine base editors (DdCBEs) have potential therapeutic implications in rescuing the mtDNA mutations. However, the performance of DdCBEs relies on designing different targets or improving combinations of split-DddA halves and orientations, lacking knowledge of predicting the results before its application. Methods: A series of DdCBE pairs for wide ranges of aC or tC targets was constructed, and transfected into Neuro-2a cells. The mutation rate of targets was compared to figure out the potential editing rules. Results: It is found that DdCBEs mediated mtDNA editing is predictable: 1) aC targets have a concentrated editing window for mtDNA editing in comparison with tC targets, which at 5'C8-11 (G1333) and 5'C10-13 (G1397) for aC target, while 5'C4-13 (G1333) and 5'C5-14 (G1397) for tC target with 16bp spacer. 2) G1333 mediated C>T conversion at aC targets in DddA-half-specific manner, while G1333 and G1397 mediated C>T conversion are DddA-half-prefer separately for tC and aC targets. 3) The nucleotide adjacent to the 3' end of aC motif affects mtDNA editing. Finally, by the guidance of these rules, a cell model harboring a pathogenic mtDNA mutation was constructed with high efficiency and no bystander effects. Discussion: In summary, this discovery helps us conceive the optimal strategy for accurate mtDNA editing, avoiding time- and effort-consuming optimized screening jobs.
    Keywords:  DdCBEs; gene editing; mitochondrial genome; mtDNA; predictability
    DOI:  https://doi.org/10.3389/fbioe.2024.1372211
  54. Curr Opin Pediatr. 2024 Jun 01. 36(3): 331-341
    Emerging therapies for childhood-onset movement disorders.
    Lindsey Vogt, Vicente Quiroz, Darius Ebrahimi-Fakhari.
       PURPOSE OF REVIEW: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying).
    RECENT FINDINGS: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound.
    SUMMARY: Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.
    DOI:  https://doi.org/10.1097/MOP.0000000000001354
  55. Neurobiol Dis. 2024 Apr 20. pii: S0969-9961(24)00105-0. [Epub ahead of print] 106506
    Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.
    Chiara Buoso, Markus Seifert, Martin Lang, Corey M Griffith, Begoña Talavera Andújar, Maria Paulina Castelo Rueda, Christine Fischer, Carolina Doerrier, Heribert Talasz, Alessandra Zanon, Peter P Pramstaller, Emma L Schymanski, Irene Pichler, Guenter Weiss.
      Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.
    Keywords:  Dopamine; Iron; Mitochondrial function; Parkinson's disease; hiPSC-derived neurons
    DOI:  https://doi.org/10.1016/j.nbd.2024.106506
  56. Cell Rep Med. 2024 Apr 14. pii: S2666-3791(24)00187-3. [Epub ahead of print] 101518
    Genome-first evaluation with exome sequence and clinical data uncovers underdiagnosed genetic disorders in a large healthcare system.
    Iain S Forrest, Áine Duffy, Joshua K Park, Ha My T Vy, Louis R Pasquale, Girish N Nadkarni, Judy H Cho, Ron Do.
      Population-based genomic screening may help diagnose individuals with disease-risk variants. Here, we perform a genome-first evaluation for nine disorders in 29,039 participants with linked exome sequences and electronic health records (EHRs). We identify 614 individuals with 303 pathogenic/likely pathogenic or predicted loss-of-function (P/LP/LoF) variants, yielding 644 observations; 487 observations (76%) lack a corresponding clinical diagnosis in the EHR. Upon further investigation, 75 clinically undiagnosed observations (15%) have evidence of symptomatic untreated disease, including familial hypercholesterolemia (3 of 6 [50%] undiagnosed observations with disease evidence) and breast cancer (23 of 106 [22%]). These genetic findings enable targeted phenotyping that reveals new diagnoses in previously undiagnosed individuals. Disease yield is greater with variants in penetrant genes for which disease is observed in carriers in an independent cohort. The prevalence of P/LP/LoF variants exceeds that of clinical diagnoses, and some clinically undiagnosed carriers are discovered to have disease. These results highlight the potential of population-based genomic screening.
    Keywords:  American College of Medical Genetics and Genomics; biobank; breast cancer; cardiomyopathy; electronic health record; exome sequence; genome-first; penetrance; precision medicine; underdiagnosis
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101518
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