bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023‒11‒26
forty-nine papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial phosphoproteomes are functionally specialized across tissues.
  2. Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.
  3. Mechanisms of stress management in mitochondrial protein import.
  4. Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
  5. Progress in diagnosis and treatment of Leber's hereditary optic neuropathy.
  6. Structure and biochemical characterization of L-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of L-2-hydroxyglutaric aciduria.
  7. Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
  8. Mitochondrial DNA and Inflammation in Alzheimer's Disease.
  9. Co-fractionation-mass spectrometry to characterize native mitochondrial protein assemblies in mammalian neurons and brain.
  10. Assessing the Role of Post-Translational Modifications of Mitochondrial RNA Polymerase.
  11. Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.
  12. Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
  13. Exploring the Role of Mitochondrial Hydrogen Sulfide in Maintaining Polarity and mtDNA Integrity with a Multichannel Fluorescent Probe.
  14. Mitochondrial Calcium Waves by Electrical Stimulation in Cultured Hippocampal Neurons.
  15. Nicotinamide Riboside Supplementation Restores Myocardial Nicotinamide Adenine Dinucleotide Levels, Improves Survival, and Promotes Protective Environment Post Myocardial Infarction.
  16. Status of Mitochondrial Oxidative Phosphorylation during the Development of Heart Failure.
  17. In vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor.
  18. The mitochondrial calcium uniporter is necessary for synaptic plasticity and proper mitochondrial morphology and distribution in the distal dendrites of CA2 neurons.
  19. Federated Learning for multi-omics: a performance evaluation in Parkinson's disease.
  20. Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy.
  21. Mitochondrial Proteomes in Neural Cells: A Systematic Review.
  22. Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
  23. Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I.
  24. HLA-Homozygous iPSC-Derived Mesenchymal Stem Cells Rescue Rotenone-Induced Experimental Leber's Hereditary Optic Neuropathy-like Models In Vitro and In Vivo.
  25. Targeting Mitochondrial Dysfunction and Oxidative Stress to Prevent the Neurodegeneration of Retinal Ganglion Cells.
  26. Deep learning-based phenotype imputation on population-scale biobank data increases genetic discoveries.
  27. NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders.
  28. The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.
  29. Towards robust clinical genome interpretation: developing a consistent terminology to characterize Mendelian disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.
  30. A century of the Warburg effect.
  31. A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.
  32. Vitamin B12-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice.
  33. Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.
  34. A machine learning method to process voice samples for identification of Parkinson's disease.
  35. CHARR efficiently estimates contamination from DNA sequencing data.
  36. Benchmark Dataset for Training Machine Learning Models to Predict the Pathway Involvement of Metabolites.
  37. Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.
  38. Omics data integration suggests a potential idiopathic Parkinson's disease signature.
  39. Purification and characterization of different proteasome species from mammalian cells.
  40. Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production.
  41. Towards personalized genome-scale modeling of inborn errors of metabolism for systems medicine applications.
  42. Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review.
  43. Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing.
  44. Quick tips for interpreting cell death experiments.
  45. How AI is expanding art history.
  46. Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases.
  47. Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing.
  48. Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.
  49. The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.
  1. Life Sci Alliance. 2024 Feb;pii: e202302147. [Epub ahead of print]7(2):
    Mitochondrial phosphoproteomes are functionally specialized across tissues.
    Fynn M Hansen, Laura S Kremer, Ozge Karayel, Isabell Bludau, Nils-Göran Larsson, Inge Kühl, Matthias Mann.
      Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins (mitophos.de). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.
    DOI:  https://doi.org/10.26508/lsa.202302147
  2. Hum Mol Genet. 2023 Nov 21. pii: ddad194. [Epub ahead of print]
    Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.
    Stuart J Cannon, Timothy Hall, Gareth Hawkes, Kevin Colclough, Roisin M Boggan, Caroline F Wright, Sarah J Pickett, Andrew T Hattersley, Michael N Weedon, Kashyap A Patel.
      BACKGROUND: Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population.METHOD: Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes.
    RESULTS: We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5 respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk.
    CONCLUSION: Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.
    Keywords:  UK biobank; maternally inherited diabetes and deafness; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.1093/hmg/ddad194
  3. Biochem Soc Trans. 2023 Nov 21. pii: BST20230377. [Epub ahead of print]
    Mechanisms of stress management in mitochondrial protein import.
    Maryam Mukhtar, Krutika Thakkur, Agnieszka Chacinska, Piotr Bragoszewski.
      Mitochondria are vital to the functions of eukaryotic cells. Most mitochondrial proteins are transported into the organelle following their synthesis by cytoplasmic ribosomes. However, precise protein targeting is complex because the two diverse lipid membranes encase mitochondria. Efficient protein translocation across membranes and accurate sorting to specific sub-compartments require the cooperation of multiple factors. Any failure in mitochondrial protein import can disrupt organelle fitness. Proteins intended for mitochondria make up a significant portion of all proteins produced in the cytosol. Therefore, import defects causing their mislocalization can significantly stress cellular protein homeostasis. Recognition of this phenomenon has increased interest in molecular mechanisms that respond to import-related stress and restore proteostasis, which is the focus of this review. Significantly, disruptions in protein homeostasis link strongly to the pathology of several degenerative disorders highly relevant in ageing societies. A comprehensive understanding of protein import quality control will allow harnessing this machinery in therapeutic approaches.
    Keywords:  mitochondria; protein degradation; protein transport; proteostasis; proteotoxicity; stress
    DOI:  https://doi.org/10.1042/BST20230377
  4. Nat Commun. 2023 11 18. 14(1): 7525
    Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
    Alon Stern, Mariam Fokra, Boris Sarvin, Ahmad Abed Alrahem, Won Dong Lee, Elina Aizenshtein, Nikita Sarvin, Tomer Shlomi.
      The inability to inspect metabolic activities within distinct subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Previous work addressed this challenge by analyzing metabolism in isolated organelles, which grossly bias metabolic activity. Here, we describe a method for inferring physiological metabolic fluxes and metabolite concentrations in mitochondria and cytosol based on isotope tracing experiments performed with intact cells. This is made possible by computational deconvolution of metabolite isotopic labeling patterns and concentrations into cytosolic and mitochondrial counterparts, coupled with metabolic and thermodynamic modelling. Our approach lowers the uncertainty regarding compartmentalized fluxes and concentrations by one and three orders of magnitude compared to existing modelling approaches, respectively. We derive a quantitative view of mitochondrial and cytosolic metabolic activities in central carbon metabolism across cultured cell lines without performing cell fractionation, finding major variability in compartmentalized malate-aspartate shuttle fluxes. We expect our approach for inferring metabolism at a subcellular resolution to be instrumental for a variety of studies of metabolic dysfunction in human disease and for bioengineering.
    DOI:  https://doi.org/10.1038/s41467-023-42824-z
  5. J Mol Med (Berl). 2023 Nov 20.
    Progress in diagnosis and treatment of Leber's hereditary optic neuropathy.
    Qingyue Ma, Ying Sun, Ke Lei, Wenjuan Luo.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease with central vision loss as the main symptom. It is one of the diseases that cause vision loss and optic atrophy in young and middle-aged people. The mutations of these three primary mitochondrial mutations, m.11778G>A, m.14484T>C, and m.3460G>A, are the main molecular basis, but their pathogenesis is also affected by nuclear genes, mitochondrial genetic background, and environmental factors. This article summarizes the research progress on molecular pathogenesis, clinical symptoms, and treatment of LHON in recent years, aiming to summarize the genetic pathogenesis and clinical treatment points of LHON.
    Keywords:  Diagnosis; Leber’s hereditary optic neuropathy; Progress; Treatment; mtDNA
    DOI:  https://doi.org/10.1007/s00109-023-02389-2
  6. J Biol Chem. 2023 Nov 21. pii: S0021-9258(23)02519-X. [Epub ahead of print] 105491
    Structure and biochemical characterization of L-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of L-2-hydroxyglutaric aciduria.
    Jun Yang, Xingchen Chen, Shan Jin, Jianping Ding.
      L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane associated metabolic enzyme, which catalyzes the oxidation of L-2-hydroxyglutarate (L-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of L-2-HG which causes a neurometabolic disorder named L-2-hydroxyglutaric aciduria (L-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH in FAD-bound form and in complex with FAD and 2-OG, and show that dmL2HGDH exhibits high activity and substrate specificity for L-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction, and showed that most of the mutations of dmL2HGDH equivalent to L-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH, and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of L-2-HGA.
    Keywords:  2-hydroxyglutaric aciduria; L-2-hydroxyglutarate dehydrogenase; catalytic mechanism; protein crystallography; substrate specificity
    DOI:  https://doi.org/10.1016/j.jbc.2023.105491
  7. Cell Rep. 2023 Nov 23. pii: S2211-1247(23)01484-5. [Epub ahead of print]42(12): 113472
    Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
    Qixin Chen, Liu-Yi Liu, Zhiqi Tian, Zhou Fang, Kang-Nan Wang, Xintian Shao, Chengying Zhang, Weiwei Zou, Fiona Rowan, Kangqiang Qiu, Baohua Ji, Jun-Lin Guan, Dechang Li, Zong-Wan Mao, Jiajie Diao.
      Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs. By combining mtGLP with structured illumination microscopy to monitor mitochondrial dynamics, we discover the formation of nucleoid condensates in damaged mitochondria. We further reveal that nucleoid condensates promoted the peripheral fission of damaged mitochondria via asymmetric segregation. Through simulations, we find that the peripheral fission events occurred when the nucleoid condensates interacted with the highly curved membrane regions at the two ends of the mitochondria. Overall, we show that mitochondrial nucleoid condensates utilize peripheral fission to maintain mitochondrial homeostasis.
    Keywords:  CP: Cell biology; chemical biology
    DOI:  https://doi.org/10.1016/j.celrep.2023.113472
  8. Curr Issues Mol Biol. 2023 Oct 25. 45(11): 8586-8606
    Mitochondrial DNA and Inflammation in Alzheimer's Disease.
    Giacoma Galizzi, Marta Di Carlo.
      Mitochondrial dysfunction and neuroinflammation are implicated in the pathogenesis of most neurodegenerative diseases, such as Alzheimer's disease (AD). In fact, although a growing number of studies show crosstalk between these two processes, there remain numerous gaps in our knowledge of the mechanisms involved, which requires further clarification. On the one hand, mitochondrial dysfunction may lead to the release of mitochondrial damage-associated molecular patterns (mtDAMPs) which are recognized by microglial immune receptors and contribute to neuroinflammation progression. On the other hand, inflammatory molecules released by glial cells can influence and regulate mitochondrial function. A deeper understanding of these mechanisms may help identify biomarkers and molecular targets useful for the treatment of neurodegenerative diseases. This review of works published in recent years is focused on the description of the mitochondrial contribution to neuroinflammation and neurodegeneration, with particular attention to mitochondrial DNA (mtDNA) and AD.
    Keywords:  Alzheimer’s disease; DAMPs; glia; microglia; mitochondria; mitochondrial dysfunction; mtDNA; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3390/cimb45110540
  9. Nat Protoc. 2023 Nov 20.
    Co-fractionation-mass spectrometry to characterize native mitochondrial protein assemblies in mammalian neurons and brain.
    Mara Zilocchi, Matineh Rahmatbakhsh, Mohamed Taha Moutaoufik, Kirsten Broderick, Alla Gagarinova, Matthew Jessulat, Sadhna Phanse, Hiroyuki Aoki, Khaled A Aly, Mohan Babu.
      Human mitochondrial (mt) protein assemblies are vital for neuronal and brain function, and their alteration contributes to many human disorders, e.g., neurodegenerative diseases resulting from abnormal protein-protein interactions (PPIs). Knowledge of the composition of mt protein complexes is, however, still limited. Affinity purification mass spectrometry (MS) and proximity-dependent biotinylation MS have defined protein partners of some mt proteins, but are too technically challenging and laborious to be practical for analyzing large numbers of samples at the proteome level, e.g., for the study of neuronal or brain-specific mt assemblies, as well as altered mtPPIs on a proteome-wide scale for a disease of interest in brain regions, disease tissues or neurons derived from patients. To address this challenge, we adapted a co-fractionation-MS platform to survey native mt assemblies in adult mouse brain and in human NTERA-2 embryonal carcinoma stem cells or differentiated neuronal-like cells. The workflow consists of orthogonal separations of mt extracts isolated from chemically cross-linked samples to stabilize PPIs, data-dependent acquisition MS to identify co-eluted mt protein profiles from collected fractions and a computational scoring pipeline to predict mtPPIs, followed by network partitioning to define complexes linked to mt functions as well as those essential for neuronal and brain physiological homeostasis. We developed an R/CRAN software package, Macromolecular Assemblies from Co-elution Profiles for automated scoring of co-fractionation-MS data to define complexes from mtPPI networks. Presently, the co-fractionation-MS procedure takes 1.5-3.5 d of proteomic sample preparation, 31 d of MS data acquisition and 8.5 d of data analyses to produce meaningful biological insights.
    DOI:  https://doi.org/10.1038/s41596-023-00901-z
  10. Int J Mol Sci. 2023 Nov 07. pii: 16050. [Epub ahead of print]24(22):
    Assessing the Role of Post-Translational Modifications of Mitochondrial RNA Polymerase.
    Karlie R Platz, Emma J Rudisel, Katelynn V Paluch, Taylor R Laurin, Kristin E Dittenhafer-Reed.
      The mitochondrial proteome is subject to abundant post-translational modifications, including lysine acetylation and phosphorylation of serine, threonine, and tyrosine. The biological function of the majority of these protein modifications is unknown. Proteins required for the transcription and translation of mitochondrial DNA (mtDNA) are subject to modification. This suggests that reversible post-translational modifications may serve as a regulatory mechanism for mitochondrial gene transcription, akin to mechanisms controlling nuclear gene expression. We set out to determine whether acetylation or phosphorylation controls the function of mitochondrial RNA polymerase (POLRMT). Mass spectrometry was used to identify post-translational modifications on POLRMT. We analyzed three POLRMT modification sites (lysine 402, threonine 315, threonine 993) found in distinct structural regions. Amino acid point mutants that mimic the modified and unmodified forms of POLRMT were employed to measure the effect of acetylation or phosphorylation on the promoter binding ability of POLRMT in vitro. We found a slight decrease in binding affinity for the phosphomimic at threonine 315. We did not identify large changes in viability, mtDNA content, or mitochondrial transcript level upon overexpression of POLRMT modification mimics in HeLa cells. Our results suggest minimal biological impact of the POLRMT post-translational modifications studied in our system.
    Keywords:  acetylation; mitochondrial DNA; mitochondrial genome; mitochondrial proteins; phosphorylation; post-translational protein modification; transcription
    DOI:  https://doi.org/10.3390/ijms242216050
  11. Genes (Basel). 2023 Oct 24. pii: 1981. [Epub ahead of print]14(11):
    Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.
    Emmanuelle C Genin, Mélanie Abou-Ali, Véronique Paquis-Flucklinger.
      Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.
    Keywords:  ALS genes; CHCHD10; amyotrophic lateral sclerosis; frontotemporal dementia; mitochondria; motor neuron disease
    DOI:  https://doi.org/10.3390/genes14111981
  12. J Cell Biol. 2024 Jan 01. pii: e202305048. [Epub ahead of print]223(1):
    Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
    Anupama Tiwari, Arsalan Hashemiaghdam, Marissa A Laramie, Dario Maschi, Tristaan Haddad, Marion I Stunault, Carmen Bergom, Ali Javaheri, Vitaly Klyachko, Ghazaleh Ashrafi.
      Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.
    DOI:  https://doi.org/10.1083/jcb.202305048
  13. Anal Chem. 2023 Nov 21.
    Exploring the Role of Mitochondrial Hydrogen Sulfide in Maintaining Polarity and mtDNA Integrity with a Multichannel Fluorescent Probe.
    Shuai Mu, Taihe Han, Xiaoyun Zhang, Jia Liu, Huipeng Sun, Jinlong Zhang, Xiaoyan Liu, Haixia Zhang.
      Abnormal mitochondrial state has been implicated in the pathogenesis of various diseases including neurodegenerative disorders, myopathies, cardiovascular diseases, and cancers. Assessing mitochondrial functionality can be achieved by monitoring alterations in mitochondrial polarity and mitochondrial DNA (mtDNA) integrity, which serve as valuable biomarkers. Hydrogen sulfide (H2S), a gaseous signaling molecule, plays a regulatory role in mitochondrial respiratory chain activity, ATP synthesis, and calcium ion balance, thereby influencing cellular metabolism and signal transduction. Investigating the interplay between mitochondrial H2S, polarity, and mtDNA can enhance our understanding of the underlying regulatory mechanisms involved in H2S-mediated mitochondrial functions. To address this, we designed a mitochondria-targeted multichannel fluorescent probe, HNA, capable of cascaded detection of H2S and polarity, as well as parallel detection of mtDNA. The probe exhibited a significant turn-on response to H2S, emitting at approximately 604 nm, while the product HNAP demonstrated high sensitivity to polarity within the wavelength range of 526-591 nm. Additionally, the probe was able to bind to DNA, resulting in an enhanced long-wave emission at 668 nm. Facilitated by HNA, our study provides novel insights into the role of mitochondrial H2S in maintaining mitochondrial polarity and validates its protective effect on mtDNA through antioxidative mechanisms. Overall, this work proposes a potential therapeutic strategy for modulating the inflammatory process in mitochondrial-related diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.3c03663
  14. Mol Neurobiol. 2023 Nov 23.
    Mitochondrial Calcium Waves by Electrical Stimulation in Cultured Hippocampal Neurons.
    Yunkyung Eom, Sung Rae Kim, Yeong-Kyeong Kim, Sung Hoon Lee.
      Mitochondria are critical to cellular Ca2+ homeostasis via the sequestering of cytosolic Ca2+ in the mitochondrial matrix. Mitochondrial Ca2+ buffering regulates neuronal activity and neuronal death by shaping cytosolic and presynaptic Ca2+ or controlling energy metabolism. Dysfunction in mitochondrial Ca2+ buffering has been implicated in psychological and neurological disorders. Ca2+ wave propagation refers to the spreading of Ca2+ for buffering and maintaining the associated rise in Ca2+ concentration. We investigated mitochondrial Ca2+ waves in hippocampal neurons using genetically encoded Ca2+ indicators. Neurons transfected with mito-GCaMP5G, mito-RCaMP1h, and CEPIA3mt exhibited evidence of mitochondrial Ca2+ waves with electrical stimulation. These waves were observed with 200 action potentials at 40 Hz or 20 Hz but not with lower frequencies or fewer action potentials. The application of inhibitors of mitochondrial calcium uniporter and oxidative phosphorylation suppressed mitochondrial Ca2+ waves. However, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-d-aspartate receptor blockade had no effect on mitochondrial Ca2+ wave were propagation. The Ca2+ waves were not observed in endoplasmic reticula, presynaptic terminals, or cytosol in association with electrical stimulation of 200 action potentials at 40 Hz. These results offer novel insights into the mechanisms underlying mitochondrial Ca2+ buffering and the molecular basis of mitochondrial Ca2+ waves in neurons in response to electrical stimulation.
    Keywords:  Ca2+ waves; Electrical stimulation; Genetically encoded calcium indicators; Hippocampal neurons; Mitochondria
    DOI:  https://doi.org/10.1007/s12035-023-03795-w
  15. Cardiovasc Drugs Ther. 2023 Nov 24.
    Nicotinamide Riboside Supplementation Restores Myocardial Nicotinamide Adenine Dinucleotide Levels, Improves Survival, and Promotes Protective Environment Post Myocardial Infarction.
    Cynthia Tannous, Rana Ghali, Ahmed Karoui, Nada J Habeichi, Ghadir Amin, George W Booz, Mathias Mericskay, Marwan Refaat, Fouad A Zouein.
      AIMS: Myocardial infarction (MI) is a major cause of death. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme in oxidative phosphorylation and substrate of sirtuins and poly-ADP ribose polymerases, enzymes critical for cardiac remodeling post-MI. Decreased NAD+ is reported in several heart failure models with paradoxically an upregulation of nicotinamide riboside kinase 2, which uses nicotinamide riboside (NR) as substrate in an NAD+ biosynthetic pathway. We hypothesized that stimulating nicotinamide riboside kinase 2 pathway by NR supplementation exerts cardioprotective effects.METHODS AND RESULTS: MI was induced by LAD ligation in 2-3-month-old male mice. NR was administered daily (1 µmole/g body weight) over 7 days. RT-PCR showed a 60-fold increase in nicotinamide riboside kinase 2 expression 4 days post-MI with a 60% drop in myocardial NAD+ and overall survival of 61%. NR restored NAD+ levels and improved survival to 92%. Assessment of respiration in cardiac fibers revealed mitochondrial dysfunction post-MI, and NR improved complexes II and IV activities and citrate synthase activity, a measure of mitochondrial content. Additionally, NR reduced elevated PARP1 levels and activated a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response.
    CONCLUSION: Our data show that nicotinamide riboside could be useful for MI management.
    Keywords:  Cardiac remodeling; Cytokine; Energy metabolism; Inflammation
    DOI:  https://doi.org/10.1007/s10557-023-07525-1
  16. Antioxidants (Basel). 2023 Oct 31. pii: 1941. [Epub ahead of print]12(11):
    Status of Mitochondrial Oxidative Phosphorylation during the Development of Heart Failure.
    Sukhwinder K Bhullar, Naranjan S Dhalla.
      Mitochondria are specialized organelles, which serve as the "Power House" to generate energy for maintaining heart function. These organelles contain various enzymes for the oxidation of different substrates as well as the electron transport chain in the form of Complexes I to V for producing ATP through the process of oxidative phosphorylation (OXPHOS). Several studies have shown depressed OXPHOS activity due to defects in one or more components of the substrate oxidation and electron transport systems which leads to the depletion of myocardial high-energy phosphates (both creatine phosphate and ATP). Such changes in the mitochondria appear to be due to the development of oxidative stress, inflammation, and Ca2+-handling abnormalities in the failing heart. Although some investigations have failed to detect any changes in the OXPHOS activity in the failing heart, such results appear to be due to a loss of Ca2+ during the mitochondrial isolation procedure. There is ample evidence to suggest that mitochondrial Ca2+-overload occurs, which is associated with impaired mitochondrial OXPHOS activity in the failing heart. The depression in mitochondrial OXPHOS activity may also be due to the increased level of reactive oxygen species, which are formed as a consequence of defects in the electron transport complexes in the failing heart. Various metabolic interventions which promote the generation of ATP have been reported to be beneficial for the therapy of heart failure. Accordingly, it is suggested that depression in mitochondrial OXPHOS activity plays an important role in the development of heart failure.
    Keywords:  cardiac dysfunction; heart failure; mitochondrial Ca2+-overload; mitochondrial electron transport chain; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.3390/antiox12111941
  17. Nat Commun. 2023 Nov 24. 14(1): 7722
    In vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor.
    Yanan Li, Yonghua Wu, Ru Xu, Jialing Guo, Fenglei Quan, Yongyuan Zhang, Di Huang, Yiran Pei, Hua Gao, Wei Liu, Junjie Liu, Zhenzhong Zhang, Ruijie Deng, Jinjin Shi, Kaixiang Zhang.
      Mutations in mitochondrial DNA (mtDNA) play critical roles in many human diseases. In vivo visualization of cells bearing mtDNA mutations is important for resolving the complexity of these diseases, which remains challenging. Here we develop an integrated nano Cas12a sensor (InCasor) and show its utility for efficient imaging of mtDNA mutations in live cells and tumor-bearing mouse models. We co-deliver Cas12a/crRNA, fluorophore-quencher reporters and Mg2+ into mitochondria. This process enables the activation of Cas12a's trans-cleavage by targeting mtDNA, which efficiently cleave reporters to generate fluorescent signals for robustly sensing and reporting single-nucleotide variations (SNVs) in cells. Since engineered crRNA significantly increase Cas12a's sensitivity to mismatches in mtDNA, we can identify tumor tissue and metastases by visualizing cells with mutant mtDNAs in vivo using InCasor. This CRISPR imaging nanoprobe holds potential for applications in mtDNA mutation-related basic research, diagnostics and gene therapies.
    DOI:  https://doi.org/10.1038/s41467-023-43552-0
  18. bioRxiv. 2023 Nov 11. pii: 2023.11.10.566606. [Epub ahead of print]
    The mitochondrial calcium uniporter is necessary for synaptic plasticity and proper mitochondrial morphology and distribution in the distal dendrites of CA2 neurons.
    Katy E Pannoni, Quentin S Fischer, Renesa Tarannum, Mikel L Cawley, Mayd M Alsalman, Nicole Acosta, Chisom Ezigbo, Daniela V Gil, Logan A Campbell, Shannon Farris.
      Mitochondria are dynamic organelles that are morphologically and functionally diverse across different cell types and subcellular compartments in order to meet unique energy demands. In neurons, mitochondria are critical to support synapses and synaptic plasticity. However, the mechanisms regulating mitochondria in synaptic plasticity are largely unknown. The mitochondrial calcium uniporter (MCU) regulates calcium entry into the mitochondria, which in turn regulates the bioenergetics and distribution of mitochondria to active synapses. Evidence suggests that calcium influx via MCU couples neuronal activity to mitochondrial metabolism and ATP production, which would allow neurons to rapidly adapt to changing energy demands. Intriguingly, MCU is uniquely enriched in CA2 distal dendrites relative to neighboring CA1 or CA3 distal dendrites, suggesting mitochondria there are molecularly distinct. However, the functional significance of this enrichment is not clear. Synapses onto CA2 distal dendrites, unlike synapses onto CA2 proximal dendrites, readily undergo long-term potentiation (LTP), but the mechanisms underlying the different plasticity profiles are unknown. Therefore, we investigated the role of MCU in regulating dendritic mitochondria and synaptic plasticity in CA2 distal dendrites. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU is required for LTP at CA2 distal dendrite synapses. Loss of LTP correlated with a trend for decreased spine density in CA2 distal dendrites of cKO mice compared to control (CTL) mice, which was predominantly seen in immature spines Moreover, mitochondria were significantly smaller and more numerous across all dendritic layers of CA2 in cKO mice compared to CTL mice, suggesting an overall increase in mitochondrial fragmentation. Fragmented mitochondria might have functional changes, such as altered ATP production, that might explain a deficit in synaptic plasticity. Collectively, our data reveal that MCU regulates layer-specific forms of plasticity in CA2 dendrites, potentially by maintaining proper mitochondria morphology and distribution within dendrites. Differences in MCU expression across different cell types and circuits might be a general mechanism to tune the sensitivity of mitochondria to cytoplasmic calcium levels to power synaptic plasticity.MAIN TAKE HOME POINTS: The mitochondrial calcium uniporter regulates plasticity selectively at synapses in CA2 distal dendrites.The MCU-cKO induced LTP deficit at synapses in CA2 distal dendrites correlates with a trending reduction in spine density.Loss of MCU in CA2 results in ultrastructural changes in dendritic mitochondria that suggest an increase in mitochondrial fragmentation. These ultrastructural changes could result in functional consequences, such as decreased ATP production, that could underlie the plasticity deficit.
    DOI:  https://doi.org/10.1101/2023.11.10.566606
  19. bioRxiv. 2023 Oct 06. pii: 2023.10.04.560604. [Epub ahead of print]
    Federated Learning for multi-omics: a performance evaluation in Parkinson's disease.
    Benjamin Danek, Mary B Makarious, Anant Dadu, Dan Vitale, Mike A Nalls, Jimeng Sun, Faraz Faghri.
      While machine learning (ML) research has recently grown more in popularity, its application in the omics domain is constrained by access to sufficiently large, high-quality datasets needed to train ML models. Federated Learning (FL) represents an opportunity to enable collaborative curation of such datasets among participating institutions. We compare the simulated performance of several models trained using FL against classically trained ML models on the task of multi-omics Parkinson's Disease prediction. We find that FL model performance tracks centrally trained ML models, where the most performant FL model achieves an AUC-PR of 0.876 ± 0.009, 0.014 ± 0.003 less than its centrally trained variation. We also determine that the dispersion of samples within a federation plays a meaningful role in model performance. Our study implements several open source FL frameworks and aims to highlight some of the challenges and opportunities when applying these collaborative methods in multi-omics studies.The Bigger Picture: The wide-scale application of Artificial Intelligence and computationally intensive analytical approaches in the biomedical and clinical domain is largely restricted by access to sufficient training data. This data scarcity exists due to the siloed nature of biomedical and clinical institutions, mandated by patient privacy policies in the health system or government legislation. The authors study the feasibility of applying Federated Learning (FL), a machine learning approach that facilitates sample-private, collaborative model training, to multi-omics Parkinson's disease prediction. Additionally, the authors describe the performance characteristics that FL exhibits to better understand the opportunities and challenges in applying such methods in the broader biomedical research community. Federated Learning approach will enable more productive and resource-efficient collaborations across research institutions; it provides access to high-quality datasets and enhances deeper analysis and, ultimately, the nascence of large-scale precision medicine studies.
    DOI:  https://doi.org/10.1101/2023.10.04.560604
  20. Int J Mol Sci. 2023 Nov 16. pii: 16412. [Epub ahead of print]24(22):
    Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy.
    Claudia Theys, Joe Ibrahim, Ligia Mateiu, Archibold Mposhi, Laura García-Pupo, Tim De Pooter, Peter De Rijk, Mojca Strazisar, İkbal Agah İnce, Iuliana Vintea, Marianne G Rots, Wim Vanden Berghe.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This hepatic lipotoxicity is associated with a dysregulation of the first step in lipid catabolism, known as beta oxidation, which occurs in the mitochondrial matrix. Eventually, this dysregulation will lead to mitochondrial dysfunction. To evaluate the possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction, we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and, to a lesser extent, CpG methylation increase bile acid metabolic gene expression, inducing the onset of cholestasis through mito-nuclear epigenetic reprogramming. Moreover, both increase the expression of metabolic nuclear receptors and thereby induce basal overactivation of mitochondrial respiration. The latter promotes mitochondrial swelling, favoring lipid accumulation and metabolic-stress-induced mitophagy and autophagy stress responses. In conclusion, both mitochondrial GpC and CpG methylation create a metabolically challenging environment that induces mitochondrial dysfunction, which may contribute to the progression of MASLD.
    Keywords:  MASLD; autophagy; bile acid metabolism; cholestasis; lipid metabolism; mitochondrial epigenetics
    DOI:  https://doi.org/10.3390/ijms242216412
  21. Biomolecules. 2023 Nov 11. pii: 1638. [Epub ahead of print]13(11):
    Mitochondrial Proteomes in Neural Cells: A Systematic Review.
    Aya Nusir, Patricia Sinclair, Nadine Kabbani.
      Mitochondria are ancient endosymbiotic double membrane organelles that support a wide range of eukaryotic cell functions through energy, metabolism, and cellular control. There are over 1000 known proteins that either reside within the mitochondria or are transiently associated with it. These mitochondrial proteins represent a functional subcellular protein network (mtProteome) that is encoded by mitochondrial and nuclear genomes and significantly varies between cell types and conditions. In neurons, the high metabolic demand and differential energy requirements at the synapses are met by specific modifications to the mtProteome, resulting in alterations in the expression and functional properties of the proteins involved in energy production and quality control, including fission and fusion. The composition of mtProteomes also impacts the localization of mitochondria in axons and dendrites with a growing number of neurodegenerative diseases associated with changes in mitochondrial proteins. This review summarizes the findings on the composition and properties of mtProteomes important for mitochondrial energy production, calcium and lipid signaling, and quality control in neural cells. We highlight strategies in mass spectrometry (MS) proteomic analysis of mtProteomes from cultured cells and tissue. The research into mtProteome composition and function provides opportunities in biomarker discovery and drug development for the treatment of metabolic and neurodegenerative disease.
    Keywords:  bioinformatics; energetics; evolution; mass spectrometry; neurodegeneration; protein quantification; synapses
    DOI:  https://doi.org/10.3390/biom13111638
  22. Nat Metab. 2023 Nov 20.
    Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
    Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang, Jian-Guo Chen.
      Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.
    DOI:  https://doi.org/10.1038/s42255-023-00924-6
  23. Sci Rep. 2023 Nov 21. 13(1): 20413
    Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I.
    Jason Tae Yi, Panyue Wang, Alexei A Stuchebrukhov.
      In all resolved structures of complex I, there exists a tunnel-like Q-chamber for ubiquinone binding and reduction. The entrance to the Q-chamber in ND1 subunit forms a narrow bottleneck, which is rather tight and requires thermal conformational changes for ubiquinone to get in and out of the binding chamber. The substitution of alanine with threonine at the bottleneck (AlaThr MUT), associated with 3460/ND1 mtDNA mutation in human complex I, is implicated in Leber's Hereditary Optic Neuropathy (LHON). Here, we show the AlaThr MUT further narrows the Q-chamber entrance cross-section area by almost 30%, increasing the activation free energy barrier of quinone passage by approximately 5 kJ mol-1. This severely disrupts quinone binding and reduction as quinone passage through the bottleneck is slowed down almost tenfold. Our estimate of the increase in free energy barrier is entirely due to the bottleneck narrowing, leading to a reduction of the transition state entropy between WT and MUT, and thus more difficult quinone passage. Additionally, we investigate details of possible water exchange between the Q-chamber and membrane. We find water exchange is dynamic in WT but may be severely slowed in MUT. We propose that LHON symptoms caused by 3460/ND1 mtDNA mutation are due to slowed quinone binding. This leads to an increased production of reactive oxidative species due to upstream electron backup at the FMN site of complex I, thus resulting in a mt bioenergetic defect.
    DOI:  https://doi.org/10.1038/s41598-023-47314-2
  24. Cells. 2023 Nov 13. pii: 2617. [Epub ahead of print]12(22):
    HLA-Homozygous iPSC-Derived Mesenchymal Stem Cells Rescue Rotenone-Induced Experimental Leber's Hereditary Optic Neuropathy-like Models In Vitro and In Vivo.
    En-Tung Tsai, Shih-Yuan Peng, You-Ren Wu, Tai-Chi Lin, Chih-Ying Chen, Yu-Hao Liu, Yu-Hsin Tseng, Yu-Jer Hsiao, Huan-Chin Tseng, Wei-Yi Lai, Yi-Ying Lin, Yi-Ping Yang, Shih-Hwa Chiou, Shih-Pin Chen, Yueh Chien.
      BACKGROUND: Mesenchymal stem cells (MSCs) hold promise for cell-based therapy, yet the sourcing, quality, and invasive methods of MSCs impede their mass production and quality control. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) can be infinitely expanded, providing advantages over conventional MSCs in terms of meeting unmet clinical demands.METHODS: The potential of MSC therapy for Leber's hereditary optic neuropathy (LHON) remains uncertain. In this study, we used HLA-homozygous induced pluripotent stem cells to generate iMSCs using a defined protocol, and we examined their therapeutic potential in rotenone-induced LHON-like models in vitro and in vivo.
    RESULTS: The iMSCs did not cause any tumorigenic incidence or inflammation-related lesions after intravitreal transplantation, and they remained viable for at least nine days in the mouse recipient's eyes. In addition, iMSCs exhibited significant efficacy in safeguarding retinal ganglion cells (RGCs) from rotenone-induced cytotoxicity in vitro, and they ameliorated CGL+IPL layer thinning and RGC loss in vivo. Optical coherence tomography (OCT) and an electroretinogram demonstrated that iMSCs not only prevented RGC loss and impairments to the retinal architecture, but they also improved retinal electrophysiology performance.
    CONCLUSION: The generation of iMSCs via the HLA homozygosity of iPSCs offers a compelling avenue for overcoming the current limitations of MSC-based therapies. The results underscore the potential of iMSCs when addressing retinal disorders, and they highlight their clinical significance, offering renewed hope for individuals affected by LHON and other inherited retinal conditions.
    Keywords:  HLA-homozygous iPSCs; Leber’s hereditary optic neuropathy; cell therapy; mesenchymal stem cells; mitochondrial complex I; rotenone
    DOI:  https://doi.org/10.3390/cells12222617
  25. Antioxidants (Basel). 2023 Nov 17. pii: 2011. [Epub ahead of print]12(11):
    Targeting Mitochondrial Dysfunction and Oxidative Stress to Prevent the Neurodegeneration of Retinal Ganglion Cells.
    Elisabetta Catalani, Kashi Brunetti, Simona Del Quondam, Davide Cervia.
      The imbalance of redox homeostasis contributes to neurodegeneration, including that related to the visual system. Mitochondria, essential in providing energy and responsible for several cell functions, are a significant source of reactive oxygen and/or nitrogen species, and they are, in turn, sensitive to free radical imbalance. Dysfunctional mitochondria are implicated in the development and progression of retinal pathologies and are directly involved in retinal neuronal degeneration. Retinal ganglion cells (RGCs) are higher energy consumers susceptible to mitochondrial dysfunctions that ultimately cause RGC loss. Proper redox balance and mitochondrial homeostasis are essential for maintaining healthy retinal conditions and inducing neuroprotection. In this respect, the antioxidant treatment approach is effective against neuronal oxidative damage and represents a challenge for retinal diseases. Here, we highlighted the latest findings about mitochondrial dysfunction in retinal pathologies linked to RGC degeneration and discussed redox-related strategies with potential neuroprotective properties.
    Keywords:  ganglion cells; mitochondria; neurodegeneration; redox homeostasis; retina
    DOI:  https://doi.org/10.3390/antiox12112011
  26. Nat Genet. 2023 Nov 20.
    Deep learning-based phenotype imputation on population-scale biobank data increases genetic discoveries.
    Ulzee An, Ali Pazokitoroudi, Marcus Alvarez, Lianyun Huang, Silviu Bacanu, Andrew J Schork, Kenneth Kendler, Päivi Pajukanta, Jonathan Flint, Noah Zaitlen, Na Cai, Andy Dahl, Sriram Sankararaman.
      Biobanks that collect deep phenotypic and genomic data across many individuals have emerged as a key resource in human genetics. However, phenotypes in biobanks are often missing across many individuals, limiting their utility. We propose AutoComplete, a deep learning-based imputation method to impute or 'fill-in' missing phenotypes in population-scale biobank datasets. When applied to collections of phenotypes measured across ~300,000 individuals from the UK Biobank, AutoComplete substantially improved imputation accuracy over existing methods. On three traits with notable amounts of missingness, we show that AutoComplete yields imputed phenotypes that are genetically similar to the originally observed phenotypes while increasing the effective sample size by about twofold on average. Further, genome-wide association analyses on the resulting imputed phenotypes led to a substantial increase in the number of associated loci. Our results demonstrate the utility of deep learning-based phenotype imputation to increase power for genetic discoveries in existing biobank datasets.
    DOI:  https://doi.org/10.1038/s41588-023-01558-w
  27. Int J Neonatal Screen. 2023 Oct 30. pii: 63. [Epub ahead of print]9(4):
    NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders.
    Kee Chan, Zhanzhi Hu, Lynn W Bush, Heidi Cope, Ingrid A Holm, Stephen F Kingsmore, Kevin Wilhelm, Curt Scharfe, Amy Brower.
      Rapid advances in the screening, diagnosis, and treatment of genetic disorders have increased the number of conditions that can be detected through universal newborn screening (NBS). However, the addition of conditions to the Recommended Uniform Screening Panel (RUSP) and the implementation of nationwide screening has been a slow process taking several years to accomplish for individual conditions. Here, we describe web-based tools and resources developed and implemented by the newborn screening translational research network (NBSTRN) to advance newborn screening research and support NBS stakeholders worldwide. The NBSTRN's tools include the Longitudinal Pediatric Data Resource (LPDR), the NBS Condition Resource (NBS-CR), the NBS Virtual Repository (NBS-VR), and the Ethical, Legal, and Social Issues (ELSI) Advantage. Research programs, including the Inborn Errors of Metabolism Information System (IBEM-IS), BabySeq, EarlyCheck, and Family Narratives Use Cases, have utilized NBSTRN's tools and, in turn, contributed research data to further expand and refine these resources. Additionally, we discuss ongoing tool development to facilitate the expansion of genetic disease screening in increasingly diverse populations. In conclusion, NBSTRN's tools and resources provide a trusted platform to enable NBS stakeholders to advance NBS research and improve clinical care for patients and their families.
    Keywords:  NBSTRN; Recommended Uniform Screening Panel (RUSP); databases; ethical; genome sequencing; legal; newborn screening; online tools; public health; social implications (ELSI)
    DOI:  https://doi.org/10.3390/ijns9040063
  28. Cell Metab. 2023 Nov 11. pii: S1550-4131(23)00385-6. [Epub ahead of print]
    The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.
    Meng-Kai Ge, Cheng Zhang, Na Zhang, Ping He, Hai-Yan Cai, Song Li, Shuai Wu, Xi-Li Chu, Yu-Xue Zhang, Hong-Ming Ma, Li Xia, Shuo Yang, Jian-Xiu Yu, Shi-Ying Yao, Xiao-Long Zhou, Bing Su, Guo-Qiang Chen, Shao-Ming Shen.
      Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.
    Keywords:  FBXO22; GCN2; amino acids; mTOR; mTORC1; ubiquitination; uncharged tRNA
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.016
  29. Genet Med. 2023 Nov 16. pii: S1098-3600(23)01045-6. [Epub ahead of print] 101029
    Towards robust clinical genome interpretation: developing a consistent terminology to characterize Mendelian disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.
    Angharad M Roberts, Marina T DiStefano, Erin Rooney Riggs, Katherine S Josephs, Fowzan S Alkuraya, Joanna Amberger, Mutaz Amin, Jonathan S Berg, Fiona Cunningham, Karen Eilbeck, Helen V Firth, Julia Foreman, Ada Hamosh, Eleanor Hay, Sarah Leigh, Christa L Martin, Ellen M McDonagh, Daniel Perrett, Erin M Ramos, Peter N Robinson, Ana Rath, David W Sant, Zornitza Stark, Nicola Whiffin, Heidi L Rehm, James S Ware.
      PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated.
    RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources.
    CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.
    Keywords:  Allelic requirement; Disease mechanisms; GenCC; Gene Curation; Inheritance modes; Ontology; The Gene Curation Coalition
    DOI:  https://doi.org/10.1016/j.gim.2023.101029
  30. Nat Metab. 2023 Nov;5(11): 1840-1843
    A century of the Warburg effect.
    Craig B Thompson, Karen H Vousden, Randall S Johnson, Willem H Koppenol, Helmut Sies, Zhimin Lu, Lydia W S Finley, Christian Frezza, Jiyeon Kim, Zeping Hu, Caroline R Bartman.
      
    DOI:  https://doi.org/10.1038/s42255-023-00927-3
  31. Nat Commun. 2023 Nov 23. 14(1): 7674
    A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.
    Sebastian Schmidt, Constantin Stautner, Duc Tung Vu, Alexander Heinz, Martin Regensburger, Ozge Karayel, Dietrich Trümbach, Anna Artati, Sabine Kaltenhäuser, Mohamed Zakaria Nassef, Sina Hembach, Letyfee Steinert, Beate Winner, Winkler Jürgen, Martin Jastroch, Malte D Luecken, Fabian J Theis, Gil Gregor Westmeyer, Jerzy Adamski, Matthias Mann, Karsten Hiller, Florian Giesert, Daniela M Vogt Weisenhorn, Wolfgang Wurst.
      Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.
    DOI:  https://doi.org/10.1038/s41467-023-42862-7
  32. J Nutr Biochem. 2023 Nov 17. pii: S0955-2863(23)00269-3. [Epub ahead of print] 109536
    Vitamin B12-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice.
    Ela Mishra, Mahendra Kumar Thakur.
      Memory impairment during aging and amnesia is attributed to compromised mitochondrial dynamics and mitophagy and other mitochondrial quality control mechanisms. Mitochondrial dynamics involves the continuous process of fission and fusion of mitochondria within a cell and is a fundamental mechanism for regulating mitochondrial quality and function. An extensive range of potential nutritional supplements has been shown to improve mitochondrial health, synaptic plasticity, and cognitive functions. Previous findings revealed that supplementation of vitamin B12-folic acid reduces locomotor deficits and mitochondrial abnormalities but enhances mitochondrial and neuronal health. The present study aims to explore the impact of combined vitamin B12-folic acid supplementation on mitochondrial dynamics, neuronal health, and memory decline in old age and scopolamine-induced amnesia, which remains elusive. The results demonstrated that supplementation led to a noteworthy increase in recognition and spatial memory and expression of memory-related protein BDNF in old and amnesic mice. Moreover, the decrease in the fragmented mitochondrial number was validated by the downregulation of mitochondrial fission p-Drp1 (S616) protein and the increase in elongated mitochondria by the upregulation of mitochondrial fusion Mfn2 protein. The increased spine density and dendritic arborization in old and amnesic mice upon supplementation were confirmed by the enhanced expression level of PSD95 and synaptophysin. Furthermore, supplementation reduced ROS production, inhibited Caspase-3 activation, mitigated neurodegeneration, and enhanced mitochondrial membrane potential, ATP production, Vdac1 expression, myelination, in old and amnesic mice. Collectively, our findings imply that combined supplementation of vitamin B12-folic acid improves mitochondrial dynamics and neuronal health, and leads to recovery of memory during old age and amnesia.
    Keywords:  Aging; Amnesia; Memory; Mitochondrial dynamics; Neurodegeneration; Nutritional supplement
    DOI:  https://doi.org/10.1016/j.jnutbio.2023.109536
  33. Brain Sci. 2023 Nov 05. pii: 1551. [Epub ahead of print]13(11):
    Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.
    Athira Anirudhan, S Mahema, Sheikh F Ahmad, Talha Bin Emran, Shiek S S J Ahmed, Prabu Paramasivam.
      Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (-9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (-4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.
    Keywords:  Parkinson’s disease; mitochondria-associated membranes (MAMs); mitochondrial-ER; neuroinflammation; systems biology
    DOI:  https://doi.org/10.3390/brainsci13111551
  34. Sci Rep. 2023 Nov 23. 13(1): 20615
    A machine learning method to process voice samples for identification of Parkinson's disease.
    Anu Iyer, Aaron Kemp, Yasir Rahmatallah, Lakshmi Pillai, Aliyah Glover, Fred Prior, Linda Larson-Prior, Tuhin Virmani.
      Machine learning approaches have been used for the automatic detection of Parkinson's disease with voice recordings being the most used data type due to the simple and non-invasive nature of acquiring such data. Although voice recordings captured via telephone or mobile devices allow much easier and wider access for data collection, current conflicting performance results limit their clinical applicability. This study has two novel contributions. First, we show the reliability of personal telephone-collected voice recordings of the sustained vowel /a/ in natural settings by collecting samples from 50 people with specialist-diagnosed Parkinson's disease and 50 healthy controls and applying machine learning classification with voice features related to phonation. Second, we utilize a novel application of a pre-trained convolutional neural network (Inception V3) with transfer learning to analyze the spectrograms of the sustained vowel from these samples. This approach considers speech intensity estimates across time and frequency scales rather than collapsing measurements across time. We show the superiority of our deep learning model for the task of classifying people with Parkinson's disease as distinct from healthy controls.
    DOI:  https://doi.org/10.1038/s41598-023-47568-w
  35. Am J Hum Genet. 2023 Nov 15. pii: S0002-9297(23)00364-6. [Epub ahead of print]
    CHARR efficiently estimates contamination from DNA sequencing data.
    Wenhan Lu, Laura D Gauthier, Timothy Poterba, Edoardo Giacopuzzi, Julia K Goodrich, Christine R Stevens, Daniel King, Mark J Daly, Benjamin M Neale, Konrad J Karczewski.
      DNA sample contamination is a major issue in clinical and research applications of whole-genome and -exome sequencing. Even modest levels of contamination can substantially affect the overall quality of variant calls and lead to widespread genotyping errors. Currently, popular tools for estimating the contamination level use short-read data (BAM/CRAM files), which are expensive to store and manipulate and often not retained or shared widely. We propose a metric to estimate DNA sample contamination from variant-level whole-genome and -exome sequence data called CHARR, contamination from homozygous alternate reference reads, which leverages the infiltration of reference reads within homozygous alternate variant calls. CHARR uses a small proportion of variant-level genotype information and thus can be computed from single-sample gVCFs or callsets in VCF or BCF formats, as well as efficiently stored variant calls in Hail VariantDataset format. Our results demonstrate that CHARR accurately recapitulates results from existing tools with substantially reduced costs, improving the accuracy and efficiency of downstream analyses of ultra-large whole-genome and exome sequencing datasets.
    Keywords:  DNA sequencing; contamination; data science; genetic research; quality control; variant calling
    DOI:  https://doi.org/10.1016/j.ajhg.2023.10.011
  36. Metabolites. 2023 Nov 01. pii: 1120. [Epub ahead of print]13(11):
    Benchmark Dataset for Training Machine Learning Models to Predict the Pathway Involvement of Metabolites.
    Erik D Huckvale, Christian D Powell, Huan Jin, Hunter N B Moseley.
      Metabolic pathways are a human-defined grouping of life sustaining biochemical reactions, metabolites being both the reactants and products of these reactions. But many public datasets include identified metabolites whose pathway involvement is unknown, hindering metabolic interpretation. To address these shortcomings, various machine learning models, including those trained on data from the Kyoto Encyclopedia of Genes and Genomes (KEGG), have been developed to predict the pathway involvement of metabolites based on their chemical descriptions; however, these prior models are based on old metabolite KEGG-based datasets, including one benchmark dataset that is invalid due to the presence of over 1500 duplicate entries. Therefore, we have developed a new benchmark dataset derived from the KEGG following optimal standards of scientific computational reproducibility and including all source code needed to update the benchmark dataset as KEGG changes. We have used this new benchmark dataset with our atom coloring methodology to develop and compare the performance of Random Forest, XGBoost, and multilayer perceptron with autoencoder models generated from our new benchmark dataset. Best overall weighted average performance across 1000 unique folds was an F1 score of 0.8180 and a Matthews correlation coefficient of 0.7933, which was provided by XGBoost binary classification models for 11 KEGG-defined pathway categories.
    Keywords:  KEGG; atom color; kegg_pull; machine learning; md_harmonize; metabolite; pathway
    DOI:  https://doi.org/10.3390/metabo13111120
  37. Nat Metab. 2023 Nov 23.
    Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.
    Valerian E Kagan, Yulia Y Tyurina, Karolina Mikulska-Ruminska, Deena Damschroder, Eduardo Vieira Neto, Alessia Lasorsa, Alexander A Kapralov, Vladimir A Tyurin, Andrew A Amoscato, Svetlana N Samovich, Austin B Souryavong, Haider H Dar, Abu Ramim, Zhuqing Liang, Pablo Lazcano, Jiajia Ji, Michael W Schmidtke, Kirill Kiselyov, Aybike Korkmaz, Georgy K Vladimirov, Margarita A Artyukhova, Pushpa Rampratap, Laura K Cole, Ammanamanchi Niyatie, Emma-Kate Baker, Jim Peterson, Grant M Hatch, Jeffrey Atkinson, Jerry Vockley, Bernhard Kühn, Robert Wessells, Patrick C A van der Wel, Ivet Bahar, Hülya Bayir, Miriam L Greenberg.
      Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.
    DOI:  https://doi.org/10.1038/s42255-023-00926-4
  38. Commun Biol. 2023 Nov 20. 6(1): 1179
    Omics data integration suggests a potential idiopathic Parkinson's disease signature.
    Alise Zagare, German Preciat, Sarah L Nickels, Xi Luo, Anna S Monzel, Gemma Gomez-Giro, Graham Robertson, Christian Jaeger, Jafar Sharif, Haruhiko Koseki, Nico J Diederich, Enrico Glaab, Ronan M T Fleming, Jens C Schwamborn.
      The vast majority of Parkinson's disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis. Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson's disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes.
    DOI:  https://doi.org/10.1038/s42003-023-05548-w
  39. STAR Protoc. 2023 Nov 23. pii: S2666-1667(23)00715-3. [Epub ahead of print]4(4): 102748
    Purification and characterization of different proteasome species from mammalian cells.
    Insuk Byun, Hoseok Seo, Jiseong Kim, Dawon Jeong, Dohyun Han, Min Jae Lee.
      Proteasomes are heterogeneous in forms and functions, but how the equilibrium among the 20S, 26S, and 30S proteasomes is achieved and altered is elusive. Here, we present a protocol for purifying and characterizing proteasome species. We describe steps for generating stable cell lines; affinity purifying the proteasome species; and characterizing them through native PAGE, activity assay, size-exclusion chromatography, and mass spectrometry. These standardized methods may contribute to biochemical studies of cellular proteasomes under both physiological and pathological conditions. For complete details on the use and execution of this protocol, please refer to Choi et al. (2023).1.
    Keywords:  Cell Biology; Mass Cytometry; Protein Biochemistry; Protein expression and purification
    DOI:  https://doi.org/10.1016/j.xpro.2023.102748
  40. bioRxiv. 2023 Nov 07. pii: 2023.11.07.566074. [Epub ahead of print]
    Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production.
    Angelo Y Meliton, Rengül Cetin-Atalay, Yufeng Tian, Jennifer C Houpy Szafran, Kun Woo D Shin, Takugo Cho, Kaitlyn A Sun, Parker S Woods, Obada R Shamaa, Bohao Chen, Alexander Muir, Gökhan M Mutlu, Robert B Hamanaka.
      A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires de novo synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4- dependent transcriptional programs. SHMT2, the final enzyme of the de novo serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO 2 . It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis in vivo . Here, we demonstrate that TGF-β induces the expression of MTHFD2 , MTHFD1L , and ALDH1L2 in human lung fibroblasts. MTHFD2 expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production. Combined knockdown of both MTHFD1L and ALDH1L2 also inhibited glycine accumulation and collagen protein production downstream of TGF-β; however knockdown of either protein alone had no inhibitory effect, suggesting that lung fibroblasts can utilize either enzyme to regenerate THF. Pharmacologic inhibition of MTHFD2 recapitulated the effects of MTHFD2 knockdown in lung fibroblasts and ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo . Our results provide insight into the metabolic requirements of lung fibroblasts and provide support for continued development of MTHFD2 inhibitors for the treatment of IPF and other fibrotic diseases.
    DOI:  https://doi.org/10.1101/2023.11.07.566074
  41. Metabolism. 2023 Nov 18. pii: S0026-0495(23)00342-6. [Epub ahead of print]150 155738
    Towards personalized genome-scale modeling of inborn errors of metabolism for systems medicine applications.
    Almut Heinken, Sandra El Kouche, Rosa-Maria Guéant-Rodriguez, Jean-Louis Guéant.
      Inborn errors of metabolism (IEMs) are a group of more than 1000 inherited diseases that are individually rare but have a cumulative global prevalence of 50 per 100,000 births. Recently, it has been recognized that like common diseases, patients with rare diseases can greatly vary in the manifestation and severity of symptoms. Here, we review omics-driven approaches that enable an integrated, holistic view of metabolic phenotypes in IEM patients. We focus on applications of Constraint-based Reconstruction and Analysis (COBRA), a widely used mechanistic systems biology approach, to model the effects of inherited diseases. Moreover, we review evidence that the gut microbiome is also altered in rare diseases. Finally, we outline an approach using personalized metabolic models of IEM patients for the prediction of biomarkers and tailored therapeutic or dietary interventions. Such applications could pave the way towards personalized medicine not just for common, but also for rare diseases.
    Keywords:  Constraint-based reconstruction and analysis; Inborn errors of cobalamin metabolism; Inborn errors of metabolism; Microbiome; Systems biology
    DOI:  https://doi.org/10.1016/j.metabol.2023.155738
  42. Neurol Sci. 2023 Nov 22.
    Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review.
    Martha Cecilia Piñeros-Fernández, Beatriz Morte, José Luis García-Giménez.
      Diagnosis of neuromuscular diseases (NMD) can be challenging because of the heterogeneity of this group of diseases. This review aimed to describe the diagnostic yield of whole exome sequencing (WES) for pediatric-onset neuromuscular disease diagnosis, as well as other benefits of this approach in patient management since WES can contribute to appropriate treatment selection in NMD patients. WES increases the possibility of reaching a conclusive genetic diagnosis when other technologies have failed and even exploring new genes not previously associated with a specific NMD. Moreover, this strategy can be useful when a dual diagnosis is suspected in complex congenital anomalies and undiagnosed cases.
    Keywords:  Diagnostic yield; Exome; Neuromuscular disease; Next-generation sequencing; Pediatric patients
    DOI:  https://doi.org/10.1007/s10072-023-07210-z
  43. Nat Commun. 2023 Nov 21. 14(1): 7575
    Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing.
    Lien D Nguyen, Zhiyun Wei, M Catarina Silva, Sergio Barberán-Soler, Jiarui Zhang, Rosalia Rabinovsky, Christina R Muratore, Jonathan M S Stricker, Colin Hortman, Tracy L Young-Pearse, Stephen J Haggarty, Anna M Krichevsky.
      MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer's disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.
    DOI:  https://doi.org/10.1038/s41467-023-43293-0
  44. Nat Cell Biol. 2023 Nov 20.
    Quick tips for interpreting cell death experiments.
    Scott J Dixon, Michael J Lee.
      
    DOI:  https://doi.org/10.1038/s41556-023-01288-5
  45. Nature. 2023 Nov;623(7988): 685-687
    How AI is expanding art history.
    David G Stork.
      
    Keywords:  Arts; Computer science; Culture; History; Machine learning
    DOI:  https://doi.org/10.1038/d41586-023-03604-3
  46. Genes (Basel). 2023 Nov 18. pii: 2100. [Epub ahead of print]14(11):
    Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases.
    Tatyana E Lazareva, Yury A Barbitoff, Yulia A Nasykhova, Nadezhda S Pavlova, Polina M Bogaychuk, Andrey S Glotov.
      Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene-disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene-disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity.
    Keywords:  genetic variants; phenotypic heterogeneity; rare disease; variant interpretation; variant localization
    DOI:  https://doi.org/10.3390/genes14112100
  47. J Allergy Clin Immunol. 2023 Nov 16. pii: S0091-6749(23)01462-8. [Epub ahead of print]
    Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing.
    ALPS study group
      BACKGROUND: Elevated TCRαβ+CD4-CD8- double-negative T-cells (DNT) and serum biomarkers help identifying FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified upon standard exon sequencing (ALPS-undetermined: ALPS-U).OBJECTIVE: We aimed to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases.
    METHODS: Genetic analysis included whole FAS gene sequencing, copy number variation analysis and sequencing of FAS cDNA and other FAS pathway related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss-of-heterozygosity (sLOH).
    RESULTS: Nine of 16 ALPS-U patients lacked FAS expression on CD57+DNT predicting heterozygous "loss of expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7/9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT, one patient showed a FAS exon duplication. Three patients had reduced FAS expression, two of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the four ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.
    CONCLUSION: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.
    CLINICAL IMPLICATION: Detection of complex FAS pathway gene alterations by extended genetic analysis allows targeted therapy with sirolimus.
    Keywords:  ALPS; ALPS-U; DNT; FADD; FAS; double negative T-cells; genetic defect accumulation; loss of heterozygosity; promoter; somatic mutation
    DOI:  https://doi.org/10.1016/j.jaci.2023.11.006
  48. Neuroscience. 2023 Nov 21. pii: S0306-4522(23)00516-X. [Epub ahead of print]
    Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.
    Chunyan Diao, Zhengxuan Yang, Qing Hu, Pengfei Yao, Xiaodong Qu, Changdong Li, Shenghao Zhang, Jie Zhou.
      Mitochondrial oxidative stress is one of the characteristics of secondary brain injury (SBI) after intracerebral hemorrhage (ICH), contributing largely to the apoptosis of neurons. Celastrol, a quinone methide triterpene that possesses antioxidant and mitochondrial protective properties, has emerged as a neuroprotective agent. However, the activity of celastrol has not been tested in ICH-induced SBI. In this study, we found that celastrol could effectively alleviate neurological function deficits and reduce brain oedema and neuronal apoptosis caused by ICH. Through electron microscopy, we found that celastrol could significantly attenuate mitochondrial morphology impairment. Therefore, we tested the regulatory proteins of mitochondrial dynamics and found that celastrol could reverse the downwards trend of OPA1 expression after ICH. In view of this, by culturing OPA1-deficient primary neurons and constructing neuron-specific OPA1 conditional knockout mice, we found that the protective effects of celastrol on mitochondrial morphology and function after ICH were counteracted in the absence of OPA1. Further experiments also showed that OPA1 is indispensable for the protective effects of celastrol on ICH-induced secondary brain injury. In summary, we have demonstrated that celastrol is a potential drug for the treatment of ICH and have revealed a novel mechanism by which celastrol exerts its antioxidant effects by promoting OPA1-mediated mitochondrial fusion.
    Keywords:  Celastrol; ICH; Mitochondria; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.11.022
  49. Nucleic Acids Res. 2023 Nov 24. pii: gkad1082. [Epub ahead of print]
    The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.
    Tim E Putman, Kevin Schaper, Nicolas Matentzoglu, Vincent P Rubinetti, Faisal S Alquaddoomi, Corey Cox, J Harry Caufield, Glass Elsarboukh, Sarah Gehrke, Harshad Hegde, Justin T Reese, Ian Braun, Richard M Bruskiewich, Luca Cappelletti, Seth Carbon, Anita R Caron, Lauren E Chan, Christopher G Chute, Katherina G Cortes, Vinícius De Souza, Tommaso Fontana, Nomi L Harris, Emily L Hartley, Eric Hurwitz, Julius O B Jacobsen, Madan Krishnamurthy, Bryan J Laraway, James A McLaughlin, Julie A McMurry, Sierra A T Moxon, Kathleen R Mullen, Shawn T O'Neil, Kent A Shefchek, Ray Stefancsik, Sabrina Toro, Nicole A Vasilevsky, Ramona L Walls, Patricia L Whetzel, David Osumi-Sutherland, Damian Smedley, Peter N Robinson, Christopher J Mungall, Melissa A Haendel, Monica C Munoz-Torres.
      Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI's ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.
    DOI:  https://doi.org/10.1093/nar/gkad1082
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