bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024‒03‒31
sixty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
  2. Precision mitochondrial medicine.
  3. DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy.
  4. Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
  5. A Two-Genome Portrayal of Mitochondrial Disorders: A Review with Clinical Presentations.
  6. Transfer and fates of damaged mitochondria: role in health and disease.
  7. Generation of iPSCs from identical twin, one affected by LHON and one unaffected, both carrying a combination of two mitochondrial variants: m.14484 T>C and m.10680G>A.
  8. Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
  9. A semi-automatic method for extracting mitochondrial cristae characteristics from 3D focused ion beam scanning electron microscopy data.
  10. OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
  11. Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
  12. Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.
  13. MPV17-related mtDNA depletion syndrome complicated by postreperfusion syndrome during liver transplantation.
  14. The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber's Hereditary Optic Neuropathy.
  15. Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
  16. Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control.
  17. Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.
  18. Therapeutic outcome of patients with Lennox-Gastaut syndrome with mitochondrial respiratory chain complex I deficiency.
  19. Quantitative imaging and semiotic phenotyping of mitochondrial network morphology in live human cells.
  20. Complex I activity in hypoxia: implications for oncometabolism.
  21. Supplementation of Nicotinic Acid and Its Derivatives Up-Regulates Cellular NAD+ Level Rather than Nicotinamide Derivatives in Cultured Normal Human Epidermal Keratinocytes.
  22. Expression of Concern: Mitochondrial Genome Sequencing with Short Overlapping Amplicons on Miseq FGx System.
  23. Protocol to assess bioenergetics and mitochondrial fuel usage in murine autoreactive immunocytes using the Seahorse Extracellular Flux Analyzer.
  24. Deafness-associated tRNAPhe mutation impaired mitochondrial and cellular integrity.
  25. Bioorthogonal photocatalytic proximity labeling in primary living samples.
  26. Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature.
  27. An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases.
  28. Correction to: Aggregated chromosomes/chromatin transfer: a novel approach for mitochondrial replacement with minimal mitochondrial carryover: the implications of mouse experiments for human aggregated chromosome transfer.
  29. Lessons and pitfalls of whole genome sequencing.
  30. Cloflucarban Illuminates Specificity and Context-Dependent Activation of the PINK1-Parkin Pathway by Mitochondrial Complex Inhibition.
  31. Novel Insights in Genetic Variant Classification.
  32. Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
  33. Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.
  34. Emerging mechanisms in the redox regulation of mitochondrial cytochrome c oxidase assembly and function.
  35. Mitochondrial respiratory supercomplexes of the yeast Saccharomyces cerevisiae.
  36. Brain Mitochondria as a Therapeutic Target for Carnosic Acid.
  37. Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action.
  38. Meningoencephalitis in a novel mutation in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) ending a familial diagnostic odyssey: A case series report.
  39. Integrating Genome Sequencing and Untargeted Metabolomics in Monozygotic Twins with a Rare Complex Neurological Disorder.
  40. A practical and robust method to evaluate metabolic fluxes in primary pancreatic islets.
  41. Ethical issues raised by new genomic technologies: the case study of newborn genome screening.
  42. Spatial proteomics in neurons at single-protein resolution.
  43. Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology.
  44. HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.
  45. Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases.
  46. Precision diagnostics in children.
  47. Discovery of a triphenylamine-based ligand that targets mitochondrial DNA G-quadruplexes and activates the cGAS-STING immunomodulatory pathway.
  48. The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.
  49. Programmed axon death: a promising target for treating retinal and optic nerve disorders.
  50. Mitochondrial extracellular vesicles, autoimmunity and myocarditis.
  51. From genetic variation to precision medicine.
  52. Nickel induces mitochondrial damage in renal cells in vitro and in vivo through its effects on mitochondrial biogenesis, fusion, and fission.
  53. Genetics of liver disease in adults.
  54. Sulfide catabolism in hibernation and neuroprotection.
  55. Clinical and Genetic Analysis of Patients With TK2 Deficiency.
  56. Understanding large scale sequencing datasets through changes to protein folding.
  57. Astrocytes: The Stars in Neurodegeneration?
  58. MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons.
  59. Genetic variation across and within individuals.
  60. Dynamics of Mitochondrial DNA Copy Number and Membrane Potential in Mouse Pre-Implantation Embryos: Responses to Diverse Types of Oxidative Stress.
  61. Editorial: AI and multi-omics for rare diseases: challenges, advances and perspectives, Volume III.
  62. Review: Opportunities and barriers for omics-based biomarker discovery in steatotic liver diseases.
  63. Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.
  64. Mitophagy modulation for the treatment of cardiovascular diseases.
  65. Rapamycin alleviates mitochondrial dysfunction in anti-NMDAR encephalitis mice.
  66. Digital Anti-Aging Healthcare: An Overview of the Applications of Digital Technologies in Diet Management.
  1. Biochim Biophys Acta Mol Basis Dis. 2024 Mar 21. pii: S0925-4439(24)00120-0. [Epub ahead of print] 167131
    A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
    Amy E Vincent, Chun Chen, Tiago Bernardino Gomes, Valeria Di Leo, Tuomas Laalo, Kamil Pabis, Rodrick Capaldi, Michael F Marusich, David McDonald, Andrew Filby, Andrew Fuller, Diana Lehmann Urban, Stephan Zierz, Marcus Deschauer, Doug Turnbull, Amy K Reeve, Conor Lawless.
      Mitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre.
    Keywords:  Cell signalling; Mitochondrial DNA deletion; Mitochondrial disease; Myopathy; OXPHOS
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167131
  2. Camb Prism Precis Med. 2023 ;1 e6
    Precision mitochondrial medicine.
    Patrick F Chinnery.
      Mitochondria play a key role in cell homeostasis as a major source of intracellular energy (adenosine triphosphate), and as metabolic hubs regulating many canonical cell processes. Mitochondrial dysfunction has been widely documented in many common diseases, and genetic studies point towards a causal role in the pathogenesis of specific late-onset disorder. Together this makes targeting mitochondrial genes an attractive strategy for precision medicine. However, the genetics of mitochondrial biogenesis is complex, with over 1,100 candidate genes found in two different genomes: the nuclear DNA and mitochondrial DNA (mtDNA). Here, we review the current evidence associating mitochondrial genetic variants with distinct clinical phenotypes, with some having clear therapeutic implications. The strongest evidence has emerged through the investigation of rare inherited mitochondrial disorders, but genome-wide association studies also implicate mtDNA variants in the risk of developing common diseases, opening to door for the incorporation of mitochondrial genetic variant analysis in population disease risk stratification.
    Keywords:  genetic polymorphism; genetic risk score; genetics; genomics; metabolic diseases
    DOI:  https://doi.org/10.1017/pcm.2022.8
  3. bioRxiv. 2024 Feb 29. pii: 2024.02.29.582673. [Epub ahead of print]
    DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy.
    Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.
      Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy. Here, we identified that diverse mitochondrial myopathy models elicit a protective mitochondrial integrated stress response (mt-ISR), mediated by OMA1-DELE1 signaling. The response was similar following disruptions in mtDNA maintenance, from knockout of Tfam , and mitochondrial protein unfolding, from disease-causing mutations in CHCHD10 (G58R and S59L). The preponderance of the response was directed at upregulating pathways for aminoacyl-tRNA biosynthesis, the intermediates for protein synthesis, and was similar in heart and skeletal muscle but more limited in brown adipose challenged with cold stress. Strikingly, models with early DELE1 mt-ISR activation failed to grow and survive to adulthood in the absence of Dele1 , accounting for some but not all of OMA1's protection. Notably, the DELE1 mt-ISR did not slow net protein synthesis in stressed striated muscle, but instead prevented loss of translation-associated proteostasis in muscle fibers. Together our findings identify that the DELE1 mt-ISR mediates a stereotyped response to diverse forms of mitochondrial stress and is particularly critical for maintaining growth and survival in early-onset mitochondrial myopathy.
    DOI:  https://doi.org/10.1101/2024.02.29.582673
  4. J Neurol. 2024 Mar 28.
    Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
    Tomas Ferreira, Kiran Polavarapu, Catarina Olimpio, Ida Paramonov, Hanns Lochmüller, Rita Horvath.
      BACKGROUND: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed.METHODS: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients. These patients' genetic data were then analysed and searched for variants in known mitochondrial disease genes.
    RESULTS: A total of 1,379 rare variants were identified, 44 of which were included in this study as either reported pathogenic or likely causative in 42 patients from 36 families. The most common genes found to be likely causative for an autosomal dominant neuropathy were GDAP1 and GARS1. We also detected heterozygous likely pathogenic variants in DNA2, MFN2, DNM2, PDHA1, SDHA, and UCHL1. Biallelic variants in SACS, SPG7, GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH and DARS2 and variants in the mitochondrial DNA (mtDNA)-encoded MT-ATP6 and MT-TK were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP.
    CONCLUSION: Variants in mitochondrial disease genes are frequent in patients with inherited peripheral neuropathies. Due to the clinical overlap between mitochondrial disease and CMT, agnostic exome or genome sequencing have better diagnostic yields than targeted gene panels.
    Keywords:  CMT; Genetic heterogeneity; Genome-phenome analysis platform (GPAP); Mitochondrial disease; Peripheral neuropathies; Rare variants
    DOI:  https://doi.org/10.1007/s00415-024-12319-y
  5. Front Biosci (Schol Ed). 2024 Mar 14. 16(1): 7
    A Two-Genome Portrayal of Mitochondrial Disorders: A Review with Clinical Presentations.
    Jude M Abadie.
      Disorders of mitochondrial function are responsible for many inherited neuromuscular and metabolic diseases. Their combination of high mortality, multi-systemic involvement, and economic burden cause devastating effects on patients and their families. Molecular diagnostic tools are becoming increasingly important in providing earlier diagnoses and guiding more precise therapeutic treatments for patients suffering from mitochondrial disorders. This review addresses fundamental molecular concepts relating to the pathogenesis of mitochondrial dysfunction and disorders. A series of short cases highlights the various clinical presentations, inheritance patterns, and pathogenic mutations in nuclear and mitochondrial genes that cause mitochondrial diseases. Graphical and tabular representations of the results are presented to guide the understanding of the important concepts related to mitochondrial molecular genetics and pathology. Emerging technology is incorporating preimplantation genetic testing for mtDNA disorders, while mitochondrial replacement shows promise in significantly decreasing the transfer of diseased mitochondrial DNA (mtDNA) to embryos. Medical professionals must maintain an in-depth understanding of the gene mutations and molecular mechanisms underlying mitochondrial disorders. Continued diagnostic advances and comprehensive management of patients with mitochondrial disorders are essential to achieve robust clinical impacts from comprehensive genomic testing. This is especially true when supported by non-genetic tests such as biochemical analysis, histochemical stains, and imaging studies. Such a multi-pronged investigation should improve the management of mitochondrial disorders by providing accurate and timely diagnoses to reduce disease burden and improve the lives of patients and their families.
    Keywords:  maternal inheritance; mitochondrial disorders; mitochondrial genome
    DOI:  https://doi.org/10.31083/j.fbs1601007
  6. FEBS J. 2024 Mar 28.
    Transfer and fates of damaged mitochondria: role in health and disease.
    Hanbing Li, Weiyun Sun, Wenwen Gong, Yubing Han.
      Intercellular communication is pivotal in mediating the transfer of mitochondria from donor to recipient cells. This process orchestrates various biological functions, including tissue repair, cell proliferation, differentiation and cancer invasion. Typically, dysfunctional and depolarized mitochondria are eliminated through intracellular or extracellular pathways. Nevertheless, increasing evidence suggests that intercellular transfer of damaged mitochondria is associated with the pathogenesis of diverse diseases. This review investigates the prevalent triggers of mitochondrial damage and the underlying mechanisms of mitochondrial transfer, and elucidates the role of directional mitochondrial transfer in both physiological and pathological contexts. Additionally, we propose potential previously unknown mechanisms mediating mitochondrial transfer and explore their prospective roles in disease prevention and therapy.
    Keywords:  cell communication; disease; extracellular vesicles; mitochondria; mitochondrial quality control; mitochondrial transfer
    DOI:  https://doi.org/10.1111/febs.17119
  7. Stem Cell Res. 2024 Mar 24. pii: S1873-5061(24)00104-1. [Epub ahead of print]77 103406
    Generation of iPSCs from identical twin, one affected by LHON and one unaffected, both carrying a combination of two mitochondrial variants: m.14484 T>C and m.10680G>A.
    Camille Peron, Andrea Cavaliere, Chiara Fasano, Angelo Iannielli, Manuela Spagnolo, Andrea Legati, Maria Nicol Colombo, Ambra Rizzo, Francesca L Sciacca, Valerio Carelli, Vania Broccoli, Costanza Lamperti, Valeria Tiranti.
      Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial illness, causing retinal ganglion cell degeneration and central vision loss. It stems from point mutations in mitochondrial DNA (mtDNA), with key mutations being m.3460G > A, m.11778G > A, and m.14484 T > C. Fibroblasts from identical twins, sharing m.14484 T > C and m.10680G > A variants each with 70 % heteroplasmy, were used to generate iPSC lines. Remarkably, one twin, a LHON patient, displayed symptoms, while the other, a carrier, remained asymptomatic. These iPSCs offer a valuable tool for studying factors influencing disease penetrance and unravelling the role of m.10680G > A, which is still debated.
    DOI:  https://doi.org/10.1016/j.scr.2024.103406
  8. Cell Rep. 2024 Mar 28. pii: S2211-1247(24)00346-2. [Epub ahead of print]43(4): 114018
    Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
    Lea Bertgen, Jan-Eric Bökenkamp, Tim Schneckmann, Christian Koch, Markus Räschle, Zuzana Storchová, Johannes M Herrmann.
      Mitochondria consist of hundreds of proteins, most of which are inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions remains poorly understood. Here, we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Two different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble, aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis, presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 is part of a second type of intramitochondrial aggregate that transiently sequesters proteins and promotes their folding or Pim1-mediated degradation. Thus, mitochondrial proteins actively control the formation of distinct types of intramitochondrial protein aggregates, which cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.
    Keywords:  CP: Cell biology; CP: Molecular biology; Hsp78; MitoStores; Pim1 protease; Var1 bodies; aggregates; chaperones; mitochondria; mitoribosome; protein folding; protein import
    DOI:  https://doi.org/10.1016/j.celrep.2024.114018
  9. Commun Biol. 2024 Mar 28. 7(1): 377
    A semi-automatic method for extracting mitochondrial cristae characteristics from 3D focused ion beam scanning electron microscopy data.
    Chenhao Wang, Leif Østergaard, Stine Hasselholt, Jon Sporring.
      Mitochondria are the main suppliers of energy for cells and their bioenergetic function is regulated by mitochondrial dynamics: the constant changes in mitochondria size, shape, and cristae morphology to secure cell homeostasis. Although changes in mitochondrial function are implicated in a wide range of diseases, our understanding is challenged by a lack of reliable ways to extract spatial features from the cristae, the detailed visualization of which requires electron microscopy (EM). Here, we present a semi-automatic method for the segmentation, 3D reconstruction, and shape analysis of mitochondria, cristae, and intracristal spaces based on 2D EM images of the murine hippocampus. We show that our method provides a more accurate characterization of mitochondrial ultrastructure in 3D than common 2D approaches and propose an operational index of mitochondria's internal organization. With an improved consistency of 3D shape analysis and a decrease in the workload needed for large-scale analysis, we speculate that this tool will help increase our understanding of mitochondrial dynamics in health and disease.
    DOI:  https://doi.org/10.1038/s42003-024-06045-4
  10. J Cell Biol. 2024 May 06. pii: e202306051. [Epub ahead of print]223(5):
    OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
    Magda Krakowczyk, Anna M Lenkiewicz, Tomasz Sitarz, Dominika Malinska, Mayra Borrero, Ben Hur Marins Mussulini, Vanessa Linke, Andrzej A Szczepankiewicz, Joanna M Biazik, Agata Wydrych, Hanna Nieznanska, Remigiusz A Serwa, Agnieszka Chacinska, Piotr Bragoszewski.
      Most mitochondrial proteins originate from the cytosol and require transport into the organelle. Such precursor proteins must be unfolded to pass through translocation channels in mitochondrial membranes. Misfolding of transported proteins can result in their arrest and translocation failure. Arrested proteins block further import, disturbing mitochondrial functions and cellular proteostasis. Cellular responses to translocation failure have been defined in yeast. We developed the cell line-based translocase clogging model to discover molecular mechanisms that resolve failed import events in humans. The mechanism we uncover differs significantly from these described in fungi, where ATPase-driven extraction of blocked protein is directly coupled with proteasomal processing. We found human cells to rely primarily on mitochondrial factors to clear translocation channel blockage. The mitochondrial membrane depolarization triggered proteolytic cleavage of the stalled protein, which involved mitochondrial protease OMA1. The cleavage allowed releasing the protein fragment that blocked the translocase. The released fragment was further cleared in the cytosol by VCP/p97 and the proteasome.
    DOI:  https://doi.org/10.1083/jcb.202306051
  11. Mol Biol Cell. 2024 Mar 27. mbcE24010041
    Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
    Nicole Madrazo, Zinia Khattar, Evan T Powers, Jessica D Rosarda, R Luke Wiseman.
      Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronically disrupted of mitochondrial proteostasis.
    DOI:  https://doi.org/10.1091/mbc.E24-01-0041
  12. Curr Issues Mol Biol. 2024 Mar 02. 46(3): 1987-2026
    Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.
    Sydney Bartman, Giuseppe Coppotelli, Jaime M Ross.
      Mitochondria are thought to have become incorporated within the eukaryotic cell approximately 2 billion years ago and play a role in a variety of cellular processes, such as energy production, calcium buffering and homeostasis, steroid synthesis, cell growth, and apoptosis, as well as inflammation and ROS production. Considering that mitochondria are involved in a multitude of cellular processes, mitochondrial dysfunction has been shown to play a role within several age-related diseases, including cancers, diabetes (type 2), and neurodegenerative diseases, although the underlying mechanisms are not entirely understood. The significant increase in lifespan and increased incidence of age-related diseases over recent decades has confirmed the necessity to understand the mechanisms by which mitochondrial dysfunction impacts the process of aging and age-related diseases. In this review, we will offer a brief overview of mitochondria, along with structure and function of this important organelle. We will then discuss the cause and consequence of mitochondrial dysfunction in the aging process, with a particular focus on its role in inflammation, cognitive decline, and neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease. We will offer insight into therapies and interventions currently used to preserve or restore mitochondrial functioning during aging and neurodegeneration.
    Keywords:  aging; mitochondria; mitochondrial dysfunction; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cimb46030130
  13. Int J Surg Case Rep. 2024 Mar 16. pii: S2210-2612(24)00334-1. [Epub ahead of print]117 109553
    MPV17-related mtDNA depletion syndrome complicated by postreperfusion syndrome during liver transplantation.
    Josef Finsterer.
      
    Keywords:  Liver failure; Liver transplantation; MPV17; Mitochondrial disorder; Post-reperfusion syndrome; mtDNA depletion
    DOI:  https://doi.org/10.1016/j.ijscr.2024.109553
  14. Biomedicines. 2024 Mar 06. pii: 584. [Epub ahead of print]12(3):
    The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber's Hereditary Optic Neuropathy.
    Pierre Layrolle, Christophe Orssaud, Maryse Leleu, Pierre Payoux, Stéphane Chavanas.
      Optic neuropathies are characterized by the degeneration of the optic nerves and represent a considerable individual and societal burden. Notably, Leber's hereditary optic neuropathy (LHON) is a devastating vision disease caused by mitochondrial gene mutations that hinder oxidative phosphorylation and increase oxidative stress, leading to the loss of retinal ganglion neurons and axons. Loss of vision is rapid and severe, predominantly in young adults. Penetrance is incomplete, and the time of onset is unpredictable. Recent findings revealed that the incidence of genetic LHON susceptibility is around 1 in 1000, much higher than believed till now. Environmental factors are critical in LHON triggering or severity. Families at risk have a very strong demand for how to prevent the onset or limit the severity of the disease. Here, we review recent knowledge of the extrinsic determinants of LHON expression, including lifestyle, dietary supplements, common chemicals, and drugs.
    Keywords:  Leber’s hereditary optic neuropathy; drugs; environmental factors; mitochondrial disease; neurodegeneration; optic neuropathy
    DOI:  https://doi.org/10.3390/biomedicines12030584
  15. Science. 2024 Mar 29. 383(6690): 1484-1492
    Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
    Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.
      Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.
    DOI:  https://doi.org/10.1126/science.adh2771
  16. Proc Natl Acad Sci U S A. 2024 Apr 02. 121(14): e2217019121
    Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control.
    Xiaoying Liu, Linyu Xu, Yutong Song, Zhihao Zhao, Xinyu Li, Cheuk-Yiu Wong, Rong Chen, Jianxiong Feng, Yitao Gou, Yajing Qi, Hei-Man Chow, Shuhuai Yao, Yi Wang, Song Gao, Xingguo Liu, Liting Duan.
      Mitochondria constantly fuse and divide for mitochondrial inheritance and functions. Here, we identified a distinct type of naturally occurring fission, tail-autotomy fission, wherein a tail-like thin tubule protrudes from the mitochondrial body and disconnects, resembling autotomy. Next, utilizing an optogenetic mitochondria-specific mechanostimulator, we revealed that mechanical tensile force drives tail-autotomy fission. This force-induced fission involves DRP1/MFF and endoplasmic reticulum tubule wrapping. It redistributes mitochondrial DNA, producing mitochondrial fragments with or without mitochondrial DNA for different fates. Moreover, tensile force can decouple outer and inner mitochondrial membranes, pulling out matrix-excluded tubule segments. Subsequent tail-autotomy fission separates the matrix-excluded tubule segments into matrix-excluded mitochondrial-derived vesicles (MDVs) which recruit Parkin and LC3B, indicating the unique role of tail-autotomy fission in segregating only outer membrane components for mitophagy. Sustained force promotes fission and MDV biogenesis more effectively than transient one. Our results uncover a mechanistically and functionally distinct type of fission and unveil the role of tensile forces in modulating fission and MDV biogenesis for quality control, underscoring the heterogeneity of fission and mechanoregulation of mitochondrial dynamics.
    Keywords:  mitochondrial fission; mitochondrial quality control; optogenetics; photoactivatable proteins; tensile force
    DOI:  https://doi.org/10.1073/pnas.2217019121
  17. Ann Clin Transl Neurol. 2024 Mar 27.
    Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.
    Rhett G Marchant, Samantha J Bryen, Melanie Bahlo, Anita Cairns, Katherine R Chao, Alastair Corbett, Mark R Davis, Vijay S Ganesh, Roula Ghaoui, Kristi J Jones, Andrew J Kornberg, Monkol Lek, Christina Liang, Daniel G MacArthur, Emily C Oates, Anne O'Donnell-Luria, Gina L O'Grady, Ikeoluwa A Osei-Owusu, Haloom Rafehi, Stephen W Reddel, Richard H Roxburgh, Monique M Ryan, Sarah A Sandaradura, Liam W Scott, Elise Valkanas, Ben Weisburd, Helen Young, Frances J Evesson, Leigh B Waddell, Sandra T Cooper.
      OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice.METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required.
    RESULTS: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today.
    INTERPRETATION: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.
    DOI:  https://doi.org/10.1002/acn3.52041
  18. Front Neurol. 2024 ;15 1305404
    Therapeutic outcome of patients with Lennox-Gastaut syndrome with mitochondrial respiratory chain complex I deficiency.
    Ji-Hoon Na, Young-Mock Lee.
      Background: Lennox-Gastaut syndrome (LGS), a severe developmental epileptic encephalopathy, has various underlying causes. Mitochondrial respiratory chain complex I (MRC I) deficiency is an important cause of metabolic disorders such as mitochondrial dysfunction that can compromise brain function, thereby causing intractable epilepsy, including LGS. Thus, it can be expected that the presence or absence of MRC I deficiency may affect the treatment outcome of patients with LGS.Objectives: In this retrospective study, we aimed to investigate differences in the epilepsy characteristics and treatment outcomes between patients with LGS with and without MRC I deficiency.
    Methods: We retrospectively reviewed the medical records of 92 patients with LGS. We divided 68 patients with LGS according to the presence (n = 30) or absence (n = 38) of MRC I deficiency and compared their epilepsy characteristics.
    Results: Generalized tonic and drop seizures were significantly worse in patients with LGS and MRC I deficiency than in those without MRC I deficiency group at the 1-year follow-up (p < 0.001) and final follow-up 1 (p < 0.001). Patients with LGS and MRC I deficiency had significantly fewer electroencephalogram (EEG) improvements compared to those without MRC I deficiency at the 1-year follow-up (p = 0.031). Additionally, in the final follow-up period, patients with LGS and MRC I deficiency had significantly less improvement in EEG findings compared to patients without MRC I deficiency (p < 0.001).
    Conclusion: The overall treatment prognosis-in terms of improvement in traumatic generalized tonic seizure, drop seizure, and EEG findings-is worse in patients with LGS and MRC I deficiency than that in patients with LGS but without MRC I deficiency. Additional and targeted treatment is required to treat LGS with MRC I deficiency.
    Keywords:  Lennox–Gastaut syndrome (LGS); epilepsy; mitochondrial disease; mitochondrial dysfunction; mitochondrial respiratory chain complex I deficiency
    DOI:  https://doi.org/10.3389/fneur.2024.1305404
  19. PLoS One. 2024 ;19(3): e0301372
    Quantitative imaging and semiotic phenotyping of mitochondrial network morphology in live human cells.
    Sophie Charrasse, Victor Racine, Charlotte Saint-Omer, Titouan Poquillon, Loïc Lionnard, Marine Ledru, Christophe Gonindard, Sandrine Delaunois, Karima Kissa, Richard E Frye, Manuela Pastore, Christelle Reynes, Mathilde Frechet, Hanane Chajra, Abdel Aouacheria.
      The importance of mitochondria in tissue homeostasis, stress responses and human diseases, combined to their ability to transition between various structural and functional states, makes them excellent organelles for monitoring cell health. There is therefore a need for technologies to accurately analyze and quantify changes in mitochondrial organization in a variety of cells and cellular contexts. Here we present an innovative computerized method that enables accurate, multiscale, fast and cost-effective analysis of mitochondrial shape and network architecture from confocal fluorescence images by providing more than thirty features. In order to facilitate interpretation of the quantitative results, we introduced two innovations: the use of Kiviat-graphs (herein named MitoSpider plots) to present highly multidimensional data and visualization of the various mito-cellular configurations in the form of morphospace diagrams (called MitoSigils). We tested our fully automated image analysis tool on rich datasets gathered from live normal human skin cells cultured under basal conditions or exposed to specific stress including UVB irradiation and pesticide exposure. We demonstrated the ability of our proprietary software (named MitoTouch) to sensitively discriminate between control and stressed dermal fibroblasts, and between normal fibroblasts and other cell types (including cancer tissue-derived fibroblasts and primary keratinocytes), showing that our automated analysis captures subtle differences in morphology. Based on this novel algorithm, we report the identification of a protective natural ingredient that mitigates the deleterious impact of hydrogen peroxide (H2O2) on mitochondrial organization. Hence we conceived a novel wet-plus-dry pipeline combining cell cultures, quantitative imaging and semiotic analysis for exhaustive analysis of mitochondrial morphology in living adherent cells. Our tool has potential for broader applications in other research areas such as cell biology and medicine, high-throughput drug screening as well as predictive and environmental toxicology.
    DOI:  https://doi.org/10.1371/journal.pone.0301372
  20. Biochem Soc Trans. 2024 Mar 25. pii: BST20230189. [Epub ahead of print]
    Complex I activity in hypoxia: implications for oncometabolism.
    Christos Chinopoulos.
      Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis - a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised.
    Keywords:  OXPHOS; cancer; hypoxia; mitochondria; mtSLP
    DOI:  https://doi.org/10.1042/BST20230189
  21. Life (Basel). 2024 Mar 20. pii: 413. [Epub ahead of print]14(3):
    Supplementation of Nicotinic Acid and Its Derivatives Up-Regulates Cellular NAD+ Level Rather than Nicotinamide Derivatives in Cultured Normal Human Epidermal Keratinocytes.
    Takahiro Oyama, Takumi Yamamoto, Takeshi Kameda, Takanori Kamiya, Hideaki Abe, Takehiko Abe, Sei-Ichi Tanuma.
      Nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in various physiological processes within mammalian cells, including energy metabolism, redox homeostasis, and genetic regulation. In the majority of mammalian cellular contexts, NAD+ biosynthesis primarily relies on vitamin B3, including nicotinamide (NAM) and nicotinic acid (NA). The concept of NAD+ augmentation therapy has recently emerged as a promising strategy to mitigate aging-associated phenomena, termed rejuvenation. Despite the involvement of diverse enzymatic cascades in NAD+ biosynthesis, certain cellular environments exhibit deficiencies in specific enzymes, suggesting cell type-dependent variability in optimal NAD+ precursor selection. However, the optimization of NAD+ precursors for topical formulations has received scant attention thus far. In the present investigation, we sought to delineate the most efficacious precursor for augmenting NAD+ levels in human skin keratinocytes. Remarkably, NA supplementation led to a significant 1.3-fold elevation in intracellular NAD+ levels, even in the presence of nicotinamide phosphoribosyltransferase inhibition by FK866. Additionally, NA mononucleotide demonstrated a 1.5-fold increase (but not significant) in NAD+ levels following 100 μM application. Conversely, NAM and its derivatives failed to elicit a NAD+ response in keratinocytes. Notably, NA supplementation elicited up-regulation of mitochondrial superoxide dismutase (SOD2) and sirtuin 3 (SIRT3), indicative of its beneficial impact on mitochondrial function. Furthermore, NA mitigated rotenone-induced mitochondrial reactive oxygen species (ROS) accumulation. Collectively, these findings advocate for the potential utility of NA in topical applications aimed at skin rejuvenation.
    Keywords:  NAD+; inflammaging; keratinocyte; nicotinic acid; rejuvenation
    DOI:  https://doi.org/10.3390/life14030413
  22. Forensic Sci Res. 2024 Mar;9(1): owae012
    Expression of Concern: Mitochondrial Genome Sequencing with Short Overlapping Amplicons on Miseq FGx System.
      
    DOI:  https://doi.org/10.1093/fsr/owae012
  23. STAR Protoc. 2024 Mar 25. pii: S2666-1667(24)00136-9. [Epub ahead of print]5(2): 102971
    Protocol to assess bioenergetics and mitochondrial fuel usage in murine autoreactive immunocytes using the Seahorse Extracellular Flux Analyzer.
    Colleen L Mayberry, John J Wilson, Britney Sison, Chih-Hao Chang.
      Efficient metabolism, or the means by which cells produce energy resources, is critical for proper effector function. Here, we present a protocol for examining the bioenergetics and mitochondrial fuel utilization of primary murine autoreactive immunocytes using cellular metabolism-modulating drugs. We describe steps for plate calibration, isolation of primary immunocytes, and Seahorse assay plate preparation. We then detail procedures for performing the XF Cell Mito Stress Test followed by bioenergetics calculations and statistics. For complete details on the use and execution of this protocol, please refer to Wilson et al.1.
    Keywords:  Cell-based Assays; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2024.102971
  24. J Biol Chem. 2024 Mar 27. pii: S0021-9258(24)01732-0. [Epub ahead of print] 107235
    Deafness-associated tRNAPhe mutation impaired mitochondrial and cellular integrity.
    Xiaowan Chen, Feilong Meng, Chao Chen, Shujuan Li, Zhiqiang Chou, Baicheng Xu, Jun Q Mo, Yufen Guo, Min-Xin Guan.
      Defects in mitochondrial RNA metabolism have been linked to sensorineural deafness that often occurs as a consequence of damaged or deficient inner ear hair cells. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAPhe 593T>C mutation that changed a highly conserved uracil to cytosine at the position 17 of DHU-loop. The m.593T>C mutation altered tRNAPhe structure and function, including increased melting temperature, resistance to S1 nuclease-mediated digestion and conformational changes. The aberrant tRNA metabolism impaired mitochondrial translation, which was especially pronounced by decreases in levels of ND1, ND5, CYTB, CO1 and CO3 harboring higher numbers of phenylalanine. These alterations resulted in aberrant assembly, instability and reduced activities of respiratory chain enzyme complexes I, III, IV and intact supercomplexes overall. Furthermore, we found that the m.593T>C mutation caused markedly diminished membrane potential, and increased the production of reactive oxygen species in the mutant cell lines carrying the m.593T>C mutation. These mitochondrial dysfunctions led to the mitochondrial dynamic imbalance via increasing fission with abnormal mitochondrial morphology. Excessive fission impaired the process of autophagy including initiation phase, formation and maturation of the autophagosome. In particular, the m.593T>C mutation upregulated the PARKIN-dependent mitophagy pathway. These alterations promoted an intrinsic apoptotic process for the removal of damaged cells. Our findings provide critical insights into the pathophysiology of maternally inherited deafness arising from tRNA mutation-induced defects in mitochondrial and cellular integrity.
    Keywords:  apoptosis; deafness; mitochondrial dynamics; mitochondrial tRNA mutation; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2024.107235
  25. Nat Commun. 2024 Mar 28. 15(1): 2712
    Bioorthogonal photocatalytic proximity labeling in primary living samples.
    Ziqi Liu, Fuhu Guo, Yufan Zhu, Shengnan Qin, Yuchen Hou, Haotian Guo, Feng Lin, Peng R Chen, Xinyuan Fan.
      In situ profiling of subcellular proteomics in primary living systems, such as native tissues or clinic samples, is crucial for understanding life processes and diseases, yet challenging due to methodological obstacles. Here we report CAT-S, a bioorthogonal photocatalytic chemistry-enabled proximity labeling method, that expands proximity labeling to a wide range of primary living samples for in situ profiling of mitochondrial proteomes. Powered by our thioQM labeling warhead development and targeted bioorthogonal photocatalytic chemistry, CAT-S enables the labeling of mitochondrial proteins in living cells with high efficiency and specificity. We apply CAT-S to diverse cell cultures, dissociated mouse tissues as well as primary T cells from human blood, portraying the native-state mitochondrial proteomic characteristics, and unveiled hidden mitochondrial proteins (PTPN1, SLC35A4 uORF, and TRABD). Furthermore, CAT-S allows quantification of proteomic perturbations on dysfunctional tissues, exampled by diabetic mouse kidneys, revealing the alterations of lipid metabolism that may drive disease progression. Given the advantages of non-genetic operation, generality, and spatiotemporal resolution, CAT-S may open exciting avenues for subcellular proteomic investigations of primary samples that are otherwise inaccessible.
    DOI:  https://doi.org/10.1038/s41467-024-46985-3
  26. Int J Mol Sci. 2024 Mar 14. pii: 3303. [Epub ahead of print]25(6):
    Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature.
    Nicole Natarelli, Nimrit Gahoonia, Shaliz Aflatooni, Sahibjot Bhatia, Raja K Sivamani.
      Mitochondria are eukaryotic cellular organelles that function in energy metabolism, ROS production, and programmed cell death. Cutaneous epithelial and hair follicle dermal papilla cells are energy-rich cells that thereby may be affected by mitochondrial dysfunction and DNA mutation accumulation. In this review, we aimed to summarize the medical literature assessing dermatologic conditions and outcomes associated with mitochondrial dysfunction. A search of PubMed and Embase was performed with subsequent handsearching to retrieve additional relevant articles. Mitochondrial DNA (mtDNA) deletions, mutation accumulation, and damage are associated with phenotypic signs of cutaneous aging, hair loss, and impaired wound healing. In addition, several dermatologic conditions are associated with aberrant mitochondrial activity, such as systemic lupus erythematosus, psoriasis, vitiligo, and atopic dermatitis. Mouse model studies have better established causality between mitochondrial damage and dermatologic outcomes, with some depicting reversibility upon restoration of mitochondrial function. Mitochondrial function mediates a variety of dermatologic conditions, and mitochondrial components may be a promising target for therapeutic strategies.
    Keywords:  UVR; aging; atopic dermatitis; dermatology; hair loss; lupus; mitochondria; psoriasis; vitiligo; wound healing
    DOI:  https://doi.org/10.3390/ijms25063303
  27. Hum Genet. 2024 Mar 23.
    An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases.
    S Zucca, G Nicora, F De Paoli, M G Carta, R Bellazzi, P Magni, E Rizzo, I Limongelli.
      Identifying disease-causing variants in Rare Disease patients' genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called "Suggested Diagnosis", whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality. Starting from (1) the VCF file containing proband's variants, (2) the list of proband's phenotypes encoded in Human Phenotype Ontology terms, and optionally (3) the information about family members (if available), the "Suggested Diagnosis" ranks all the variants according to their machine learning prediction. This method significantly reduces the number of variants that need to be evaluated by geneticists by pinpointing causative variants in the very first positions of the prioritized list. Most importantly, our approach proved to be among the top performers within the CAGI6 Rare Genome Project Challenge, where it was able to rank the true causative variant among the first positions and, uniquely among all the challenge participants, increased the diagnostic yield of 12.5% by solving 2 undiagnosed cases.
    DOI:  https://doi.org/10.1007/s00439-023-02638-x
  28. Mol Hum Reprod. 2024 Mar 28. pii: gaae013. [Epub ahead of print]30(4):
    Correction to: Aggregated chromosomes/chromatin transfer: a novel approach for mitochondrial replacement with minimal mitochondrial carryover: the implications of mouse experiments for human aggregated chromosome transfer.
      
    DOI:  https://doi.org/10.1093/molehr/gaae013
  29. Pract Neurol. 2024 Mar 28. pii: pn-2023-004083. [Epub ahead of print]
    Lessons and pitfalls of whole genome sequencing.
    Christopher J Record, Mary M Reilly.
      Whole-genome sequencing (WGS) has recently become the first-line genetic investigation for many suspected genetic neurological disorders. While its diagnostic capabilities are innumerable, as with any test, it has its limitations. Clinicians should be aware of where WGS is extremely reliable (detecting single-nucleotide variants), where its reliability is much improved (detecting copy number variants and small repeat expansions) and where it may miss/misinterpret a variant (large repeat expansions, balanced structural variants or low heteroplasmy mitochondrial DNA variants). Bioinformatic technology and virtual gene panels are constantly evolving, and it is important to know what genes and what types of variant are being tested; the current National Health Service Genomic Medicine Service WGS offers more than early iterations of the 100 000 Genomes Project analysis. Close communication between clinician and laboratory, ideally through a multidisciplinary team meeting, is encouraged where there is diagnostic uncertainty.
    Keywords:  GENETICS; HMSN (CHARCOT-MARIE-TOOTH); NEUROGENETICS; NEUROPATHY
    DOI:  https://doi.org/10.1136/pn-2023-004083
  30. Biomolecules. 2024 Feb 20. pii: 248. [Epub ahead of print]14(3):
    Cloflucarban Illuminates Specificity and Context-Dependent Activation of the PINK1-Parkin Pathway by Mitochondrial Complex Inhibition.
    Adrian T Ramirez, Zeyu Liu, Quanbin Xu, Sarah Nowosadtko, Xuedong Liu.
      The PTEN-induced kinase 1 (PINK1)-Parkin pathway plays a vital role in maintaining a healthy pool of mitochondria in higher eukaryotic cells. While the downstream components of this pathway are well understood, the upstream triggers remain less explored. In this study, we conducted an extensive analysis of inhibitors targeting various mitochondrial electron transport chain (ETC) complexes to investigate their potential as activators of the PINK1-Parkin pathway. We identified cloflucarban, an antibacterial compound, as a novel pathway activator that simultaneously inhibits mitochondrial complexes III and V, and V. RNA interference (RNAi) confirmed that the dual inhibition of these complexes activates the PINK1-Parkin pathway. Intriguingly, we discovered that albumin, specifically bovine serum albumin (BSA) and human serum albumin (HSA) commonly present in culture media, can hinder carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced pathway activation. However, cloflucarban's efficacy remains unaffected by albumin, highlighting its reliability for studying the PINK1-Parkin pathway. This study provides insights into the activation of the upstream PINK1-Parkin pathway and underscores the influence of culture conditions on research outcomes. Cloflucarban emerges as a promising tool for investigating mitochondrial quality control and neurodegenerative diseases.
    Keywords:  CCCP; PINK1; Parkin; bovine serum albumin; cloflucarban; complex V; electron transport complex III; human serum albumin; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3390/biom14030248
  31. Anticancer Res. 2024 Apr;44(4): 1799-1802
    Novel Insights in Genetic Variant Classification.
    Anthoula Chatzikyriakidou.
      
    Keywords:  Complex inheritance; Mendelian inheritance; Single nucleotide polymorphism; VUS; benign; dominant; genetic heterogeneity; human disease; incomplete penetrance; pathogenic; recessive; variant classification
    DOI:  https://doi.org/10.21873/anticanres.16980
  32. Cell Death Differ. 2024 Mar 22.
    Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
    Shun-Ichi Yamashita, Yuki Sugiura, Yuta Matsuoka, Rae Maeda, Keiichi Inoue, Kentaro Furukawa, Tomoyuki Fukuda, David C Chan, Tomotake Kanki.
      Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.
    DOI:  https://doi.org/10.1038/s41418-024-01280-y
  33. Nutrients. 2024 Mar 13. pii: 812. [Epub ahead of print]16(6):
    Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.
    Dorota Wesół-Kucharska, Milena Greczan, Magdalena Kaczor, Ewa Ehmke Vel Emczyńska-Seliga, Małgorzata Hajdacka, Edyta Czekuć-Kryśkiewicz, Dorota Piekutowska-Abramczuk, Paulina Halat-Wolska, Elżbieta Ciara, Maciej Jaworski, Aleksandra Jezela-Stanek, Dariusz Rokicki.
      Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started (n = 11); group 2-patients with MD remaining on an ordinary diet (n = 10); group 3-patients without MD in whom KD treatment was initiated (n = 10), group 4-patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.
    Keywords:  IPMDS; ketogenic diet; mitochondrial diseases; mtDNA; nDNA
    DOI:  https://doi.org/10.3390/nu16060812
  34. Biochem Soc Trans. 2024 Mar 25. pii: BST20231183. [Epub ahead of print]
    Emerging mechanisms in the redox regulation of mitochondrial cytochrome c oxidase assembly and function.
    Suleva Povea-Cabello, Michele Brischigliaro, Erika Fernández-Vizarra.
      In eukaryotic cells, mitochondria perform cellular respiration through a series of redox reactions ultimately reducing molecular oxygen to water. The system responsible for this process is the respiratory chain or electron transport system (ETS) composed of complexes I-IV. Due to its function, the ETS is the main source of reactive oxygen species (ROS), generating them on both sides of the mitochondrial inner membrane, i.e. the intermembrane space (IMS) and the matrix. A correct balance between ROS generation and scavenging is important for keeping the cellular redox homeostasis and other important aspects of cellular physiology. However, ROS generated in the mitochondria are important signaling molecules regulating mitochondrial biogenesis and function. The IMS contains a large number of redox sensing proteins, containing specific Cys-rich domains, that are involved in ETS complex biogenesis. The large majority of these proteins function as cytochrome c oxidase (COX) assembly factors, mainly for the handling of copper ions necessary for the formation of the redox reactive catalytic centers. A particular case of ROS-regulated COX assembly factor is COA8, whose intramitochondrial levels are increased by oxidative stress, promoting COX assembly and/or protecting the enzyme from oxidative damage. In this review, we will discuss the current knowledge concerning the role played by ROS in regulating mitochondrial activity and biogenesis, focusing on the COX enzyme and with a special emphasis on the functional role exerted by the redox sensitive Cys residues contained in the COX assembly factors.
    Keywords:  complex IV; mitochondrial dysfunction; reactive oxygen species; redox signaling; respiratory chain assembly
    DOI:  https://doi.org/10.1042/BST20231183
  35. IUBMB Life. 2024 Mar 26.
    Mitochondrial respiratory supercomplexes of the yeast Saccharomyces cerevisiae.
    Mazzen H Eldeeb, Lizeth J Camacho Lopez, Flavia Fontanesi.
      The functional and structural relationship among the individual components of the mitochondrial respiratory chain constitutes a central aspect of our understanding of aerobic catabolism. This interplay has been a subject of intense debate for over 50 years. It is well established that individual respiratory enzymes associate into higher-order structures known as respiratory supercomplexes, which represent the evolutionarily conserved organizing principle of the mitochondrial respiratory chain. In the yeast Saccharomyces cerevisiae, supercomplexes are formed by a complex III homodimer flanked by one or two complex IV monomers, and their high-resolution structures have been recently elucidated. Despite the wealth of structural information, several proposed supercomplex functions remain speculative and our understanding of their physiological relevance is still limited. Recent advances in the field were made possible by the construction of yeast strains where the association of complex III and IV into supercomplexes is impeded, leading to diminished respiratory capacity and compromised cellular competitive fitness. Here, we discuss the experimental evidence and hypotheses relative to the functional roles of yeast respiratory supercomplexes. Moreover, we review the current models of yeast complex III and IV assembly in the context of supercomplex formation and highlight the data scattered throughout the literature suggesting the existence of cross talk between their biogenetic processes.
    Keywords:  III2IV1; III2IV2; OXPHOS biogenesis; Saccharomyces cerevisiae; cellular respiratory capacity; mitochondrial respiratory supercomplexes
    DOI:  https://doi.org/10.1002/iub.2817
  36. J Integr Neurosci. 2024 Mar 07. 23(3): 53
    Brain Mitochondria as a Therapeutic Target for Carnosic Acid.
    Vittoria Infantino, Ilaria Pappalardo, Anna Santarsiero, Swapnil Tripathi, Gyanendra Singh, Marcos Roberto de Oliveira.
      Carnosic acid (CA), a diterpene obtained mainly from Rosmarinus officinalis and Salvia officinalis, exerts antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. At least in part, those benefits are associated with the ability that CA modulates mitochondrial physiology. CA attenuated bioenergetics collapse and redox impairments in the mitochondria obtained from brain cells exposed to several toxicants in both in vitro and in vivo experimental models. CA is a potent inducer of the major modulator of the redox biology in animal cells, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of a myriad of genes whose products are involved with cytoprotection in different contexts. Moreover, CA upregulates signaling pathways related to the degradation of damaged mitochondria (mitophagy) and with the synthesis of these organelles (mitochondrial biogenesis). Thus, CA may be considered an agent that induces mitochondrial renewal, depending on the circumstances. In this review, we discuss about the mechanisms of action by which CA promotes mitochondrial protection in brain cells.
    Keywords:  Nrf2; antioxidant; brain; carnosic acid; mitochondria; neurons
    DOI:  https://doi.org/10.31083/j.jin2303053
  37. NPJ Genom Med. 2024 Mar 27. 9(1): 23
    Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action.
    Medical Genome Initiative
      
    DOI:  https://doi.org/10.1038/s41525-024-00410-2
  38. J Cent Nerv Syst Dis. 2024 ;16 11795735241241423
    Meningoencephalitis in a novel mutation in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) ending a familial diagnostic odyssey: A case series report.
    Noor Redha, Zahra Al-Sahlawi, Hasan Hasan, Sara Ghareeb, Hani Humaidan.
      MNGIE (Mitochondrial Neurogastrointestinal Encephalomyopathy) is an ultra-rare autosomal recessive disorder that leads to mutations in the nuclear genes encoding thymidine phosphorylase. Symptoms include gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoplegia, sensorimotor neuropathy and asymptomatic leukoencephalopathy. We describe the first case of MNGIE with meningoencephalitis that ultimately led to a familial diagnosis ending a diagnostic odyssey. We retrospectively reviewed the electronic medical records and sent whole exome sequencing for the index case and his family members. We report the variant c.877T>C p.(Cys293Arg) found in TYMP gene in all affected siblings showed typical clinical manifestations related to MNGIE. To the best of our knowledge, this is not described in the literature nor in the population databases dbSNP (Single Nucleotide Polymorphism Database) and gnomAD (Genome Aggregation Database). Additionally, it is located in a highly conserved residue and the bioinformatic analysis suggests it is most probably deleterious. Moreover, we estimated 550 number of cases of MNGIE (including 5 cases in this study) after performing an extensive search in the literature across 3 databases from 1983-2023. In addition, we identified 44 patients with MNGIE-like phenotype in genes other than TYMP. MNGIE-like phenotype affects POLG1, RRM2B, LIG3, RRM1, MTTV1, and MT-RNR1 genes.
    Keywords:  Mitochondrial neurogastrointestinal encephalomyopathy; atypical; case series; meningoencephalitis; novel mutation
    DOI:  https://doi.org/10.1177/11795735241241423
  39. Metabolites. 2024 Mar 04. pii: 152. [Epub ahead of print]14(3):
    Integrating Genome Sequencing and Untargeted Metabolomics in Monozygotic Twins with a Rare Complex Neurological Disorder.
    Rulan Shaath, Aljazi Al-Maraghi, Haytham Ali, Jehan AlRayahi, Adam D Kennedy, Karen L DeBalsi, Sura Hussein, Najwa Elbashir, Sujitha S Padmajeya, Sasirekha Palaniswamy, Sarah H Elsea, Ammira A Akil, Noha A Yousri, Khalid A Fakhro.
      Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy-Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms.
    Keywords:  multi-omics approaches; rare complex disease; untargeted metabolomics; whole-genome sequencing
    DOI:  https://doi.org/10.3390/metabo14030152
  40. Mol Metab. 2024 Mar 21. pii: S2212-8778(24)00053-X. [Epub ahead of print] 101922
    A practical and robust method to evaluate metabolic fluxes in primary pancreatic islets.
    Debora S Rocha, Antonio C Manucci, Alexandre Bruni-Cardoso, Alicia J Kowaltowski, Eloisa A Vilas-Boas.
      OBJECTIVE: Evaluation of mitochondrial oxygen consumption and ATP production is important to investigate pancreatic islet pathophysiology. Most studies use cell lines due to difficulties in measuring primary islet respiration, which requires specific equipment and consumables, is expensive and poorly reproducible. Our aim was to establish a practical method to assess primary islet metabolic fluxes using standard commercial consumables.METHODS: Pancreatic islets were isolated from mice/rats, dispersed with trypsin, and adhered to pre-coated standard Seahorse or Resipher microplates. Oxygen consumption was evaluated using a Seahorse Extracellular Flux Analyzer or a Resipher Real-time Cell Analyzer.
    RESULTS: We provide a detailed protocol with all steps to optimize islet isolation with high yield and functionality. Our method requires a few islets per replicate; both rat and mouse islets present robust basal respiration and proper response to mitochondrial modulators and glucose. The technique was validated by other functional assays, which show these cells present conserved calcium influx and insulin secretion in response to glucose. We also show that our dispersed islets maintain robust basal respiration levels, in addition to maintaining up to 89% viability after five days in dispersed cultures. Furthermore, OCRs can be measured in Seahorse analyzers and in other plate respirometry systems, using standard materials.
    CONCLUSIONS: Overall, we established a practical and robust method to assess islet metabolic fluxes and oxidative phosphorylation, a valuable tool to uncover basic β-cell metabolic mechanisms as well as for translational investigations, such as pharmacological candidate discovery and islet transplantation protocols.
    Keywords:  Mitochondrial respiration; Oxidative phosphorylation; Oxygen consumption; Pancreatic islets
    DOI:  https://doi.org/10.1016/j.molmet.2024.101922
  41. Camb Prism Precis Med. 2023 ;1 e2
    Ethical issues raised by new genomic technologies: the case study of newborn genome screening.
    Rachel Horton, Anneke Lucassen.
      Over the last two decades, the ability to sequence a person's genetic code has improved exponentially, while the cost of doing so has plummeted. As genome sequencing is used more widely, diagnoses are being found for people with previously unexplained rare disease, and this has raised hopes that such analysis might usefully be employed to detect and mitigate diseases as early as possible in the life course. However, research with adults by initiatives such as population biobanks should shake our confidence in our ability to make clear health predictions from a genetic code - in many cases, we are learning that the links between genomic variants and disease are far less strong than we once thought. The UK Newborn Genomes Programme aspires to sequence up to 200,000 babies at birth, and analyse their genomic data aiming to identify 'actionable genetic conditions which may affect their health in early years. This aims to ensure timely diagnosis, access to treatment pathways, and enable better outcomes and quality of life for babies and their families' (Genomics England, 2021). This is a laudable aim, but the path from obtaining genome sequences to enabling better outcomes will not be straightforward and illustrates many of the ethical challenges raised by the use of new genomic technologies. We focus particularly on the challenge of determining 'results' from the analysis of a genetic code, against a backdrop of promotional public discourses which tend to amplify best case scenarios from genome sequencing while minimising its potential to generate uncertainty.
    Keywords:  bioethics; data; ethics; genomics; screening
    DOI:  https://doi.org/10.1017/pcm.2022.2
  42. Cell. 2024 Mar 28. pii: S0092-8674(24)00248-4. [Epub ahead of print]187(7): 1785-1800.e16
    Spatial proteomics in neurons at single-protein resolution.
    Eduard M Unterauer, Sayedali Shetab Boushehri, Kristina Jevdokimenko, Luciano A Masullo, Mahipal Ganji, Shama Sograte-Idrissi, Rafal Kowalewski, Sebastian Strauss, Susanne C M Reinhardt, Ana Perovic, Carsten Marr, Felipe Opazo, Eugenio F Fornasiero, Ralf Jungmann.
      To understand biological processes, it is necessary to reveal the molecular heterogeneity of cells by gaining access to the location and interaction of all biomolecules. Significant advances were achieved by super-resolution microscopy, but such methods are still far from reaching the multiplexing capacity of proteomics. Here, we introduce secondary label-based unlimited multiplexed DNA-PAINT (SUM-PAINT), a high-throughput imaging method that is capable of achieving virtually unlimited multiplexing at better than 15 nm resolution. Using SUM-PAINT, we generated 30-plex single-molecule resolved datasets in neurons and adapted omics-inspired analysis for data exploration. This allowed us to reveal the complexity of synaptic heterogeneity, leading to the discovery of a distinct synapse type. We not only provide a resource for researchers, but also an integrated acquisition and analysis workflow for comprehensive spatial proteomics at single-protein resolution.
    Keywords:  DNA-PAINT; excitatory synapses; inhibitory synapses; multiplexing; neuron atlas; neuron imaging; proteomics; spatial-omics; super-resolution microscopy; synapse; synapse diversity; synaptic proteins
    DOI:  https://doi.org/10.1016/j.cell.2024.02.045
  43. Nat Commun. 2024 Mar 26. 15(1): 2642
    Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology.
    Thomas M Goralski, Lindsay Meyerdirk, Libby Breton, Laura Brasseur, Kevin Kurgat, Daniella DeWeerd, Lisa Turner, Katelyn Becker, Marie Adams, Daniel J Newhouse, Michael X Henderson.
      A key hallmark of Parkinson's disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with α-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril α-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans.
    DOI:  https://doi.org/10.1038/s41467-024-47027-8
  44. J Cell Mol Med. 2024 Apr;28(8): e18276
    HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.
    Nan Zhang, Zi-Ying Zhou, Yan-Yan Meng, Hai-Han Liao, Shan-Qi Mou, Zheng Lin, Han Yan, Si Chen, Qi-Zhu Tang.
      Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.
    Keywords:  HINT2; NDUFs; cardiac remodelling; hypertrophy; mitochondrial complex I
    DOI:  https://doi.org/10.1111/jcmm.18276
  45. Hum Gene Ther. 2024 Mar 27.
    Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases.
    Chujiao Lin, Matthew Greenblatt, Guangping Gao, Jae-Hyuck Shim.
      Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low post-infection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations in AAV-mediated gene therapy strategies, such as gene addition, gene replacement, gene silencing, and gene editing, offer new approaches to clinical application. Recently, the increasing pre-clinical applications of AAV to rare skeletal diseases, such as fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI), and prevalent bone diseases, such as osteoporosis, bone fracture, critical-sized bone defects, and osteoarthritis, have been reported. Despite existing limitations in clinical use, such as high cost and safety, the AAV-mediated gene transfer platform is a promising approach to deliver therapeutic gene(s) to the skeleton to treat skeletal disorders, including those otherwise intractable by other therapeutic approaches. This review provides a comprehensive overview of the therapeutic advancements, challenges, limitations, and solutions within AAV-based gene therapy for prevalent and rare skeletal diseases.
    DOI:  https://doi.org/10.1089/hum.2024.022
  46. Camb Prism Precis Med. 2023 ;1 e17
    Precision diagnostics in children.
    Paul Dimitri.
      Medical practice is transforming from a reactive to a pro-active and preventive discipline that is underpinned by precision medicine. The advances in technologies in such fields as genomics, proteomics, metabolomics, transcriptomics and artificial intelligence have resulted in a paradigm shift in our understanding of specific diseases in childhood, greatly enhanced by our ability to combine data from changes within cells to the impact of environmental and population changes. Diseases in children have been reclassified as we understand more about their genomic origin and their evolution. Genomic discoveries, additional 'omics' data and advances such as optical genome mapping have driven rapid improvements in the precision and speed of diagnoses of diseases in children and are now being incorporated into newborn screening, have improved targeted therapies in childhood and have supported the development of predictive biomarkers to assess therapeutic impact and determine prognosis in congenital and acquired diseases of childhood. New medical device technologies are facilitating data capture at a population level to support higher diagnostic accuracy and tailored therapies in children according to predicted population outcome, and digital ecosystems now tailor therapies and provide support for their specific needs. By capturing biological and environmental data as early as possible in childhood, we can understand factors that predict disease or maintain health and track changes across a more extensive longitudinal path. Data from multiple health and external sources over long-time periods starting from birth or even in the in utero environment will provide further clarity about how to sustain health and prevent or predict disease. In this respect, we will not only use data to diagnose disease, but precision diagnostics will aid the 'diagnosis of good health'. The principle of 'start early and change more' will thus underpin the value of applying a personalised medicine approach early in life.
    Keywords:  children; machine learning; omics; precision diagnostics; precision medicine
    DOI:  https://doi.org/10.1017/pcm.2023.4
  47. Eur J Med Chem. 2024 Mar 26. pii: S0223-5234(24)00241-1. [Epub ahead of print]269 116361
    Discovery of a triphenylamine-based ligand that targets mitochondrial DNA G-quadruplexes and activates the cGAS-STING immunomodulatory pathway.
    Xiao-Dong Wang, Yong-Si Liu, Meng-Die Chen, Ming-Hao Hu.
      Stabilization of G-quadruplex (G4) structures in mitochondria leads to the damage of mitochondrial DNA (mtDNA), making mtDNA G4s a promising target in the field of cancer therapy in recent years. Damaged mtDNA released into the cytosol can stimulate cytosolic DNA-sensing pathways, and cGAS-STING pathway is a typical one with potent immunostimulatory effects. A few small molecule ligands of mtDNA G4s are identified with antitumor efficacy, but little is known about their results and mechanisms on immunomodulation. In this study, we engineered a series of triphenylamine-based analogues targeting mtDNA G4s, and A6 was determined as the most promising compound. Cellular studies indicated that A6 caused severe mtDNA damage. Then, damaged mtDNA stimulated cGAS-STING pathway, resulting in the following cytokine production of tumor cells and the maturation of DCs. In vivo experiments certified that A6 exerted suppressive influences on tumor growth and metastasis in 4T1 cell-bearing mice by the regulation of TME, including the remodeling of macrophages and the activation of T cells. To our knowledge, it is the first time to report a ligand targeting mtDNA G4s to activate the cGAS-STING immunomodulatory pathway, providing a novel strategy for the future development of mtDNA G4-based antitumor agents.
    Keywords:  G-quadruplex; Mitochondrial DNA; cGAS-STING
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116361
  48. Cells. 2024 Mar 07. pii: 473. [Epub ahead of print]13(6):
    The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.
    Fernanda L Basei, Ivan Rosa E Silva, Pedro R Firmino Dias, Camila C Ferezin, Andressa Peres de Oliveira, Luidy K Issayama, Livia A R Moura, Fernando Riback da Silva, Jörg Kobarg.
      Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family.
    Keywords:  Nek kinase family functions; cell cycle; cellular signaling; mitochondrial homeostasis
    DOI:  https://doi.org/10.3390/cells13060473
  49. Eye (Lond). 2024 Mar 27.
    Programmed axon death: a promising target for treating retinal and optic nerve disorders.
    Andrea Loreto, Elisa Merlini, Michael P Coleman.
      Programmed axon death is a druggable pathway of axon degeneration that has garnered considerable interest from pharmaceutical companies as a promising therapeutic target for various neurodegenerative disorders. In this review, we highlight mechanisms through which this pathway is activated in the retina and optic nerve, and discuss its potential significance for developing therapies for eye disorders and beyond. At the core of programmed axon death are two enzymes, NMNAT2 and SARM1, with pivotal roles in NAD metabolism. Extensive preclinical data in disease models consistently demonstrate remarkable, and in some instances, complete and enduring neuroprotection when this mechanism is targeted. Findings from animal studies are now being substantiated by genetic human data, propelling the field rapidly toward clinical translation. As we approach the clinical phase, the selection of suitable disorders for initial clinical trials targeting programmed axon death becomes crucial for their success. We delve into the multifaceted roles of programmed axon death and NAD metabolism in retinal and optic nerve disorders. We discuss the role of SARM1 beyond axon degeneration, including its potential involvement in neuronal soma death and photoreceptor degeneration. We also discuss genetic human data and environmental triggers of programmed axon death. Lastly, we touch upon potential therapeutic approaches targeting NMNATs and SARM1, as well as the nicotinamide trials for glaucoma. The extensive literature linking programmed axon death to eye disorders, along with the eye's suitability for drug delivery and visual assessments, makes retinal and optic nerve disorders strong contenders for early clinical trials targeting programmed axon death.
    DOI:  https://doi.org/10.1038/s41433-024-03025-0
  50. Front Immunol. 2024 ;15 1374796
    Mitochondrial extracellular vesicles, autoimmunity and myocarditis.
    Damian N Di Florio, Danielle J Beetler, Elizabeth J McCabe, Jon Sin, Tsuneya Ikezu, DeLisa Fairweather.
      For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish. Recent studies have shown that viral infections that are commonly associated with viral myocarditis and other autoimmune diseases such as coxsackievirus B3 (CVB3) and SARS-CoV-2 target mitochondria and are released from cells in mitochondrial vesicles that are able to activate the innate immune response. Studies have shown that Toll-like receptor (TLR)4 and the inflammasome pathway are activated by mitochondrial components. Autoreactivity against cardiac myosin and heart-specific immune responses that occur after infection with viruses where the heart is not the primary site of infection (e.g., CVB3, SARS-CoV-2) may occur because the heart has the highest density of mitochondria in the body. Evidence exists for autoantibodies against mitochondrial antigens in patients with myocarditis and dilated cardiomyopathy. Defects in tolerance mechanisms like autoimmune regulator gene (AIRE) may further increase the likelihood of autoreactivity against mitochondrial antigens leading to autoimmune disease. The focus of this review is to summarize current literature regarding the role of viral infection in the production of extracellular vesicles containing mitochondria and virus and the development of myocarditis.
    Keywords:  AIRE; autoimmune disease; coxsackievirus; extracellular vesicles; mitochondria; mitochondrial-derived vesicles; myocarditis
    DOI:  https://doi.org/10.3389/fimmu.2024.1374796
  51. Camb Prism Precis Med. 2023 ;1 e7
    From genetic variation to precision medicine.
    Panagiotis I Sergouniotis, Tomas Fitzgerald, Ewan Birney.
      Genetics has been an important tool for discovering new aspects of biology across life. In humans, there is growing momentum behind the application of this knowledge to drive innovation in clinical care, most notably through developments in precision medicine. Nowhere has the impact of genetics on clinical practice been more striking than in the field of rare disorders. For most of these conditions, individual disease susceptibility is influenced by DNA sequence variation in a single or a small number of genes. In contrast, most common disorders are multifactorial and are caused by a complex interplay of multiple genetic, environmental and stochastic factors. The longstanding division of human disease genetics into rare and common components has obscured the continuum of human traits and echoes aspects of the century-old debate between the Mendelian and biometric views of human genetics. In this article, we discuss the differences in data and concepts between rare and common disease genetics. Opportunities to unify these two areas are noted and the importance of adopting a holistic perspective that integrates diverse genetic and environmental factors is discussed.
    Keywords:  data integration; genetics; genomics; personalized medicine
    DOI:  https://doi.org/10.1017/pcm.2022.11
  52. Chem Biol Interact. 2024 Mar 27. pii: S0009-2797(24)00121-2. [Epub ahead of print] 110975
    Nickel induces mitochondrial damage in renal cells in vitro and in vivo through its effects on mitochondrial biogenesis, fusion, and fission.
    Heng Yin, Xinglai Li, Chengbi Wang, Xiaocong Li, Jingbo Liu.
      Nickel (Ni) and its compounds are common, widely distributed components of hazardous waste in the chemical industry. Excessive exposure to Ni can cause kidney damage in humans and animals. We investigated the impact of Ni on renal mitochondria using in vivo and in vitro models of Ni nephrotoxicity, and explored the Ni nephrotoxic mechanism. We showed that nickel chloride (NiCl2) damaged the renal mitochondria, causing mitochondrial swelling, breakage of the mitochondrial cristae, increased levels of mitochondrial reactive oxygen species (mt-ROS), and depolarization of the mitochondrial membrane potential (MMP). The levels of the mitochondrial respiratory chain complexes I-IV were reduced in the kidneys of mice treated with NiCl2. In addition, NiCl2 treatment inhibited mitochondrial biogenesis in renal cells by down-regulating mRNA and the protein expression of TFAM, PGC-1α, and NRF1. Moreover, NiCl2 reduced the levels of the proteins involved in mitochondrial fusion, including Mfn1 and Mfn2, while significantly augmenting the levels of the proteins Fis1 and Drip1 involved in mitochondrial fission in renal cells. Taken together, these results suggested that NiCl2 inhibited mitochondrial biogenesis, suppressed mitochondrial fusion, and promoted mitochondrial fission, resulting in mitochondrial dysfunction in renal cells, ultimately causing renal injury. This study provided novel insights into the mechanisms of nephrotoxicity of Ni and new ideas for the development of targeted treatments for Ni-induced kidney injury.
    Keywords:  Kidney; Mitochondria; Mitochondrial biogenesis; Mitochondrial division; Mitochondrial fusion; Nickel
    DOI:  https://doi.org/10.1016/j.cbi.2024.110975
  53. Hepatol Commun. 2024 Apr 01. pii: e0408. [Epub ahead of print]8(4):
    Genetics of liver disease in adults.
    Chigoziri Konkwo, Shanin Chowdhury, Silvia Vilarinho.
      Chronic liver disease stands as a significant global health problem with an estimated 2 million annual deaths across the globe. Combining the use of next-generation sequencing technologies with evolving knowledge in the interpretation of genetic variation across the human genome is propelling our understanding, diagnosis, and management of both rare and common liver diseases. Here, we review the contribution of risk and protective alleles to common forms of liver disease, the rising number of monogenic diseases affecting the liver, and the role of somatic genetic variants in the onset and progression of oncological and non-oncological liver diseases. The incorporation of genomic information in the diagnosis and management of patients with liver disease is driving the beginning of a new era of genomics-informed clinical hepatology practice, facilitating personalized medicine, and improving patient care.
    DOI:  https://doi.org/10.1097/HC9.0000000000000408
  54. Nitric Oxide. 2024 Mar 21. pii: S1089-8603(24)00039-9. [Epub ahead of print]146 19-23
    Sulfide catabolism in hibernation and neuroprotection.
    Fumito Ichinose, Allyson Hindle.
      The mammalian brain is exquisitely vulnerable to lack of oxygen. However, the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. In this narrative review, we present a case for sulfide catabolism as a key defense mechanism of the brain against acute oxygen shortage. We will examine literature on the role of sulfide in hypoxia/ischemia, deep hibernation, and leigh syndrome patients, and present our recent data that support the neuroprotective effects of sulfide catabolism and persulfide production. When oxygen levels become low, hydrogen sulfide (H2S) accumulates in brain cells and impairs the ability of these cells to use the remaining, available oxygen to produce energy. In recent studies, we found that hibernating ground squirrels, which can withstand very low levels of oxygen, have high levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize hydrogen sulfide in the brain. Silencing SQOR increased the sensitivity of the brain of squirrels and mice to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury in mice. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological agents that scavenge sulfide and/or increase persulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to ischemic injury to the brain or spinal cord. Drugs that oxidize hydrogen sulfide and/or increase persulfide may prove to be an effective approach to the treatment of patients experiencing brain injury caused by oxygen deprivation or mitochondrial dysfunction.
    DOI:  https://doi.org/10.1016/j.niox.2024.03.002
  55. Neurol Genet. 2024 Apr;10(2): e200138
    Clinical and Genetic Analysis of Patients With TK2 Deficiency.
    for TK2d Spanish-Group
      Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion. Subsequently, less severe variants of the disease were described, with onset of symptoms during adolescence or adulthood and associated with the presence of multiple mtDNA deletions. These less severe phenotypes have been reported in only 15% of the approximately 120 patients described worldwide. However, some reports suggest that these juvenile and adult-onset presentations may be more common. The objective of this study was to describe the clinical phenotype in a sample of patients from Spain.Methods: This study includes 53 patients harboring biallelic TK2 pathogenic variants, compiling data retrospectively from 7 Spanish centers. We analyzed allele frequency, investigated the most recent common ancestor of core haplotypes, and used the Runs of Homozygosity approach to investigate variant coalescence.
    Results: Symptom onset distribution revealed that 32 patients (60%) experienced symptoms beyond 12 years of age. Approximately 30% of patients died of respiratory insufficiency, while 56% of surviving patients needed mechanical ventilation. Genetic analysis identified 16 distinct variants in TK2. Two variants, p.Lys202del and p.Thr108Met, exhibited significantly higher prevalence in the Spanish population than that reported in gnomAD database (86-fold and 13-fold, respectively). These variants are estimated to have originated approximately 16.8 generations ago for p.Thr108Met and 95.2 generations ago for p.Lys202del within the Spanish population, with the increase in frequency attributed to various forms of inbreeding. In late-onset cases, 46.9% carried the p.Lys202del variant.
    Discussion: The higher frequency of TK2d in Spain can be partially attributed to the increased prevalence of 2 variants and consanguinity. Notably, in 60% of the cohort, the disease was late-onset, emphasizing the potential underdiagnosis of this subgroup of patients in other regions. Raising awareness of this potentially treatable disorder is of utmost importance because early interventions can significantly affect the quality of life and survival of affected individuals.
    DOI:  https://doi.org/10.1212/NXG.0000000000200138
  56. Brief Funct Genomics. 2024 Mar 23. pii: elae007. [Epub ahead of print]
    Understanding large scale sequencing datasets through changes to protein folding.
    David Shorthouse, Harris Lister, Gemma S Freeman, Benjamin A Hall.
      The expansion of high-quality, low-cost sequencing has created an enormous opportunity to understand how genetic variants alter cellular behaviour in disease. The high diversity of mutations observed has however drawn a spotlight onto the need for predictive modelling of mutational effects on phenotype from variants of uncertain significance. This is particularly important in the clinic due to the potential value in guiding clinical diagnosis and patient treatment. Recent computational modelling has highlighted the importance of mutation induced protein misfolding as a common mechanism for loss of protein or domain function, aided by developments in methods that make large computational screens tractable. Here we review recent applications of this approach to different genes, and how they have enabled and supported subsequent studies. We further discuss developments in the approach and the role for the approach in light of increasingly high throughput experimental approaches.
    Keywords:  DDG; folding; genomics; mutation; structure
    DOI:  https://doi.org/10.1093/bfgp/elae007
  57. Biomolecules. 2024 Feb 28. pii: 289. [Epub ahead of print]14(3):
    Astrocytes: The Stars in Neurodegeneration?
    Katarina Stoklund Dittlau, Kristine Freude.
      Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.
    Keywords:  astrocyte; cell autonomous; cross-disease; neurodegeneration; non-cell autonomous; reactivity
    DOI:  https://doi.org/10.3390/biom14030289
  58. Biomedicines. 2024 Mar 13. pii: 641. [Epub ahead of print]12(3):
    MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons.
    Christiane Hartmann, Marie Anskat, Marc Ehrlich, Jared Sterneckert, Arun Pal, Andreas Hermann.
      Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5-20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches.
    Keywords:  FTD; MAPT; TAU; axonal outgrowth; lysosome; microtubule; mitochondria; organelle trafficking; tubulin modification
    DOI:  https://doi.org/10.3390/biomedicines12030641
  59. Nat Rev Genet. 2024 Mar 28.
    Genetic variation across and within individuals.
    Zhi Yu, Tim H H Coorens, Md Mesbah Uddin, Kristin G Ardlie, Niall Lennon, Pradeep Natarajan.
      Germline variation and somatic mutation are intricately connected and together shape human traits and disease risks. Germline variants are present from conception, but they vary between individuals and accumulate over generations. By contrast, somatic mutations accumulate throughout life in a mosaic manner within an individual due to intrinsic and extrinsic sources of mutations and selection pressures acting on cells. Recent advancements, such as improved detection methods and increased resources for association studies, have drastically expanded our ability to investigate germline and somatic genetic variation and compare underlying mutational processes. A better understanding of the similarities and differences in the types, rates and patterns of germline and somatic variants, as well as their interplay, will help elucidate the mechanisms underlying their distinct yet interlinked roles in human health and biology.
    DOI:  https://doi.org/10.1038/s41576-024-00709-x
  60. Genes (Basel). 2024 Mar 16. pii: 367. [Epub ahead of print]15(3):
    Dynamics of Mitochondrial DNA Copy Number and Membrane Potential in Mouse Pre-Implantation Embryos: Responses to Diverse Types of Oxidative Stress.
    Yasmyn E Winstanley, Jun Liu, Deepak Adhikari, Macarena B Gonzalez, Darryl L Russell, John Carroll, Rebecca L Robker.
      Mitochondria undergo a myriad of changes during pre-implantation embryo development, including shifts in activity levels and mitochondrial DNA (mtDNA) replication. However, how these distinct aspects of mitochondrial function are linked and their responsiveness to diverse stressors is not well understood. Here, we show that mtDNA content increased between 8-cell embryos and the blastocyst stage, with similar copy numbers per cell in the inner cell mass (ICM) and trophectoderm (TE). In contrast, mitochondrial membrane potential (MMP) was higher in TE than ICM. Culture in ambient oxygen (20% O2) altered both aspects of mitochondrial function: the mtDNA copy number was upregulated in ICM, while MMP was diminished in TE. Embryos cultured in 20% O2 also exhibited delayed development kinetics, impaired implantation, and reduced mtDNA levels in E18 fetal liver. A model of oocyte mitochondrial stress using rotenone showed only a modest effect on on-time development and did not alter the mtDNA copy number in ICM; however, following embryo transfer, mtDNA was higher in the fetal heart. Lastly, endogenous mitochondrial dysfunction, induced by maternal age and obesity, altered the blastocyst mtDNA copy number, but not within the ICM. These results demonstrate that mitochondrial activity and mtDNA content exhibit cell-specific changes and are differentially responsive to diverse types of oxidative stress during pre-implantation embryogenesis.
    Keywords:  inner cell mass; mitochondrial dysfunction; mitochondrial membrane potential; mtDNA copy number
    DOI:  https://doi.org/10.3390/genes15030367
  61. Front Mol Biosci. 2024 ;11 1392943
    Editorial: AI and multi-omics for rare diseases: challenges, advances and perspectives, Volume III.
    Frank Emmert-Streib, Silvia Bottini, Leonardo Franco.
      
    Keywords:  artificial intelligence; data science; high-throughput; omics; rare disease
    DOI:  https://doi.org/10.3389/fmolb.2024.1392943
  62. J Hepatol. 2024 Mar 27. pii: S0168-8278(24)00219-8. [Epub ahead of print]
    Review: Opportunities and barriers for omics-based biomarker discovery in steatotic liver diseases.
    MicrobLiver and GALAXY consortia
      The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognosis and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to combine clinical needs with technological advancements. Omics technologies allow for advanced investigations into biological processes from the genes to transcription and regulation, to circulating protein, metabolite and lipid levels, as well as the microbiome including bacteria, viruses and fungi. We consequently find ourselves in a period of rapid progress in technology and bioinformatics that may allow for development of precision biomarkers for personalised medicine. However, there are important barriers to consider in omics biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate across diverse populations, presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression in different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated through omics-technologies holds the power of hypothesis-free discovery of a plethora of candidate biomarkers to be further validated. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches.
    Keywords:  Genetics; Metabolomics; Metagenomics; Microbiome; Non-invasive test; Viromics; lipidomics; metatranscriptomics; proteomics
    DOI:  https://doi.org/10.1016/j.jhep.2024.03.035
  63. Cell Metab. 2024 Mar 23. pii: S1550-4131(24)00082-2. [Epub ahead of print]
    Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.
    Lingfeng Tong, Zhangbing Chen, Yangyang Li, Xinxia Wang, Changjie Yang, Yakui Li, Yemin Zhu, Ying Lu, Qi Liu, Nannan Xu, Sijia Shao, Lifang Wu, Ping Zhang, Guangyu Wu, Xiaoyu Wu, Xiaosong Chen, Junwei Fang, Renbing Jia, Tianle Xu, Bin Li, Liang Zheng, Junling Liu, Xuemei Tong.
      Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.
    Keywords:  GalNAc-siRNA conjugates; MAFLD; inosine; metabolic dysfunction-associated fatty liver disease; mitochondrial function; transketolase
    DOI:  https://doi.org/10.1016/j.cmet.2024.03.003
  64. Eur J Clin Invest. 2024 Mar 26. e14199
    Mitophagy modulation for the treatment of cardiovascular diseases.
    Italian Society of Cardiology Working Group on Cellular and Molecular Biology of the Heart
      BACKGROUND: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target.METHODS: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis.
    RESULTS: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression.
    CONCLUSIONS: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge.
    Keywords:  autophagy; heart failure; metabolic cardiomyopathy; mitochondrial dysfunction; mitophagy; myocardial ischemia
    DOI:  https://doi.org/10.1111/eci.14199
  65. Int Immunopharmacol. 2024 Mar 28. pii: S1567-5769(24)00428-4. [Epub ahead of print]132 111910
    Rapamycin alleviates mitochondrial dysfunction in anti-NMDAR encephalitis mice.
    Liangbo Kong, Xiaxin Yang, Anqi Sun, Xue Yang, Xiuhe Zhao, Shengjun Wang.
      Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most prevalent forms of autoimmune encephalitis, characterized by a series of neurological and psychiatric symptoms, including cognitive impairment, seizures and psychosis. The underlying mechanism of anti-NMDAR encephalitis remains unclear. In the current study, the mouse model of anti-NMDAR encephalitis with active immunization was performed. We first uncovered excessive mitochondrial fission in the hippocampus and temporal cortex of anti-NMDAR encephalitis mice, indicated by elevated level of Phospho-DRP1 (Ser616) (p-Drp1-S616). Moreover, blockade of the autophagic flux was also demonstrated, leading to the accumulation of fragmented mitochondria, and elevated levels of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) in anti-NMDAR encephalitis. More importantly, we found that the mTOR signaling pathway was overactivated, which could aggravate mitochondrial fission and inhibit autophagy, resulting in mitochondrial dysfunction. While rapamycin, the specific inhibitor of the mTOR signaling pathway, significantly alleviated mitochondrial dysfunction by inhibiting mitochondrial fission and enhancing autophagy. Levels of mtROS and mtDNA were markedly reduced after the treatment of rapamycin. In addition, rapamycin also significantly alleviated cognitive dysfunction and anxious behaviors found in anti-NMDAR encephalitis mice. Thus, our study reveals the vital role of mitochondrial dysfunction in pathological mechanism of anti-NMDAR encephalitis and lays a theoretical foundation for rapamycin to become a clinically targeted drug for anti-NMDAR encephalitis.
    Keywords:  Autophagy; Mitochondrial dysfunction; Mitochondrial fission; Rapamycin; anti-NMDAR encephalitis; mTOR signaling
    DOI:  https://doi.org/10.1016/j.intimp.2024.111910
  66. J Pers Med. 2024 Feb 27. pii: 254. [Epub ahead of print]14(3):
    Digital Anti-Aging Healthcare: An Overview of the Applications of Digital Technologies in Diet Management.
    Tagne Poupi Theodore Armand, Hee-Cheol Kim, Jung-In Kim.
      Diet management has long been an important practice in healthcare, enabling individuals to get an insight into their nutrient intake, prevent diseases, and stay healthy. Traditional methods based on self-reporting, food diaries, and periodic assessments have been used for a long time to control dietary habits. These methods have shown limitations in accuracy, compliance, and real-time analysis. The rapid advancement of digital technologies has revolutionized healthcare, including the diet control landscape, allowing for innovative solutions to control dietary patterns and generate accurate and personalized recommendations. This study examines the potential of digital technologies in diet management and their effectiveness in anti-aging healthcare. After underlining the importance of nutrition in the aging process, we explored the applications of mobile apps, web-based platforms, wearables devices, sensors, the Internet of Things, artificial intelligence, blockchain, and other technologies in managing dietary patterns and improving health outcomes. The research further examines the effects of digital dietary control on anti-aging healthcare, including improved nutritional monitoring, personalized recommendations, and behavioral and sustainable changes in habits, leading to an expansion of longevity and health span. The challenges and limitations of digital diet monitoring are discussed, and some future directions are provided. Although many digital tools are used in diet control, their accuracy, effectiveness, and impact on health outcomes are not discussed much. This review consolidates the existing literature on digital diet management using emerging digital technologies to analyze their practical implications, guiding researchers, healthcare professionals, and policy makers toward personalized dietary management and healthy aging.
    Keywords:  anti-aging healthcare; diet management; digital technologies; healthy aging; personalized recommendations
    DOI:  https://doi.org/10.3390/jpm14030254
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