bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–02–18
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
  2. Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.
  3. The HRI branch of the integrated stress response selectively triggers mitophagy.
  4. Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
  5. Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.
  6. Perceived association of mood and symptom severity in adults with mitochondrial diseases.
  7. Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
  8. The therapeutic perspective of NAD+ precursors in age-related diseases.
  9. FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.
  10. BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
  11. The role of mitophagy in metabolic diseases and its exercise intervention.
  12. Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.
  13. Mitochondrial disorders: Emerging paradigms and the road ahead to personalized medicine.
  14. Disruption of mitochondrial unfolded protein response results in telomere shortening in mouse oocytes and somatic cells.
  15. Mitochondrial Calcium Transport During Autophagy Initiation.
  16. Cisplatin drives mitochondrial dysregulation in sensory hair cells.
  17. Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
  18. A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.
  19. COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.
  20. A Japanese Case of Leber's Hereditary Optic Neuropathy with the m.13051G>A Pathogenic Variant.
  21. Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
  22. Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
  23. Genome sequencing as a generic diagnostic strategy for rare disease.
  24. Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
  25. Unraveling the Diagnostic Puzzle: Minor Stroke-Like Lesions and Normal Muscle Histopathology in MELAS Syndrome.
  26. Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.
  27. RalA links obesity and mitochondrial dysfunction.
  28. Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.
  29. Mitochondria and diabetes: insights and potential therapies.
  30. A system for inducible mitochondria-specific protein degradation in vivo.
  31. Restricting bioenergetic efficiency enhances longevity and mitochondrial redox capacity in Drosophila melanogaster.
  32. Sequencing and characterizing short tandem repeats in the human genome.
  33. SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
  34. A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
  35. Spatial domain detection using contrastive self-supervised learning for spatial multi-omics technologies.
  36. The functional roles of S-adenosyl-methionine and S-adenosyl-homocysteine and their involvement in trisomy 21.
  37. Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.
  38. Mini-review of DNA Methylation Detection Techniques and Their Potential Applications in Disease Diagnosis, Prognosis, and Treatment.
  39. NADH: the redox sensor in aging-related disorders.
  40. Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
  41. Protocol to investigate Parkinson's patient-derived dopaminergic neurons by live-cell microscopy and oxidized dopamine assays.
  42. Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
  43. Learning to Make Rare and Complex Diagnoses With Generative AI Assistance: Qualitative Study of Popular Large Language Models.
  44. Two Turkish patients with Primary Coenzyme Q10 Deficiency-7: case report and literature review.
  45. Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.
  46. Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
  47. The cell biology of ferroptosis.
  48. Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
  49. Renal aging and mitochondrial quality control.
  50. Did mitophagy follow the origin of mitochondria?
  51. Variant and clinical landscape of Leber hereditary optic neuropathy based on 1516 families with mtDNA variants in a tertiary centre.
  52. Lived experiences of genetic diagnosis for rare disease patients: a qualitative interview study.
  53. Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
  54. Refining the clinical diagnosis of Parkinson's disease.
  55. SLC25A39 links mitochondrial GSH sensing with iron metabolism.
  56. Gene-editing breakthrough for a rare hereditary disorder.
  57. A supervised learning method for classifying methylation disorders.
  58. Eliciting parental preferences and values for the return of additional findings from genomic sequencing.
  59. Deep learning predicts prevalent and incident Parkinson's disease from UK Biobank fundus imaging.
  60. Ceramides and mitochondrial homeostasis.
  1. Nat Struct Mol Biol. 2024 Feb 12.
    Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
    R Stefan Isaac, Thomas W Tullius, Katja G Hansen, Danilo Dubocanin, Mary Couvillion, Andrew B Stergachis, L Stirling Churchman.
      Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
    DOI:  https://doi.org/10.1038/s41594-024-01225-6
  2. BMJ Neurol Open. 2024 ;6(1): e000546
    Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.
    Mika H Martikainen, Kari Majamaa.
       Background: Mitochondrial diseases are common inherited metabolic disorders. Due to improved case ascertainment and diagnosis methods, the detection of new diagnoses of mitochondrial disease can be expected to increase. In December 2009, the prevalence of mitochondrial DNA (mtDNA)-related mitochondrial disease was 4.6/100 000 (95% CI, 2.7 to 7.2) in the adult population of Southwest Finland. We investigated the number of new diagnoses and the incidence of mitochondrial disease in Southwest Finland between December 2009 and December 2022.
    Methods: We collected data on all adult patients from Southwest Finland diagnosed with mitochondrial disease on 31 December 2009 and 31 December 2022. Most patients had been diagnosed at the Turku University Hospital (TUH) neurology outpatient clinic. Patients were also identified by searching the TUH electronic patient database for relevant International Classification of Diseases, Tenth Revision codes and conducted mtDNA analyses.
    Results: 42 new patients were diagnosed giving a mean annual rate of 3.2 new diagnoses. In 2022, the minimum prevalence estimate of adult mtDNA-related mitochondrial disease was 9.2/100 000 (95% CI, 6.5 to 12.7). The prevalence of adult mtDNA disease associated with m.3243A>G was 4.2/100 000 (95% CI, 2.5 to 6.7), and that with large-scale mtDNA deletions was 1.3/100 000 (95% CI, 0.4 to 2.9). During the 13-year period, the annual incidence of adult mtDNA disease was 0.6/100 000 and that of adult m.3243A>G-related disease 0.3/100 000.
    Conclusion: Our results suggest that improved means of diagnostics and dedicated effort increase the detection of mitochondrial disease.
    Keywords:  MITOCHONDRIAL DISORDERS; NEUROEPIDEMIOLOGY
    DOI:  https://doi.org/10.1136/bmjno-2023-000546
  3. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]
    The HRI branch of the integrated stress response selectively triggers mitophagy.
    Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.
      To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
    Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
  4. Aging Cell. 2024 Feb 15. e14103
    Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
    Tse Yu Chen, Feng-Yung Wang, Pin-Jung Lee, Ao-Lin Hsu, Tsui-Ting Ching.
      S-adenosylmethionine (SAM), generated from methionine and ATP by S-adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams-1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt ) and lifespan extension. In this study, we found that depleting SAMS-1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC-25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt , suggesting that the UPRmt induced by sams-1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT-10C.2 as a major downstream effector of SAMS-1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS-1 regulates UPRmt and longevity.
    Keywords:  S-adenosyl methionine; UPRmt; longevity; mitochondrial tRNA methyltransferase
    DOI:  https://doi.org/10.1111/acel.14103
  5. Paediatr Anaesth. 2024 Feb 15.
    Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.
    Kira A Spencer, Miranda N Howe, Michael T Mulholland, Vivian Truong, Ryan W Liao, Yihan Chen, Monyreak Setha, John C Snell, Allison Hanaford, Katerina James, Philip G Morgan, Margaret M Sedensky, Simon C Johnson.
       BACKGROUND: Genetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting in infancy or early childhood. Seizures are major clinical sequelae in some mitochondrial diseases including Leigh syndrome, the most common pediatric presentation of mitochondrial disease. Dietary ketosis has been used to manage seizures in mitochondrial disease patients. Mitochondrial disease patients often require surgical interventions, leading to anesthetic exposures. Anesthetics have been shown to be toxic in the setting of mitochondrial disease, but the impact of a ketogenic diet on anesthetic toxicities in this setting has not been studied.
    AIMS: Our aim in this study was to determine whether dietary ketosis impacts volatile anesthetic toxicities in the setting of genetic mitochondrial disease.
    METHODS: The impact of dietary ketosis on toxicities of volatile anesthetic exposure in mitochondrial disease was studied by exposing young Ndufs4(-/-) mice fed ketogenic or control diet to isoflurane anesthesia. Blood metabolites were measured before and at the end of exposures, and survival and weight were monitored.
    RESULTS: Compared to a regular diet, the ketogenic diet exacerbated hyperlactatemia resulting from isoflurane exposure (control vs. ketogenic diet in anesthesia mean difference 1.96 mM, Tukey's multiple comparison adjusted p = .0271) and was associated with a significant increase in mortality during and immediately after exposures (27% vs. 87.5% mortality in the control and ketogenic diet groups, respectively, during the exposure period, Fisher's exact test p = .0121). Our data indicate that dietary ketosis and volatile anesthesia interact negatively in the setting of mitochondrial disease.
    CONCLUSIONS: Our findings suggest that extra caution should be taken in the anesthetic management of mitochondrial disease patients in dietary ketosis.
    Keywords:  anesthesia; ketogenic diet; mitochondrial disease; neurodegenerative disease
    DOI:  https://doi.org/10.1111/pan.14855
  6. medRxiv. 2024 Feb 04. pii: 2024.02.02.24302076. [Epub ahead of print]
    Perceived association of mood and symptom severity in adults with mitochondrial diseases.
    Catherine Kelly, Alex Junker, Kris Englestad, Michio Hirano, Caroline Trumpff, Martin Picard.
      Individuals with genetic mitochondrial diseases suffer from multisystemic symptoms that vary in severity from day-to-day and week-to-week, but the underlying causes of symptomatic fluctuations are not understood. Based upon observations that: i) patients and their families frequently report that stressful life events either trigger exacerbations of existing symptoms or the onset of new symptoms, ii) psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological reports document a robust connection between traumatic/stressful life events and various neurologic disorders, we hypothesized that mitochondrial disease symptom severity may vary according to participant's mood. To investigate this we administered the Stress, Health and Emotion Survey (SHES) in 70 adults (majority white (84%) cisgender women (83%), ages 18-74) with self-reported mitochondrial diseases (MELAS, 18%; CPEO, 17%; Complex I deficiency, 13%). Participants rated the severity of each of their symptom(s) over the past year on either good or bad days. On days marked by more stress, sadness and other negative emotions, some but not all symptoms were reported to be worse, including fatigue, exercise intolerance, brain fog, and fine motor coordination. By contrast, on days marked by happiness and calmness, participants reported these and other symptoms to be better, or less severe. Other symptoms including diminished sweating, hearing problems, and dystonia were in general unrelated to mood. Thus, some individuals living with mitochondrial diseases, at times perceive a connection between their mood and symptom severity. These preliminary associative results constitute an initial step towards developing more comprehensive models of the factors that influence the clinical course of mitochondrial diseases.
    DOI:  https://doi.org/10.1101/2024.02.02.24302076
  7. bioRxiv. 2024 Feb 01. pii: 2024.01.30.577830. [Epub ahead of print]
    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 biological 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, including the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the specific stress signaling pathways activated in response to mitochondrial proteostasis stress 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 individual mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to mitochondrial proteostasis stress, with no other pathway showing significant activation. Further expanding this study, we show that broad depletion of 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 mitochondrial proteostasis disruption.
    DOI:  https://doi.org/10.1101/2024.01.30.577830
  8. Biochem Biophys Res Commun. 2024 Feb 02. pii: S0006-291X(24)00125-6. [Epub ahead of print]702 149590
    The therapeutic perspective of NAD+ precursors in age-related diseases.
    Tooba Iqbal, Takashi Nakagawa.
      Nicotinamide adenine dinucleotide (NAD+) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD+ decreases with age in certain tissues, and age-related NAD+ depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD+ precursor significantly elevates NAD+ levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD+ in animal studies, the efficacy of NAD+ precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD+ precursor treatment efficiently increases NAD+ levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD+ precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD+ intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD+ metabolism. Also, the reduced form of NAD+ precursor shows their potential to raise NAD+, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD+ therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD+ metabolism.
    Keywords:  Aging; Gut microbiota; NAD(+); NAD(+) precursors; Nicotinamide mononucleotide NMN; Nicotinamide riboside NR
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149590
  9. Circulation. 2024 Feb 16.
    FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.
    Bowen Li, Fangfang Liu, Xihui Chen, Tangdong Chen, Juan Zhang, Yifeng Liu, Yan Yao, Weihong Hu, Mengjie Zhang, Bo Wang, Liwen Liu, Kun Chen, Yuanming Wu.
       BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable myocardiopathy. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the myocardiopathy phenotype.
    METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification.
    RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis.
    CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.
    Keywords:  autophagy; cardiomyopathies; heart failure; ligases; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.064489
  10. bioRxiv. 2024 Feb 04. pii: 2024.02.02.578646. [Epub ahead of print]
    BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
    Brandon Chen, Theophilus M Lynn-Nguyen, Pankaj Jadhav, Benjamin S Halligan, Nicholas J Rossiter, Rachel M Guerra, Sergei Koshkin, Imhoi Koo, Pietro Morlacchi, David A Hanna, Jason Lin, Ruma Banerjee, David J Pagliarini, Andrew D Patterson, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.
    DOI:  https://doi.org/10.1101/2024.02.02.578646
  11. Front Physiol. 2024 ;15 1339128
    The role of mitophagy in metabolic diseases and its exercise intervention.
    Shaokai Tang, Yuanwen Geng, Qinqin Lin.
      Mitochondria are energy factories that sustain life activities in the body, and their dysfunction can cause various metabolic diseases that threaten human health. Mitophagy, an essential intracellular mitochondrial quality control mechanism, can maintain cellular and metabolic homeostasis by removing damaged mitochondria and participating in developing metabolic diseases. Research has confirmed that exercise can regulate mitophagy levels, thereby exerting protective metabolic effects in metabolic diseases. This article reviews the role of mitophagy in metabolic diseases, the effects of exercise on mitophagy, and the potential mechanisms of exercise-regulated mitophagy intervention in metabolic diseases, providing new insights for future basic and clinical research on exercise interventions to prevent and treat metabolic diseases.
    Keywords:  exercise; exerkine; metabolic disease; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2024.1339128
  12. Metab Brain Dis. 2024 Feb 16.
    Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.
    Marwa Maalej, Lamia Sfaihi, Olfa-Alila Fersi, Boudour Khabou, Marwa Ammar, Rahma Felhi, Marwa Kharrat, Jihen Chouchen, Thouraya Kammoun, Abdelaziz Tlili, Faiza Fakhfakh.
      Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial β-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome. Here, we report three patients belonging to a consanguineous family who presented with mitochondrial encephalomyopathy. Whole-exome sequencing revealed a new homozygous mutation c.619G > A (p.Gly207Ser) at the last nucleotide position in exon 5 of the ECHS1 gene. Experimental analysis showed that normal ECHS1 pre-mRNA splicing occurred in all patients compared to controls. Furthermore, three-dimensional models of wild-type and mutant echs1 proteins revealed changes in catalytic site interactions, conformational changes, and intramolecular interactions, potentially disrupting echs1 protein trimerization and affecting its function. Additionally, the quantification of mtDNA copy number variation in blood leukocytes showed severe mtDNA depletion in all probands.
    Keywords:  ECHS1; Short-chain enoyl-CoA hydratase deficiency; mtDNA depletion
    DOI:  https://doi.org/10.1007/s11011-024-01343-6
  13. Neurotherapeutics. 2024 Jan;pii: S1878-7479(24)00018-7. [Epub ahead of print]21(1): e00332
    Mitochondrial disorders: Emerging paradigms and the road ahead to personalized medicine.
    Andrea Gropman, Bharatendu Chandra.
      
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00332
  14. Aging (Albany NY). 2024 Feb 12. 16
    Disruption of mitochondrial unfolded protein response results in telomere shortening in mouse oocytes and somatic cells.
    Mauro Cozzolino, Yagmur Ergun, Emma Ristori, Akanksha Garg, Gizem Imamoglu, Emre Seli.
      Caseinolytic peptidase P (CLPP) plays a central role in mitochondrial unfolded protein response (mtUPR) by promoting the breakdown of misfolded proteins and setting in motion a cascade of reactions to re-establish protein homeostasis. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Telomeres are tandem repeats of 5'-TTAGGG-3' sequences found at the ends of the chromosomes. Telomeres are essential for maintaining chromosome stability during somatic cell division and their shortening is associated with cellular senescence and aging. In this study, we asked whether the infertility and ovarian aging phenotype caused by global germline deletion of Clpp is associated with somatic aging, and tested telomere length in tissues of young and aging mice. We found that impaired mtUPR caused by the lack of CLPP is associated with accelerated telomere shortening in both oocytes and somatic cells of aging mice. In addition, expression of several genes that maintain telomere integrity was decreased, and double-strand DNA breaks were increased in telomeric regions. Our results highlight how impaired mtUPR can affect telomere integrity and demonstrate a link between loss of mitochondrial protein hemostasis, infertility, and somatic aging.
    Keywords:  Clpp; aging; mitochondrial dysfunction; telomere length; unfolded protein response
    DOI:  https://doi.org/10.18632/aging.205543
  15. Mitochondrial Commun. 2024 ;2 14-20
    Mitochondrial Calcium Transport During Autophagy Initiation.
    Sujyoti Chandra, Parul Katiyar, Aarooran S Durairaj, Xinnan Wang.
      While it has been shown that Ca2+ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca2+ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca2+ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca2+ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca2+ transport and Ca2+ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca2+ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca2+ influx is faster, which may slow the ensuing mitophagy.
    Keywords:  ER Ca2+ transient; IP3R; MCU; Parkinson; RyR; autophagy; mitochondrial Ca2+ uptake; mitophagy
    DOI:  https://doi.org/10.1016/j.mitoco.2024.01.002
  16. bioRxiv. 2024 Jan 30. pii: 2024.01.29.577846. [Epub ahead of print]
    Cisplatin drives mitochondrial dysregulation in sensory hair cells.
    David S Lee, Angela Schrader, Jiaoxia Zou, Wee Han Ang, Mark E Warchol, Lavinia Sheets.
      Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain unknown, but mitochondria have emerged as potential mediators of cisplatin ototoxicity. Direct observation of changes in hair cell mitochondrial function are challenging because the mammalian inner ear is optically inaccessible. Here, we perform live in vivo imaging of hair cells within the zebrafish lateral-line organ to evaluate the role of mitochondria in cisplatin ototoxicity. Using a genetically encoded biosensor that measures cumulative mitochondrial activity in hair cells, we demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conduct time-lapse imaging of individual hair cells to understand dynamic changes in mitochondrial homeostasis. We observe spikes in mitochondrial calcium and cytosolic calcium immediately prior to hair cell death. Furthermore, we use a mitochondrially-localized probe that fluoresces in the presence of cisplatin to show that cisplatin accumulates in hair cell mitochondria. Lastly, we demonstrate that this accumulation occurs before mitochondrial dysregulation, Caspase-3 activation, and ultimately, hair cell death. Our findings provide additional evidence that suggest mitochondria are integral to cisplatin ototoxicity and cisplatin directly targets hair cell mitochondria.
    DOI:  https://doi.org/10.1101/2024.01.29.577846
  17. Nat Ecol Evol. 2024 Feb 15.
    Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
    Isabel M Serrano, Misa Hirose, Charles C Valentine, Sharon Roesner, Elizabeth Schmidt, Gabriel Pratt, Lindsey Williams, Jesse Salk, Saleh Ibrahim, Peter H Sudmant.
      Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that 're-align' mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
    DOI:  https://doi.org/10.1038/s41559-024-02338-3
  18. J Clin Invest. 2024 Feb 15. pii: e174824. [Epub ahead of print]134(4):
    A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.
    Justin O Szot, Hartmut Cuny, Ella Mma Martin, Delicia Z Sheng, Kavitha Iyer, Stephanie Portelli, Vivien Nguyen, Jessica M Gereis, Dimuthu Alankarage, David Chitayat, Karen Chong, Ingrid M Wentzensen, Catherine Vincent-Delormé, Alban Lermine, Emma Burkitt-Wright, Weizhen Ji, Lauren Jeffries, Lynn S Pais, Tiong Y Tan, James Pitt, Cheryl A Wise, Helen Wright, Israel D Andrews, Brianna Pruniski, Theresa A Grebe, Nicole Corsten-Janssen, Katelijne Bouman, Cathryn Poulton, Supraja Prakash, Boris Keren, Natasha J Brown, Matthew F Hunter, Oliver Heath, Saquib A Lakhani, John H McDermott, David B Ascher, Gavin Chapman, Kayleigh Bozon, Sally L Dunwoodie.
      Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.
    Keywords:  Embryonic development; Genetic diseases; Mouse models; Reproductive biology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI174824
  19. Mol Cell. 2024 Jan 24. pii: S1097-2765(24)00004-2. [Epub ahead of print]
    COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.
    Ludovic Pelosi, Laura Morbiato, Arthur Burgardt, Fiorella Tonello, Abigail K Bartlett, Rachel M Guerra, Katayoun Kazemzadeh Ferizhendi, Maria Andrea Desbats, Bérengère Rascalou, Marco Marchi, Luis Vázquez-Fonseca, Caterina Agosto, Giuseppe Zanotti, Morgane Roger-Margueritat, María Alcázar-Fabra, Laura García-Corzo, Ana Sánchez-Cuesta, Plácido Navas, Gloria Brea-Calvo, Eva Trevisson, Volker F Wendisch, David J Pagliarini, Leonardo Salviati, Fabien Pierrel.
      Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.
    Keywords:  COQ4; Corynebacterium; coenzyme Q; coenzyme Q biosynthesis; coenzyme Q deficiency; mitochondria; oxidative decarboxylation; respiratory chain
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.003
  20. Neuroophthalmology. 2024 ;48(1): 51-55
    A Japanese Case of Leber's Hereditary Optic Neuropathy with the m.13051G>A Pathogenic Variant.
    Yasuyuki Takai, Mayumi Iwasa, Akiko Yamagami, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.
      Leber's hereditary optic neuropathy (LHON) is one of the hereditary optic neuropathies and is principally caused by three frequent mitochondria deoxyribonucleic acid (DNA) pathogenic variants (m.11778 G>A, m.3460 G>A, and m.14484T>C). These pathogenic variants account for 90% of LHON cases, with rare pathogenic variants accounting for the remaining cases. We report the first Japanese case of LHON with the m.13051 G>A pathogenic variant, which is a rare primary pathogenic variant of LHON. A 24-year-old woman developed subacute visual loss in both eyes over several months. The best corrected visual acuity (BCVA) was 6/120 in her right eye (OD) and 6/7.5 in her left eye (OS). A relative afferent pupillary defect was not detected. Humphrey visual field testing revealed a central scotoma OD and a temporal paracentral scotoma OS. Fundus examination showed the presence of a pale optic disc OD and optic disc swelling with peripapillary microangiopathy OS. Orbital magnetic resonance imaging showed no abnormal findings. As the mitochondrial DNA gene testing demonstrated the m.13051 G>A pathogenic variant, the patient was diagnosed with LHON. Subsequently, her BCVA worsened to 6/600 in each eye, followed by a nearly plateau-like progression thereafter. This mutation has been primarily reported in Europe but has not yet been confirmed in the Asian region. This case also indicates the importance of examining the whole mitochondrial DNA gene for pathogenic variants in cases where one of the three major pathogenic variants has not been not detected.
    Keywords:  Leber’s hereditary optic neuropathy; genetic testing; m.13051G>A pathogenic variant; mitochondrial disease; optic neuropathy
    DOI:  https://doi.org/10.1080/01658107.2023.2273480
  21. Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738
    Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
    Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
    Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2024.113738
  22. FEBS J. 2024 Feb 16.
    Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
    Ilaria Goglia, Ewelina Węglarz-Tomczak, Claudio Gioia, Yanhua Liu, Assunta Virtuoso, Marcella Bonanomi, Daniela Gaglio, Noemi Salmistraro, Ciro De Luca, Michele Papa, Lilia Alberghina, Hans V Westerhoff, Anna Maria Colangelo.
      Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.
    Keywords:  NGF differentiation; computational modeling; metabolism; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1111/febs.17083
  23. Genome Med. 2024 Feb 14. 16(1): 32
    Genome sequencing as a generic diagnostic strategy for rare disease.
    Gaby Schobers, Ronny Derks, Amber den Ouden, Hilde Swinkels, Jeroen van Reeuwijk, Ermanno Bosgoed, Dorien Lugtenberg, Su Ming Sun, Jordi Corominas Galbany, Marjan Weiss, Marinus J Blok, Richelle A C M Olde Keizer, Tom Hofste, Debby Hellebrekers, Nicole de Leeuw, Alexander Stegmann, Erik-Jan Kamsteeg, Aimee D C Paulussen, Marjolijn J L Ligtenberg, Xiangqun Zheng Bradley, John Peden, Alejandra Gutierrez, Adam Pullen, Tom Payne, Christian Gilissen, Arthur van den Wijngaard, Han G Brunner, Marcel Nelen, Helger G Yntema, Lisenka E L M Vissers.
       BACKGROUND: To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease.
    METHODS: We performed short-read GS (NovaSeq™6000; 150 bp paired-end reads, 37 × mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels < 50 bp), large variants (copy number variants and short tandem repeats) and other variants (structural variants and aneuploidies). Variant calling format files were queried per variant, from which workflow-specific true positive rates (TPRs) for detection were determined. A TPR of ≥ 98% was considered the threshold for transition to GS. A GS-first scenario was generated for our laboratory, using diagnostic efficacy and predicted false negative as primary outcome measures. As input, we modeled the diagnostic path for all 24,570 individuals referred in 2022, combining the clinical referral, the transition of the underlying workflow(s) to GS, and the variant type(s) to be detected.
    RESULTS: Overall, 95% (1206/1271) of variants were detected. Detection rates differed per variant category: small variants in 96% (826/860), large variants in 93% (341/366), and other variants in 87% (39/45). TPRs varied between workflows (79-100%), with 7/10 being replaceable by GS. Models for our laboratory indicate that a GS-first strategy would be feasible for 84.9% of clinical referrals (750/883), translating to 71% of all individuals (17,444/24,570) receiving GS as their primary test. An estimated false negative rate of 0.3% could be expected.
    CONCLUSIONS: GS can capture clinically relevant germline variants in a 'GS-first strategy' for the majority of clinical indications in a genetics diagnostic lab.
    Keywords:  Genetic diagnostic laboratories; Genome sequencing; Germline variant detection; Impact modeling; Rare disease; Reducing workflow complexity
    DOI:  https://doi.org/10.1186/s13073-024-01301-y
  24. Nat Commun. 2024 Feb 10. 15(1): 1252
    Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
    Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.
      Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41467-024-45651-y
  25. Stroke. 2024 Feb 16.
    Unraveling the Diagnostic Puzzle: Minor Stroke-Like Lesions and Normal Muscle Histopathology in MELAS Syndrome.
    Ying Zhao, Zhihong Xu, Chuanzhu Yan, Kunqian Ji.
      
    Keywords:  MELAS syndrome; magnetic resonance imaging; mitochondrial diseases
    DOI:  https://doi.org/10.1161/STROKEAHA.123.045984
  26. Development. 2024 Feb 12. pii: dev.201732. [Epub ahead of print]
    Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.
    Bhavin Uttekar, Rahul Kumar Verma, Darshika Tomer, Richa Rikhy.
      Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells in Drosophila oogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1 depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. These defects are suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2, and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2, and catalase partially restores the defects in epithelial polarity and aPKC, along with EGFR and Notch signaling in Drp1 depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation, and epithelial cell polarity formation during the differentiation of follicle epithelial cells in Drosophila oogenesis.
    Keywords:   Drosophila ; APKC; Drp1; Epithelial polarity; Mitochondria; Opa1; ROS
    DOI:  https://doi.org/10.1242/dev.201732
  27. Nat Rev Endocrinol. 2024 Feb 16.
    RalA links obesity and mitochondrial dysfunction.
    Katrin Legg.
      
    DOI:  https://doi.org/10.1038/s41574-024-00962-4
  28. Nefrologia (Engl Ed). 2023 Dec;pii: S2013-2514(24)00027-0. [Epub ahead of print]43 Suppl 2 1-7
    Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.
    Filipa Ferreira, Clara Gonçalves Bacelar, Pedro Lisboa-Gonçalves, Núria Paulo, Rita Quental, Ana Teresa Nunes, Roberto Silva, Isabel Tavares.
      Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.
    Keywords:  Enfermedades mitocondriales; Enfermedades renales; Focal segmental glomerulosclerosis; Glomeruloesclerosis focal y segmentaria; MELAS syndrome; Mitochondrial diseases; Renal disease; Síndrome MELAS; mtDNA m.3243A>G
    DOI:  https://doi.org/10.1016/j.nefroe.2024.01.017
  29. Expert Rev Endocrinol Metab. 2024 Jan 24. 1-14
    Mitochondria and diabetes: insights and potential therapies.
    Renupiriya Moorthy, Subrat Kumar Bhattamisra, Manish Pandey, Jayashree Mayuren, Chia Siang Kow, Mayuren Candasamy.
       INTRODUCTION: Type 2 diabetes (T2D) presents significant global health and economic challenges, contributing to complications such as stroke, cardiovascular disease, kidney dysfunction, and cancer. The current review explores the crucial role of mitochondria, essential for fuel metabolism, in diabetes-related processes.
    AREAS COVERED: Mitochondrial deficits impact insulin-resistant skeletal muscles, adipose tissue, liver, and pancreatic β-cells, affecting glucose and lipid balance. Exercise emerges as a key factor in enhancing mitochondrial function, thereby reducing insulin resistance. Additionally, the therapeutic potential of mitochondrial uncoupling, which generates heat instead of ATP, is discussed. We explore the intricate link between mitochondrial function and diabetes, investigating genetic interventions to mitigate diabetes-related complications. We also cover the impact of insulin deficiency on mitochondrial function, the role of exercise in addressing mitochondrial defects in insulin resistance, and the potential of mitochondrial uncoupling. Furthermore, a comprehensive analysis of Mitochondrial Replacement Therapies (MRT) techniques is presented.
    EXPERT OPINION: MRTs hold promise in preventing the transmission of mitochondrial disease. However, addressing ethical, regulatory, and technical considerations is crucial. Integrating mitochondrial-based treatments requires a careful balance between innovation and safety. Ethical dimensions and regulatory aspects of MRT are examined, emphasizing collaborative efforts for the responsible advancement of human health.
    Keywords:  Diabetes; genetic interventions; mitochondria; mitochondrial replacement therapy; mitochondrion
    DOI:  https://doi.org/10.1080/17446651.2024.2307526
  30. Nat Commun. 2024 Feb 16. 15(1): 1454
    A system for inducible mitochondria-specific protein degradation in vivo.
    Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.
      Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.
    DOI:  https://doi.org/10.1038/s41467-024-45819-6
  31. Aging Cell. 2024 Feb 11. e14107
    Restricting bioenergetic efficiency enhances longevity and mitochondrial redox capacity in Drosophila melanogaster.
    Analisa L Taylor, Olga Dubuisson, Pritika Pandey, Elizabeth R M Zunica, Bolormaa Vandanmagsar, Wagner S Dantas, Alyssa Johnson, Christopher L Axelrod, John P Kirwan.
      Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age-related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle-aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity (high-resolution respirometry/fluorometry), citrate synthase (enzyme activity), mtDNA content (qPCR), gene expression (qPCR), and protein expression (western blot) were assessed in flight muscle homogenates of middle-aged flies fed vehicle or BAM15 ND. The molar ratio of H2 O2 and O2 (H2 O2 :O2 ) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity supported by pyruvate + malate, proline, and glycerol 3-phosphate. Concurrently, BAM15 enhanced the mitochondrial H2 O2 production rate, reverse electron flow from mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H2 O2 :O2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense. BAM15-mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity.
    Keywords:  BAM15; aging; bioenergetics; mitochondrial uncoupling
    DOI:  https://doi.org/10.1111/acel.14107
  32. Nat Rev Genet. 2024 Feb 16.
    Sequencing and characterizing short tandem repeats in the human genome.
    Hope A Tanudisastro, Ira W Deveson, Harriet Dashnow, Daniel G MacArthur.
      Short tandem repeats (STRs) are highly polymorphic sequences throughout the human genome that are composed of repeated copies of a 1-6-bp motif. Over 1 million variable STR loci are known, some of which regulate gene expression and influence complex traits, such as height. Moreover, variants in at least 60 STR loci cause genetic disorders, including Huntington disease and fragile X syndrome. Accurately identifying and genotyping STR variants is challenging, in particular mapping short reads to repetitive regions and inferring expanded repeat lengths. Recent advances in sequencing technology and computational tools for STR genotyping from sequencing data promise to help overcome this challenge and solve genetically unresolved cases and the 'missing heritability' of polygenic traits. Here, we compare STR genotyping methods, analytical tools and their applications to understand the effect of STR variation on health and disease. We identify emergent opportunities to refine genotyping and quality-control approaches as well as to integrate STRs into variant-calling workflows and large cohort analyses.
    DOI:  https://doi.org/10.1038/s41576-024-00692-3
  33. Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]
    SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
    Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.
      SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.
    Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
  34. Nat Neurosci. 2024 Feb 15.
    A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
    Paula R Haynes, Elana S Pyfrom, Yongjun Li, Carly Stein, Vishnu Anand Cuddapah, Jack A Jacobs, Zhifeng Yue, Amita Sehgal.
      Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.
    DOI:  https://doi.org/10.1038/s41593-023-01568-1
  35. bioRxiv. 2024 Feb 04. pii: 2024.02.02.578662. [Epub ahead of print]
    Spatial domain detection using contrastive self-supervised learning for spatial multi-omics technologies.
    Jianing Yao, Jinglun Yu, Brian Caffo, Stephanie C Page, Keri Martinowich, Stephanie C Hicks.
      Recent advances in spatially-resolved single-omics and multi-omics technologies have led to the emergence of computational tools to detect or predict spatial domains. Additionally, histological images and immunofluorescence (IF) staining of proteins and cell types provide multiple perspectives and a more complete understanding of tissue architecture. Here, we introduce Proust, a scalable tool to predict discrete domains using spatial multi-omics data by combining the low-dimensional representation of biological profiles based on graph-based contrastive self-supervised learning. Our scalable method integrates multiple data modalities, such as RNA, protein, and H&E images, and predicts spatial domains within tissue samples. Through the integration of multiple modalities, Proust consistently demonstrates enhanced accuracy in detecting spatial domains, as evidenced across various benchmark datasets and technological platforms.
    DOI:  https://doi.org/10.1101/2024.02.02.578662
  36. Biofactors. 2024 Feb 14.
    The functional roles of S-adenosyl-methionine and S-adenosyl-homocysteine and their involvement in trisomy 21.
    Maria Caracausi, Giuseppe Ramacieri, Francesca Catapano, Michela Cicilloni, Bassam Lajin, Maria Chiara Pelleri, Allison Piovesan, Lorenza Vitale, Chiara Locatelli, Gian Luca Pirazzoli, Pierluigi Strippoli, Francesca Antonaros, Beatrice Vione.
      The one-carbon metabolism pathway is involved in critical human cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. In the homocysteine-methionine cycle S-adenosyl-methionine (SAM) and S-adenosyl-homocysteine (SAH) are synthetized, and their levels are finely regulated to ensure proper functioning of key enzymes which control cellular growth and differentiation. Here we review the main biological mechanisms involving SAM and SAH and the known related human diseases. It was recently demonstrated that SAM and SAH levels are altered in plasma of subjects with trisomy 21 (T21) but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. This review aims at providing an overview of the biological mechanisms which are altered in response to changes in the levels of SAM and SAH observed in DS.
    Keywords:  S-adenosyl-homocysteine; S-adenosyl-methionine; genetic diseases; one-carbon metabolism pathway; trisomy 21
    DOI:  https://doi.org/10.1002/biof.2044
  37. Am J Physiol Endocrinol Metab. 2024 Feb 14.
    Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.
    Michael R Martino, Mohammad Habibi, Daniel Ferguson, Rita T Brookheart, John P Thyfault, Gretchen A Meyer, Louise Lantier, Curtis C Hughey, Brian N Finck.
      Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting gluconeogenic efficiency and capacity on exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or post-exercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. The decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan crosstalk during exercise as described by the Cahill and Cori cycles.
    Keywords:  alanine transaminase; exercise; gluconeogenesis; mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1152/ajpendo.00258.2023
  38. ACS Sens. 2024 Feb 16.
    Mini-review of DNA Methylation Detection Techniques and Their Potential Applications in Disease Diagnosis, Prognosis, and Treatment.
    Huaming Zhang, Lei Liu, Min Li.
      DNA methylation is the dominant epigenetic mechanism for regulating gene expression in mammals, playing crucial roles in development, differentiation, and tissue homeostasis. Aberrations in DNA methylation are closely associated with the potential onset of various diseases. Consequently, numerous DNA methylation detection techniques have been successively developed. These methods not only facilitate the exploration of disease mechanisms but also hold significant promise for the development of diagnostic and prognostic strategies. In this Perspective, we present a comprehensive overview of commonly employed DNA methylation detection techniques as well as biosensing based on their underlying analytical techniques. For its medical applications, we begin by examining the pathogenesis of different diseases and then proceed to discuss how relevant technologies are applied in the context of these specific medical conditions. Additionally, we briefly discuss the current limitations of these techniques and highlight future challenges in advancing methylation detection and analysis methodologies.
    Keywords:  DNA methylation; DNA methylation detection; LC-MS; MSRE digestion; aberrant methylation modification; affinity enrichment; biosensing; bisulfite treatment; single-molecule sequencing
    DOI:  https://doi.org/10.1021/acssensors.3c02328
  39. Antioxid Redox Signal. 2024 Feb 17.
    NADH: the redox sensor in aging-related disorders.
    Giovanna Schiuma, Djidjell Lara, James Clement, Marco Narducci, Roberta Rizzo.
       SIGNIFICANCE: NADH represents the reduced form of NAD+, and together they constitute the two forms of the Nicotinamide adenine dinucleotide whose balance is named as the NAD+/NADH ratio. NAD+/NADH ratio is mainly involved in redox reactions since both the molecules are responsible for carrying electrons to maintain redox homeostasis. NADH acts as a reducing agent and one of the most known processes exploiting NADH function is energy metabolism. The two main pathways generating energy and involving NADH are Glycolysis and Oxidative phosphorylation, occurring in cell cytosol and in the mitochondrial matrix, respectively.
    RECENT ADVANCES: Although NADH is primarily produced through the reduction of NAD+ and consumed by its own oxidation, several are the biosynthetic and consumption pathways, reflecting the NADH role in multiple cellular processes.
    CRITICAL ISSUES: This review gathers all the main current data referring to NADH in correlation with metabolic and cellular pathways, such as its coenzyme activity, effect in cell death and on modulating redox and calcium homeostasis. Data were selected following eligibility criteria accordingly to the reviewed topic. A set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) have been used for a systematic search until January 2024 using MeSH keywords/terms (i.e., NADH, NAD+/NADH and NADH/NAD+ ratio, redox homeostasis, energy metabolism, aging, aging-related disorders, therapies).
    FUTURE DIRECTION: Gene expression control, as well as to the potential impact on neurodegenerative, cardiac disorders and infections suggest NADH application in clinical settings.
    DOI:  https://doi.org/10.1089/ars.2023.0375
  40. Nat Metab. 2024 Feb 13.
    Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
    Namgyu Lee, Sung Jin Park, Mike Lange, Tenzin Tseyang, Mihir B Doshi, Tae Yong Kim, Yoseb Song, Dong In Kim, Paul L Greer, James A Olzmann, Jessica B Spinelli, Dohoon Kim.
      The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.
    DOI:  https://doi.org/10.1038/s42255-024-00974-4
  41. STAR Protoc. 2024 Feb 09. pii: S2666-1667(24)00054-6. [Epub ahead of print]5(1): 102889
    Protocol to investigate Parkinson's patient-derived dopaminergic neurons by live-cell microscopy and oxidized dopamine assays.
    Pingping Song, Dimitri Krainc.
      Dopaminergic neurons derived from human induced pluripotent stem cells recapitulate key pathogenic phenotypes observed in Parkinson's disease (PD). Here, we present a protocol to analyze oxidized dopamine and the recruitment of parkin onto synaptic vesicles in neurons derived from patients with mutations in parkin that cause autosomal recessive PD. We describe steps for neuronal differentiation, live-cell microscopy, detection of oxidized dopamine, and labeling of synaptic vesicles. These protocols can be applied to studies of other forms of genetic and sporadic forms of PD. For complete details on the use and execution of this protocol, please refer to Song et al.1,2.
    Keywords:  Cell Biology; Neuroscience; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2024.102889
  42. bioRxiv. 2024 Feb 10. pii: 2024.01.29.577835. [Epub ahead of print]
    Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
    Julia Nguyen, Phyo W Win, Tyler Shin Nagano, Elly H Shin, Charles Newcomb, Dan E Arking, Christina A Castellani.
      Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease. Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harbouring a mitochondrial transcription factor A ( TFAM ) heterozygous knockout generated via CRISPR-Cas9, and matched control lines. We identified 4,242 differentially methylated sites, 228 differentially methylated regions, and 179 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 381 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand receptor interaction pathway, ABCD1/2 gene activity, and cell signalling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression. We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodelling relevant to development, aging, and complex disease.
    DOI:  https://doi.org/10.1101/2024.01.29.577835
  43. JMIR Med Educ. 2024 Feb 13. 10 e51391
    Learning to Make Rare and Complex Diagnoses With Generative AI Assistance: Qualitative Study of Popular Large Language Models.
    Tassallah Abdullahi, Ritambhara Singh, Carsten Eickhoff.
       BACKGROUND: Patients with rare and complex diseases often experience delayed diagnoses and misdiagnoses because comprehensive knowledge about these diseases is limited to only a few medical experts. In this context, large language models (LLMs) have emerged as powerful knowledge aggregation tools with applications in clinical decision support and education domains.
    OBJECTIVE: This study aims to explore the potential of 3 popular LLMs, namely Bard (Google LLC), ChatGPT-3.5 (OpenAI), and GPT-4 (OpenAI), in medical education to enhance the diagnosis of rare and complex diseases while investigating the impact of prompt engineering on their performance.
    METHODS: We conducted experiments on publicly available complex and rare cases to achieve these objectives. We implemented various prompt strategies to evaluate the performance of these models using both open-ended and multiple-choice prompts. In addition, we used a majority voting strategy to leverage diverse reasoning paths within language models, aiming to enhance their reliability. Furthermore, we compared their performance with the performance of human respondents and MedAlpaca, a generative LLM specifically designed for medical tasks.
    RESULTS: Notably, all LLMs outperformed the average human consensus and MedAlpaca, with a minimum margin of 5% and 13%, respectively, across all 30 cases from the diagnostic case challenge collection. On the frequently misdiagnosed cases category, Bard tied with MedAlpaca but surpassed the human average consensus by 14%, whereas GPT-4 and ChatGPT-3.5 outperformed MedAlpaca and the human respondents on the moderately often misdiagnosed cases category with minimum accuracy scores of 28% and 11%, respectively. The majority voting strategy, particularly with GPT-4, demonstrated the highest overall score across all cases from the diagnostic complex case collection, surpassing that of other LLMs. On the Medical Information Mart for Intensive Care-III data sets, Bard and GPT-4 achieved the highest diagnostic accuracy scores, with multiple-choice prompts scoring 93%, whereas ChatGPT-3.5 and MedAlpaca scored 73% and 47%, respectively. Furthermore, our results demonstrate that there is no one-size-fits-all prompting approach for improving the performance of LLMs and that a single strategy does not universally apply to all LLMs.
    CONCLUSIONS: Our findings shed light on the diagnostic capabilities of LLMs and the challenges associated with identifying an optimal prompting strategy that aligns with each language model's characteristics and specific task requirements. The significance of prompt engineering is highlighted, providing valuable insights for researchers and practitioners who use these language models for medical training. Furthermore, this study represents a crucial step toward understanding how LLMs can enhance diagnostic reasoning in rare and complex medical cases, paving the way for developing effective educational tools and accurate diagnostic aids to improve patient care and outcomes.
    Keywords:  AI assistance; Bard; ChatGPT 3.5; GPT-4; MedAlpaca; artificial intelligence; clinical decision support; complex diagnosis; complex diseases; consistency; language model; medical education; medical training; natural language processing; prediction model; prompt engineering; rare diseases; reliability
    DOI:  https://doi.org/10.2196/51391
  44. J Pediatr Endocrinol Metab. 2024 Feb 02.
    Two Turkish patients with Primary Coenzyme Q10 Deficiency-7: case report and literature review.
    Gülreyhan Sonuç Kartal, Merve Koç Yekedüz, Engin Köse, Fatma Tuba Eminoğlu.
       OBJECTIVES: Primary Coenzyme Q10 Deficiency-7 (OMIM 616276) results from bi-allelic pathogenic variants in the COQ4 gene. Common clinical findings include hypotonia, seizures, respiratory distress, and cardiomyopathy. In this report, we present two patients diagnosed with Primary Coenzyme Q10 Deficiency-7 along with a review of previously published cases, with the aim being to provide a better understanding of the clinical and laboratory manifestations of the disease.
    CASE PRESENTATION: A 3-month-and-22-day-old male was admitted to our outpatient clinic due to poor feeding and restlessness. He was born following an uneventful pregnancy to a nonconsanguineous marriage. A physical examination revealed hypotonia, a dolichocephaly, periorbital edema, and long eyelashes. Blood tests revealed metabolic acidosis and elevated serum lactate levels, while the genetic analysis revealed a variant previously reported as pathogenic, c.437T>G (p.Phe146Cys), in the COQ4 gene. Genetic tests were also conducted on both mother and father, and it revealed heterozygous variant, 0.437T>G (p.Phe146Cys), in the COQ4 gene. As a result of these findings, the patient was diagnosed with neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Primary Coenzyme Q10 Deficiency-7). A 1-year-old male was admitted to our clinic with complaints of hypotonia, seizures, and feeding difficulties. He was born following an uneventful pregnancy to a nonconsanguineous marriage. On his first day of life, he was admitted to the neonatal intensive care unit due to poor feeding and hypotonia. A physical examination revealed microcephaly, a high palate, poor feeding, weak crying, hypotonia, bilateral horizontal nystagmus, and inability to maintain eye contact. Laboratory findings were within normal limits, while a whole exome sequencing analysis revealed a homozygous variant previously reported as pathogenic, c.458C>T (p.A153V), in the COQ4 gene. The patient was diagnosed with Primary Coenzyme Q10 Deficiency-7.
    CONCLUSIONS: Primary Coenzyme Q10 Deficiency-7 should be considered in the differential diagnosis of infants presenting with neurological and dysmorphic manifestations.
    Keywords:  Primary Coenzyme Q10 Deficiency-7; coenzyme Q4 deficiency; mitochondrial disorders; neonatal encephalomyopathy–cardiomyopathy–respiratory distress syndrome
    DOI:  https://doi.org/10.1515/jpem-2023-0490
  45. Protein Sci. 2024 Mar;33(3): e4902
    Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.
    Artur Meller, Devin Kelly, Louis G Smith, Gregory R Bowman.
      The goal of precision medicine is to utilize our knowledge of the molecular causes of disease to better diagnose and treat patients. However, there is a substantial mismatch between the small number of food and drug administration (FDA)-approved drugs and annotated coding variants compared to the needs of precision medicine. This review introduces the concept of physics-based precision medicine, a scalable framework that promises to improve our understanding of sequence-function relationships and accelerate drug discovery. We show that accounting for the ensemble of structures a protein adopts in solution with computer simulations overcomes many of the limitations imposed by assuming a single protein structure. We highlight studies of protein dynamics and recent methods for the analysis of structural ensembles. These studies demonstrate that differences in conformational distributions predict functional differences within protein families and between variants. Thanks to new computational tools that are providing unprecedented access to protein structural ensembles, this insight may enable accurate predictions of variant pathogenicity for entire libraries of variants. We further show that explicitly accounting for protein ensembles, with methods like alchemical free energy calculations or docking to Markov state models, can uncover novel lead compounds. To conclude, we demonstrate that cryptic pockets, or cavities absent in experimental structures, provide an avenue to target proteins that are currently considered undruggable. Taken together, our review provides a roadmap for the field of protein science to accelerate precision medicine.
    Keywords:  Markov state models; conformational ensembles; drug discovery; machine learning; precision medicine; protein dynamics
    DOI:  https://doi.org/10.1002/pro.4902
  46. Cell. 2024 Feb 08. pii: S0092-8674(24)00067-9. [Epub ahead of print]
    Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
    Baiyu Qiu, Fereshteh Zandkarimi, Carla T Bezjian, Eduard Reznik, Rajesh Kumar Soni, Wei Gu, Xuejun Jiang, Brent R Stockwell.
      Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.
    Keywords:  PUFA; ROS; complex I; diacyl-PUFA phosphatidylcholine; electron transport chain; ferroptosis; lipids; mitochondria; phospholipid; polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.cell.2024.01.030
  47. Nat Rev Mol Cell Biol. 2024 Feb 16.
    The cell biology of ferroptosis.
    Scott J Dixon, James A Olzmann.
      Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
    DOI:  https://doi.org/10.1038/s41580-024-00703-5
  48. Nat Commun. 2024 Feb 13. 15(1): 1328
    Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
    Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.
      Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.
    DOI:  https://doi.org/10.1038/s41467-024-45524-4
  49. Biogerontology. 2024 Feb 13.
    Renal aging and mitochondrial quality control.
    Xiuli Guo, Jiao Wang, Yinjie Wu, Xinwang Zhu, Li Xu.
      Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.
    Keywords:  Aging; Mitochondrial dysfunction; Mitochondrial quality control; Renal intrinsic cells
    DOI:  https://doi.org/10.1007/s10522-023-10091-6
  50. Autophagy. 2024 Feb 15. 1-9
    Did mitophagy follow the origin of mitochondria?
    Mauro Degli Esposti.
      Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. Mitophagy was first characterized in mammalian cells and is now recognized to follow several pathways including basal forms in specific organs. Mitophagy pathways are regulated by multiple, often interconnected factors. The present review aims to streamline this complexity and evaluate common elements that may define the evolutionary origin of mitophagy. Key issues surrounding mitophagy signaling at the mitochondrial surface may fundamentally derive from mitochondrial membrane dynamics. Elements of such membrane dynamics likely originated during the endosymbiosis of the alphaproteobacterial ancestor of our mitochondria but underwent an evolutionary leap forward in basal metazoa that determined the currently known variations in mitophagy signaling.Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; ATG, autophagy related; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CALCOCO, calcium binding and coiled-coil domain; CL, cardiolipin; ER, endoplasmic reticulum; ERMES, ER-mitochondria encounter structure; FBXL4, F-box and leucine rich repeat protein 4; FUNDC1, FUN14 domain containing 1; GABARAPL1, GABA type A receptor associated protein like 1; HIF, hypoxia inducible factor; IMM, inner mitochondrial membrane; LBPA/BMP, lysobisphosphatidic acid; LIR, LC3-interacting region; LPA, lysophosphatidic acid; MAM, mitochondria-associated membranes; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MCL, monolysocardiolipin; ML, maximum likelihood; NBR1, NBR1 autophagy cargo receptor; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PACS2, phosphofurin acidic cluster sorting protein 2; PC/PLC, phosphatidylcholine; PE, phosphatidylethanolamine; PHB2, prohibitin 2; PINK1, PTEN induced kinase 1; PtdIns, phosphatidylinositol; SAR, Stramenopiles, Apicomplexa and Rhizaria; TAX1BP1, Tax1 binding protein 1; ULK1, unc-51 like autophagy activating kinase 1; VDAC/porin, voltage dependent anion channel.
    Keywords:  BNIP3; cardiolipin; evolution; membrane dynamics; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2307215
  51. Br J Ophthalmol. 2024 Feb 12. pii: bjo-2023-323557. [Epub ahead of print]
    Variant and clinical landscape of Leber hereditary optic neuropathy based on 1516 families with mtDNA variants in a tertiary centre.
    Yuxi Zheng, Yingwei Wang, Yi Jiang, Junwen Wang, Shiqiang Li, Xueshan Xiao, Wenmin Sun, Panfeng Wang, Qingjiong Zhang, Xiaoyun Jia.
       AIMS: To investigate the clinical characteristics of Leber hereditary optic neuropathy (LHON) with mtDNA primary mutations to better understand features associated with prognosis.
    METHODS: This study enrolled 1540 LHON patients from 1516 unrelated families genetically confirmed by Sanger or whole-mitochondrial sequencing between 1997 and 2022. The spectrum of variants was summarised and compared in different ethnic groups. Clinical data from outpatients were collected, including onset age, disease course, optic disc categories and the corresponding visual acuity.
    RESULTS: Of the 1516 LHON families, 13 pathogenic mtDNA variants were detected, in which the proportion of m.11778G>A, m.3460G>A and m.3635G>A was significantly different from non-East Asians (p<0.0001). About 95% (1075/1131) of patients were between 8 and 40 years old at onset, with a median onset age of 16. The eyes of m.14484T>C patients presented with better visual acuity and slower progression across patients with different onset ages and initial severity. Eyes (N=439) with available fundus images were divided into four categories (C1-C4). The progression grades were derived from the category and the corresponding time course, where a higher grade (C3-C4 within 1 year) was associated with greater visual impairment than a lower grade (C1-C2 over 1 year) (p=4.60E-05) . A prognostic matrix showed that later onset and a higher progression grade are associated with higher risk of blindness.
    CONCLUSION: Compared with non-East Asians, Chinese LHON patients had higher proportions of m.11778G>A and m.3635G>A and lower m.3460G>A mutations. A novel progression grade derived from optic disc category was proposed. The prognostic matrix indicated that lower grade and younger-onset age are the most favourable prognostic factors.
    Keywords:  Genetics; Optic Nerve
    DOI:  https://doi.org/10.1136/bjo-2023-323557
  52. Orphanet J Rare Dis. 2024 Feb 14. 19(1): 68
    Lived experiences of genetic diagnosis for rare disease patients: a qualitative interview study.
    Antonia Modelhart, Dominique Sturz, Lydia Kremslehner, Barbara Prainsack.
       BACKGROUND: Genetic diagnosis is often understood as a single event within the care pathway of rare disease patients. Legal, policy and ethical scholarship focusing on rare diseases and genetic information discusses questions of how to best deal with the process of genetic diagnosis and the communication of genetic information within a given health system. We co-created a research design with rare disease patients and their families in Austria to explore in-depth the experiences of genetic diagnosis for people affected by rare diseases. Our objective was to trace the whole pathway of genetic testing and understand how rare disease patients experience genetic diagnosis as part of their care pathway in the healthcare system.
    RESULTS: Data was collected through in-depth semi-structured qualitative interviews with 14 patients with a suspected or diagnosed rare disease or their parents, focusing on their perception of the pathway of genetic diagnosis in Austria. This pathway included the initial triggering of genetic diagnosis, the process of testing and its immediate (communication of results, counselling) and long-term, wider aftermath. Patients missed a clear link to already established forms of care such as their primary care/treating physicians. They also advocate for an integrated and interdisciplinary care pathway.
    CONCLUSIONS: Our study underscores the importance of a continuous care and communication pathway spanning from the initial genetic diagnosis process to post-test phases. It further shows the importance of exploring patients' perspectives through qualitative research methods to understand the intricate workings of public health policies and tools. Integrating genetic diagnosis into a broader care trajectory is crucial for a holistic approach to care for rare disease patients who often rely on regular interactions with the healthcare system. Achieving this holistic approach requires collaboration between experts in specific rare disease areas, primary care physicians, and support networks.
    Keywords:  Genetic diagnosis; Healthcare system; Patient experiences; Qualitative interview study; Rare diseases
    DOI:  https://doi.org/10.1186/s13023-024-03058-4
  53. ACS Appl Mater Interfaces. 2024 Feb 12.
    Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
    Liku Biswal, Mohammed Nadim Sardoiwala, Avinash Chandra Kushwaha, Syamantak Mukherjee, Surajit Karmakar.
      The molecular pathways that melatonin follows as a Parkinson's disease (PD) antagonist remain poorly elucidated, despite it being a safe and a potential neurotherapeutic drug with a few limitations such as less bioavailability, premature oxidation, brain delivery, etc. Here, we used a biocompatible protein (HSA) nanocarrier for the delivery of melatonin to the brain. This nanomelatonin showed better antioxidative and neuroprotective properties, and it not only improves mitophagy to remove unhealthy mitochondria but also improves mitochondrial biogenesis to counteract rotenone-induced toxicity in an in vitro PD model. We also showed BMI1, a member of the PRC1 complex that regulates mitophagy, whose protein expression was enhanced after nanomelatonin dosage. These effects were translated to a rodent model, where nanomelatonin improves the TH+ve neuron population in SNPC and protects against rotenone-mediated toxicity. Our findings highlight the significantly better in vitro and in vivo neuroprotective effect of nanomelatonin as well as the molecular/cellular dynamics it influences to regulate mitophagy as a measure of the potential therapeutic candidate for PD.
    Keywords:  BMI1; PTEN; Parkinson’s disease; melatonin; mitophagy
    DOI:  https://doi.org/10.1021/acsami.3c17092
  54. Parkinsonism Relat Disord. 2024 Feb 10. pii: S1353-8020(24)00053-1. [Epub ahead of print] 106041
    Refining the clinical diagnosis of Parkinson's disease.
    Eoin Mulroy, Roberto Erro, Kailash P Bhatia, Mark Hallett.
      Our ability to define, understand, and classify Parkinson's disease (PD) has undergone significant changes since the disorder was first described in 1817. Clinical features and neuropathologic signatures can now be supplemented by in-vivo interrogation of genetic and biological substrates of disease, offering great opportunity for further refining the diagnosis of PD. In this mini-review, we discuss the historical perspectives which shaped our thinking surrounding the definition and diagnosis of PD. We highlight the clinical, genetic, pathologic and biologic diversity which underpins the condition, and proceed to discuss how recent developments in our ability to define biologic and pathologic substrates of disease might impact PD definition, diagnosis, individualised prognostication, and personalised clinical care. We argue that Parkinson's 'disease', as currently diagnosed in the clinic, is actually a syndrome. It is the outward manifestation of any array of potential dysfunctional biologic processes, neuropathological changes, and disease aetiologies, which culminate in common outward clinical features which we term PD; each person has their own unique disease, which we can now define with increasing precision. This is an exciting time in PD research and clinical care. Our ability to refine the clinical diagnosis of PD, incorporating in-vivo assessments of disease biology, neuropathology, and neurogenetics may well herald the era of biologically-based, precision medicine approaches PD management. With this however comes a number of challenges, including how to integrate these technologies into clinical practice in a way which is acceptable to patients, promotes meaningful changes to care, and minimises health economic impact.
    Keywords:  Alpha-synuclein; Lewy bodies; Parkinson disease; Precision medicine
    DOI:  https://doi.org/10.1016/j.parkreldis.2024.106041
  55. Mol Cell. 2024 Feb 15. pii: S1097-2765(23)01083-3. [Epub ahead of print]84(4): 616-618
    SLC25A39 links mitochondrial GSH sensing with iron metabolism.
    Xiong Chen, Boyi Gan.
      Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.037
  56. Nat Med. 2024 Feb 14.
    Gene-editing breakthrough for a rare hereditary disorder.
    Karen O'Leary.
      
    Keywords:  CRISPR-Cas systems; Clinical trials; Gene therapy
    DOI:  https://doi.org/10.1038/d41591-024-00008-2
  57. BMC Bioinformatics. 2024 Feb 12. 25(1): 66
    A supervised learning method for classifying methylation disorders.
    Jesse R Walsh, Guangchao Sun, Jagadheshwar Balan, Jayson Hardcastle, Jason Vollenweider, Calvin Jerde, Kandelaria Rumilla, Christy Koellner, Alaa Koleilat, Linda Hasadsri, Benjamin Kipp, Garrett Jenkinson, Eric Klee.
       BACKGROUND: DNA methylation is one of the most stable and well-characterized epigenetic alterations in humans. Accordingly, it has already found clinical utility as a molecular biomarker in a variety of disease contexts. Existing methods for clinical diagnosis of methylation-related disorders focus on outlier detection in a small number of CpG sites using standardized cutoffs which differentiate healthy from abnormal methylation levels. The standardized cutoff values used in these methods do not take into account methylation patterns which are known to differ between the sexes and with age.
    RESULTS: Here we profile genome-wide DNA methylation from blood samples drawn from within a cohort composed of healthy controls of different age and sex alongside patients with Prader-Willi syndrome (PWS), Beckwith-Wiedemann syndrome, Fragile-X syndrome, Angelman syndrome, and Silver-Russell syndrome. We propose a Generalized Additive Model to perform age and sex adjusted outlier analysis of around 700,000 CpG sites throughout the human genome. Utilizing z-scores among the cohort for each site, we deployed an ensemble based machine learning pipeline and achieved a combined prediction accuracy of 0.96 (Binomial 95% Confidence Interval 0.868[Formula: see text]0.995).
    CONCLUSION: We demonstrate a method for age and sex adjusted outlier detection of differentially methylated loci based on a large cohort of healthy individuals. We present a custom machine learning pipeline utilizing this outlier analysis to classify samples for potential methylation associated congenital disorders. These methods are able to achieve high accuracy when used with machine learning methods to classify abnormal methylation patterns.
    Keywords:  Angelman syndrome; Beckwith–Wiedemann syndrome; Congenital disease; Diagnosis; Machine learning; Methylation; Prader–Willi syndrome; Russell–Silver syndrome; Silver–Russell syndrome
    DOI:  https://doi.org/10.1186/s12859-024-05673-1
  58. NPJ Genom Med. 2024 Feb 14. 9(1): 10
    Eliciting parental preferences and values for the return of additional findings from genomic sequencing.
    Ilias Goranitis, Yan Meng, Melissa Martyn, Stephanie Best, Sophie Bouffler, Yvonne Bombard, Clara Gaff, Zornitza Stark.
      Health economic evidence is needed to inform the design of high-value and cost-effective processes for returning genomic results from analyses for additional findings (AF). This study reports the results of a discrete-choice experiment designed to elicit preferences for the process of returning AF results from the perspective of parents of children with rare conditions and to estimate the value placed on AF analysis. Overall, 94 parents recruited within the Australian Genomics and Melbourne Genomics programmes participated in the survey, providing preferences in a total of 1128 choice scenarios. Statistically significant preferences were identified for the opportunity to change the choices made about AF; receiving positive AF in person from a genetic counsellor; timely access to a medical specialist and high-quality online resources; receiving automatic updates through a secure online portal if new information becomes available; and lower costs. For AF uptake rates ranging between 50-95%, the mean per person value from AF analysis was estimated at AU$450-$1700 (US$300-$1140). The findings enable the design of a value-maximising process of analysis for AF in rare-disease genomic sequencing.
    DOI:  https://doi.org/10.1038/s41525-024-00399-8
  59. Sci Rep. 2024 02 13. 14(1): 3637
    Deep learning predicts prevalent and incident Parkinson's disease from UK Biobank fundus imaging.
    Charlie Tran, Kai Shen, Kang Liu, Akshay Ashok, Adolfo Ramirez-Zamora, Jinghua Chen, Yulin Li, Ruogu Fang.
      Parkinson's disease is the world's fastest-growing neurological disorder. Research to elucidate the mechanisms of Parkinson's disease and automate diagnostics would greatly improve the treatment of patients with Parkinson's disease. Current diagnostic methods are expensive and have limited availability. Considering the insidious and preclinical onset and progression of the disease, a desirable screening should be diagnostically accurate even before the onset of symptoms to allow medical interventions. We highlight retinal fundus imaging, often termed a window to the brain, as a diagnostic screening modality for Parkinson's disease. We conducted a systematic evaluation of conventional machine learning and deep learning techniques to classify Parkinson's disease from UK Biobank fundus imaging. Our results suggest Parkinson's disease individuals can be differentiated from age and gender-matched healthy subjects with 68% accuracy. This accuracy is maintained when predicting either prevalent or incident Parkinson's disease. Explainability and trustworthiness are enhanced by visual attribution maps of localized biomarkers and quantified metrics of model robustness to data perturbations.
    DOI:  https://doi.org/10.1038/s41598-024-54251-1
  60. Cell Signal. 2024 Feb 13. pii: S0898-6568(24)00067-6. [Epub ahead of print] 111099
    Ceramides and mitochondrial homeostasis.
    Song Ding, Guorui Li, Tinglv Fu, Tianyu Zhang, Xiao Lu, Ning Li, Qing Geng.
      Lipotoxicity arises from the accumulation of lipid intermediates in non-adipose tissue, precipitating cellular dysfunction and death. Ceramide, a toxic byproduct of excessive free fatty acids, has been widely recognized as a primary contributor to lipotoxicity, mediating various cellular processes such as apoptosis, differentiation, senescence, migration, and adhesion. As the hub of lipid metabolism, the excessive accumulation of ceramides inevitably imposes stress on the mitochondria, leading to the disruption of mitochondrial homeostasis, which is typified by adequate ATP production, regulated oxidative stress, an optimal quantity of mitochondria, and controlled mitochondrial quality. Consequently, this review aims to collate current knowledge and facts regarding the involvement of ceramides in mitochondrial energy metabolism and quality control, thereby providing insights for future research.
    Keywords:  Ceramide; ETC; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111099
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:23.