bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–04–14
72 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
  2. Potential Applications of Mitochondrial Therapy with a Focus on Parkinson's Disease and Mitochondrial Transplantation.
  3. Replication and Transcription of Human Mitochondrial DNA.
  4. MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
  5. Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.
  6. Hydrogen sulfide supplementation as a potential treatment for primary mitochondrial diseases.
  7. Mitochondrial morphology, distribution and activity during oocyte development.
  8. Mitochondrial encephalopathies and myopathies: Our tertiary center's experience.
  9. Mitochondrial control of lymphocyte homeostasis.
  10. Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.
  11. Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
  12. S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.
  13. Mitochondrial complex I subunit MT-ND1 mutations affect disease progression.
  14. Cavitating leukodystrophy in a case of mitochondrial complex III deficiency due to LYRM7 mutation.
  15. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
  16. Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
  17. The Schizosaccharomyces pombe DEAD-box protein Mss116 is required for mitoribosome assembly and mitochondrial translation.
  18. Mdivi-1: Effective but complex mitochondrial fission inhibitor.
  19. Right place at the right time: Mitochondrial shape, distribution and inter-organelle interaction during skeletal muscle postnatal development.
  20. The Role of Cardiolipin in Mitochondrial Function and Neurodegenerative Diseases.
  21. Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
  22. DrivR-Base: A Feature Extraction Toolkit For Variant Effect Prediction Model Construction.
  23. Order wrapped in chaos: On the roles of intrinsically disordered proteins and RNAs in the arrangement of the mitochondrial enzymatic machines.
  24. Designer antibiotics by generative AI.
  25. Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.
  26. Human Genetics and Genomics for Drug Target Identification and Prioritization: Open Targets' Perspective.
  27. Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria.
  28. Machine learning-based 3D segmentation of mitochondria in polarized epithelial cells.
  29. MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN A DROSOPHILA MODEL OF NEURODEGENERATION.
  30. Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.
  31. Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration.
  32. Focused Exome Sequencing Gives a High Diagnostic Yield in the Indian Subcontinent.
  33. Lysosomal storage disease proteo/lipidomic profiling using nMOST links ferritinophagy with mitochondrial iron deficiencies in cells lacking NPC2.
  34. Mitochondrial stress in GABAergic neurons non-cell autonomously regulates organismal health and aging.
  35. Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2).
  36. Miro GTPases at the Crossroads of Cytoskeletal Dynamics and Mitochondrial Trafficking.
  37. Sudden cardiac death triggered by minimal alcohol consumption in the context of novel PPA2 mutations in 2 unrelated families.
  38. Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates.
  39. Mutational rescue of the activity of high-fidelity Cas9 enzymes.
  40. Poor visual prognosis of Asian patients with 3460 mitochondrial DNA mutation in Leber's hereditary optic neuropathy.
  41. Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.
  42. A novel probe to monitor lysosome-mitochondria contact sites opens up a new path to study neurodegenerative diseases.
  43. Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods.
  44. Cardiac-specific deletion of heat shock protein 60 induces mitochondrial stress and disrupts heart development in mice.
  45. A Perspective on Crowdsourcing and Human-in-the-Loop Workflows in Precision Health.
  46. Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.
  47. Oocyte mitochondria link maternal environment to offspring phenotype.
  48. GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.
  49. Ablation of Mitochondrial RCC1-L Induces Nigral Dopaminergic Neurodegeneration and Parkinsonian-like Motor Symptoms.
  50. Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?
  51. Longitudinal change in mitochondrial heteroplasmy exhibits positive selection for deleterious variants.
  52. Idebenone ameliorates statin-induced myotoxicity in atherosclerotic ApoE-/- mice by reducing oxidative stress and improving mitochondrial function.
  53. Long-term Efficacy and Safety of Elamipretide in Patients with Barth Syndrome: 168-Week Open-label Extension Results of TAZPOWER.
  54. Management of Ptosis in Kearns-Sayre Syndrome: A Case Report and Literature Review.
  55. Multimodal Omics Approaches to Aging and Age-Related Diseases.
  56. Redefining Rare Disease Care in the Digital Age: Insights and Key Takeaways from a Digital Health Symposium Focused on Empowering Rare Disease Communities.
  57. Mitochondrial membrane transporters as attractive targets for the fermentative production of succinic acid from glycerol in Saccharomyces cerevisiae.
  58. Impaired coenzyme A homeostasis in cardiac dysfunction and benefits of boosting coenzyme A production with vitamin B5 and its derivatives in the management of heart failure.
  59. The STRAT-PARK cohort: a personalized initiative to stratify Parkinson's disease.
  60. The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.
  61. Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease.
  62. An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.
  63. A genome-wide spectrum of tandem repeat expansions in 338,963 humans.
  64. A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.
  65. The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.
  66. Human telomere length is chromosome end-specific and conserved across individuals.
  67. DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.
  68. Revealing myopathy spectrum: integrating transcriptional and clinical features of human skeletal muscles with varying health conditions.
  69. Uncovering microstructural architecture from histology.
  70. Identification and characterization of a new pathologic mutation in a large Leber hereditary optic neuropathy pedigree.
  71. Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease.
  72. Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.
  1. J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01770-8. [Epub ahead of print] 107269
    Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
    Laura H Steenberge, Sean Rogers, Andrew Y Sung, Jing Fan, David J Pagliarini.
      Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.
    Keywords:  Antioxidant; Bioenergetics; Coenzyme Q10 (CoQ10); Ferroptosis; Membrane lipid; Mitochondrial respiratory chain complex; Mitochondrial therapeutics; Pyrimidine biosynthesis; Ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107269
  2. Adv Pharm Bull. 2024 Mar;14(1): 147-160
    Potential Applications of Mitochondrial Therapy with a Focus on Parkinson's Disease and Mitochondrial Transplantation.
    Pranay Wal, Ankita Wal, Himangi Vig, Danish Mahmood, Mohd Masih Uzzaman Khan.
       Purpose: Both aging and neurodegenerative illnesses are thought to be influenced by mitochondrial malfunction and free radical formation. Deformities of the energy metabolism, mitochondrial genome polymorphisms, nuclear DNA genetic abnormalities associated with mitochondria, modifications of mitochondrial fusion or fission, variations in shape and size, variations in transit, modified mobility of mitochondria, transcription defects, and the emergence of misfolded proteins associated with mitochondria are all linked to Parkinson's disease.
    Methods: This review is a condensed compilation of data from research that has been published between the years of 2014 and 2022, using search engines like Google Scholar, PubMed, and Scopus.
    Results: Mitochondrial transplantation is a one-of-a-kind treatment for mitochondrial diseases and deficits in mitochondrial biogenesis. The replacement of malfunctioning mitochondria with transplanted viable mitochondria using innovative methodologies has shown promising outcomes as a cure for Parkinson's, involving tissue sparing coupled with enhanced energy generation and lower oxidative damage. Numerous mitochondria-targeted therapies, including mitochondrial gene therapy, redox therapy, and others, have been investigated for their effectiveness and potency.
    Conclusion: The development of innovative therapeutics for mitochondria-directed treatments in Parkinson's disease may be aided by optimizing mitochondrial dynamics. Many neurological diseases have been studied in animal and cellular models, and it has been found that mitochondrial maintenance can slow the death of neuronal cells. It has been hypothesized that drug therapies for neurodegenerative diseases that focus on mitochondrial dysfunction will help to delay the onset of neuronal dysfunction.
    Keywords:  Mitochondrial dynamics; Mitochondrial therapeutics; Mitochondrial transplantation; Neurodegeneration; Parkinson’s disease
    DOI:  https://doi.org/10.34172/apb.2024.019
  3. Annu Rev Biochem. 2024 Apr 09.
    Replication and Transcription of Human Mitochondrial DNA.
    Maria Falkenberg, Nils-Göran Larsson, Claes M Gustafsson.
      Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.
    DOI:  https://doi.org/10.1146/annurev-biochem-052621-092014
  4. Autophagy. 2024 Apr 10.
    MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
    Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.
      Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.
    Keywords:  Mitochondrial import; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340399
  5. Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00035-7. [Epub ahead of print] 101877
    Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.
    Thiruvelselvan Ponnusamy, Prema Velusamy, Santhanam Shanmughapriya.
      Mitochondrial Ca2+ uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here, we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed that decreased matrix [Mg2+] is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg2+ in regulating MCU activity.
    Keywords:  Calcium; Cell death; MCU; Magnesium; Mitochondria; Mrs2; mPTP
    DOI:  https://doi.org/10.1016/j.mito.2024.101877
  6. Pharmacol Res. 2024 Apr 08. pii: S1043-6618(24)00124-5. [Epub ahead of print] 107180
    Hydrogen sulfide supplementation as a potential treatment for primary mitochondrial diseases.
    Luke Slade, Colleen S Deane, Nathaniel J Szewczyk, Timothy Etheridge, Matthew Whiteman.
      Primary mitochondrial diseases (PMD) are amongst the most common inborn errors of metabolism causing fatal outcomes within the first decade of life. With marked heterogeneity in both inheritance patterns and physiological manifestations, these conditions present distinct challenges for targeted drug therapy, where effective therapeutic countermeasures remain elusive within the clinic. Hydrogen sulfide (H2S)-based therapeutics may offer a new option for patient treatment, having been proposed as a conserved mitochondrial substrate and post-translational regulator across species, displaying therapeutic effects in age-related mitochondrial dysfunction and neurodegenerative models of mitochondrial disease. H2S can stimulate mitochondrial respiration at sites downstream of common PMD-defective subunits, augmenting energy production, mitochondrial function and reducing cell death. Here, we highlight the primary signalling mechanisms of H2S in mitochondria relevant for PMD and outline key cytoprotective proteins/pathways amenable to post-translational restoration via H2S-mediated persulfidation. The mechanisms proposed here, combined with the advent of potent mitochondria-targeted sulfide delivery molecules, could provide a framework for H2S as a countermeasure for PMD disease progression.
    Keywords:  Hydrogen sulfide; mitochondria; persulfidation; primary mitochondrial disease; therapeutics
    DOI:  https://doi.org/10.1016/j.phrs.2024.107180
  7. Trends Endocrinol Metab. 2024 Apr 09. pii: S1043-2760(24)00064-X. [Epub ahead of print]
    Mitochondrial morphology, distribution and activity during oocyte development.
    Devesh Bahety, Elvan Böke, Aida Rodríguez-Nuevo.
      Mitochondria have a crucial role in cellular function and exhibit remarkable plasticity, adjusting both their structure and activity to meet the changing energy demands of a cell. Oocytes, female germ cells that become eggs, undergo unique transformations: the extended dormancy period, followed by substantial increase in cell size and subsequent maturation involving the segregation of genetic material for the next generation, present distinct metabolic challenges necessitating varied mitochondrial adaptations. Recent findings in dormant oocytes challenged the established respiratory complex hierarchies and underscored the extent of mitochondrial plasticity in long-lived oocytes. In this review, we discuss mitochondrial adaptations observed during oocyte development across three vertebrate species (Xenopus, mouse, and human), emphasising current knowledge, acknowledging limitations, and outlining future research directions.
    Keywords:  metabolism; mitochondria; oocyte; plasticity
    DOI:  https://doi.org/10.1016/j.tem.2024.03.002
  8. Eur J Paediatr Neurol. 2024 Mar 28. pii: S1090-3798(24)00038-2. [Epub ahead of print]50 31-40
    Mitochondrial encephalopathies and myopathies: Our tertiary center's experience.
    Can Ozlu, Souad Messahel, Berge Minassian, Saima Kayani.
      Mitochondrial diseases have a heterogeneous phenotype and can result from mutations in the mitochondrial or nuclear genomes, constituting a diagnostically and therapeutically challenging group of disorders. We report our center's experience with mitochondrial encephalopathies and myopathies with a cohort of 50 genetically and phenotypically diverse patients followed in the Neurology clinic over the last ten years. Seventeen patients had mitochondrial DNA mutations, presented over a wide range of ages with seizures, feeding difficulties, extraocular movements abnormalities, and had high rates of stroke-like episodes and regression. Twenty-seven patients had nuclear DNA mutations, presented early in life with feeding difficulty, failure-to-thrive, and seizures, and had high proportions of developmental delay, wheelchair dependence, spine abnormalities and dystonia. In six patients, a mutation could not be identified, but they were included for having mitochondrial disease confirmed by histopathology, enzyme analysis and clinical features. These patients had similar characteristics to patients with nuclear DNA mutations, suggesting missed underlying mutations in the nuclear genome. Management was variable among patients, but outcomes were universally poor with severe disability in all cases. Therapeutic entryways through elucidation of disease pathways and remaining unknown genes are acutely needed.
    Keywords:  Cohort; Encephalopathy; Mitochondrial disease; Mitochondrial gene mutation; Myopathy
    DOI:  https://doi.org/10.1016/j.ejpn.2024.03.005
  9. Semin Cell Dev Biol. 2024 Apr 11. pii: S1084-9521(24)00031-4. [Epub ahead of print]161-162 42-53
    Mitochondrial control of lymphocyte homeostasis.
    Yavuz F Yazicioglu, Robert J Mitchell, Alexander J Clarke.
      Mitochondria play a multitude of essential roles within mammalian cells, and understanding how they control immunity is an emerging area of study. Lymphocytes, as integral cellular components of the adaptive immune system, rely on mitochondria for their function, and mitochondria can dynamically instruct their differentiation and activation by undergoing rapid and profound remodelling. Energy homeostasis and ATP production are often considered the primary functions of mitochondria in immune cells; however, their importance extends across a spectrum of other molecular processes, including regulation of redox balance, signalling pathways, and biosynthesis. In this review, we explore the dynamic landscape of mitochondrial homeostasis in T and B cells, and discuss how mitochondrial disorders compromise adaptive immunity.
    Keywords:  Adaptive immunity; B cells; Lymphocytes; Mitochondria; T cells
    DOI:  https://doi.org/10.1016/j.semcdb.2024.03.002
  10. Mitochondrion. 2024 Apr 09. pii: S1567-7249(24)00037-0. [Epub ahead of print]76 101879
    Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.
    Laura Bermejo-Guerrero, Ana Hernández-Voth, Pablo Serrano-Lorenzo, Alberto Blázquez, Paloma Martin-Jimenez, Miguel A Martin, Cristina Domínguez-González.
       OBJECTIVES: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d.
    METHODS: An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented.
    RESULTS: After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea.
    DISCUSSION: Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d.
    Keywords:  Case report; Mitochondrial myopathy; TK2 deficiency
    DOI:  https://doi.org/10.1016/j.mito.2024.101879
  11. Cell Rep. 2024 Apr 06. pii: S2211-1247(24)00395-4. [Epub ahead of print]43(4): 114067
    Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
    Dong Tian, Mingxue Cui, Min Han.
      Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.
    Keywords:  ATP synthase; CP: Cell biology; CP: Metabolism; Leigh syndrome; PGN; ROS; antibiotic-induced microbiome depletion; electron transfer chain; energy metabolism; intestinal epithelial cells; intestinal homeostasis; mitochondrial diseases; oxidative phosphorylation; oxidative stress; peptidoglycan
    DOI:  https://doi.org/10.1016/j.celrep.2024.114067
  12. Redox Biol. 2024 Apr 03. pii: S2213-2317(24)00126-5. [Epub ahead of print]72 103150
    S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.
    Leire Goicoechea, Sandra Torres, Laura Fàbrega, Mónica Barrios, Susana Núñez, Josefina Casas, Gemma Fabrias, Carmen García-Ruiz, José C Fernández-Checa.
      Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that Npc1-/- mice exhibit decreased brain SAM levels but unchanged S-adenosyl-l-homocysteine content and lower expression of Mat2a. Brain mitochondria from Npc1-/- mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. In vivo treatment of Npc1-/- mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. In vivo SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of Npc1-/- mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.
    Keywords:  Antioxidants; Membrane fluidity; Mitochondrial GSH; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.redox.2024.103150
  13. Heliyon. 2024 Apr 15. 10(7): e28808
    Mitochondrial complex I subunit MT-ND1 mutations affect disease progression.
    Xi Lin, Yanhong Zhou, Lei Xue.
      Mitochondrial respiratory chain complex I is an important component of the oxidative respiratory chain, with the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) being one of the core subunits. MT-ND1 plays a role in the assembly of complex I and its enzymatic function. MT-ND1 gene mutation affects pathophysiological processes, such as interfering with the early assembly of complex I, affecting the ubiquinone binding domain and proton channel of complex I, and affecting oxidative phosphorylation, thus leading to the occurrence of diseases. The relationship between MT-ND1 gene mutation and disease has been has received increasing research attention. Therefore, this article reviews the impact of MT-ND1 mutations on disease progression, focusing on the impact of such mutations on diseases and their possible mechanisms, as well as the application of targeting MT-ND1 gene mutations in disease diagnosis and treatment. We aim to provide a new perspective leading to a more comprehensive understanding of the relationship between MT-ND1 gene mutations and diseases.
    Keywords:  LHON; MT-ND1; Mitochondrial complex I; Mutation; Pathological mutation; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e28808
  14. Acta Neurol Belg. 2024 Apr 09.
    Cavitating leukodystrophy in a case of mitochondrial complex III deficiency due to LYRM7 mutation.
    Mojtaba Rezaei, Zahra Dourandish, Gilda Kiani Mehr, Askar Ghorbani, Farzad Fatehi.
      
    Keywords:  Cavitating lesions; LYRM7 protein; Leukodystrophy; Mitochondrial complex III deficiency; Mitochondrial diseases
    DOI:  https://doi.org/10.1007/s13760-024-02529-6
  15. Nat Cell Biol. 2024 Apr 09.
    Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
    Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.
      Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.
    DOI:  https://doi.org/10.1038/s41556-024-01400-3
  16. Neuron. 2024 Mar 26. pii: S0896-6273(24)00167-3. [Epub ahead of print]
    Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
    Sandra M V Kochan, Meret Cepero Malo, Milica Jevtic, Hannah M Jahn-Kelleter, Gulzar A Wani, Kristiano Ndoci, Laura Pérez-Revuelta, Felix Gaedke, Iris Schäffner, Dieter Chichung Lie, Astrid Schauss, Matteo Bergami.
      Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival but left neurons poorly responsive to experience at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.
    Keywords:  LTP; Mfn2; adult neurogenesis; competition; experience; hippocampus; mitochondria; mitochondrial fusion; neural stem cell; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuron.2024.03.013
  17. Mitochondrion. 2024 Apr 09. pii: S1567-7249(24)00039-4. [Epub ahead of print]76 101881
    The Schizosaccharomyces pombe DEAD-box protein Mss116 is required for mitoribosome assembly and mitochondrial translation.
    Yirong Wang, Gang Feng, Ying Huang.
      DEAD-box helicases are important players in mitochondrial gene expression, which is necessary for mitochondrial respiration. In this study, we characterized Schizosaccharomyces pombe Mss116 (spMss116), a member of the family of DEAD-box RNA helicases. Deletion of spmss116 in a mitochondrial intron-containing background significantly reduced the levels of mitochondrial DNA (mtDNA)-encoded cox1 and cob1 mRNAs and impaired mitochondrial translation, leading to a severe respiratory defect and a loss of cell viability during stationary phase. Deletion of mitochondrial introns restored the levels of cox1 and cob1 mRNAs to wide-type (WT) levels but could not restore mitochondrial translation and respiration in Δspmss116 cells. Furthermore, deletion of spmss116 in both mitochondrial intron-containing and intronless backgrounds impaired mitoribosome assembly and destabilization of mitoribosomal proteins. Our findings suggest that defective mitochondrial translation caused by deletion of spmss116 is most likely due to impaired mitoribosome assembly.
    Keywords:  DEAD-box protein; Mitochondrial translation; Mitoribosome assembly; OXPHOS, Respiration
    DOI:  https://doi.org/10.1016/j.mito.2024.101881
  18. Biochem Biophys Res Commun. 2024 Apr 03. pii: S0006-291X(24)00422-4. [Epub ahead of print]710 149886
    Mdivi-1: Effective but complex mitochondrial fission inhibitor.
    Seor I Ahn, Sung Kyung Choi, Myoung Jun Kim, Jinhong Wie, Jueng Soo You.
      Mdivi-1, Mitochondrial DIVIsion inhibitor 1, has been widely employed in research under the assumption that it exclusively influences mitochondrial fusion, but effects other than mitochondrial dynamics have been underinvestigated. This paper provides transcriptome and DNA methylome-wide analysis for Mdivi-1 treated SH-SY5Y human neuroblastoma cells using RNA sequencing (RNA-seq) and methyl capture sequencing (MC-seq) methods. Gene ontology analysis of RNA sequences revealed that p53 transcriptional gene network and DNA replication initiation-related genes were significantly up and down-regulated, respectively, showing the correlation with the arrest cell cycle in the G1 phase. MC-seq, a powerful sequencing method for capturing DNA methylation status in CpG sites, revealed that although Mdivi-1 does not induce dramatic DNA methylation change, the subtle alterations were concentrated within the CpG island. Integrative analysis of both sequencing data disclosed that the p53 transcriptional network was activated while the Parkinson's disease pathway was halted. Next, we investigated several changes in mitochondria in response to Mdivi-1. Copy number and transcription of mitochondrial DNA were suppressed. ROS levels increased, and elevated ROS triggered mitochondrial retrograde signaling rather than inducing direct DNA damage. In this study, we could better understand the molecular network of Mdivi-1 by analyzing DNA methylation and mRNA transcription in the nucleus and further investigating various changes in mitochondria, providing inspiration for studying nuclear-mitochondrial communications.
    Keywords:  DNA methylome; Mdivi-1; Mitochondrial dynamics; Mitochondrial retrograde signaling; Transcriptome
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149886
  19. J Physiol. 2024 Apr 11.
    Right place at the right time: Mitochondrial shape, distribution and inter-organelle interaction during skeletal muscle postnatal development.
    Itamar C G Jesus, Marcos Eliezeck, Débora L Scheffer.
      
    Keywords:  inter‐organelle interaction; lipid droplet; mitochondria; postnatal development; skeletal muscle
    DOI:  https://doi.org/10.1113/JP286517
  20. Cells. 2024 Mar 30. pii: 609. [Epub ahead of print]13(7):
    The Role of Cardiolipin in Mitochondrial Function and Neurodegenerative Diseases.
    José M Fuentes, Patricia Morcillo.
      Cardiolipin (CL) is a mitochondria-exclusive phospholipid synthesized in the inner mitochondrial membrane. CL plays a key role in mitochondrial membranes, impacting a plethora of functions this organelle performs. Consequently, it is conceivable that abnormalities in the CL content, composition, and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of diseases. This review concentrates on papers published in recent years, combined with basic and underexplored research in CL. We capture new findings on its biological functions in the mitochondria, as well as its association with neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Lastly, we explore the potential applications of CL as a biomarker and pharmacological target to mitigate mitochondrial dysfunction.
    Keywords:  biological functions; cardiolipin; mitochondria; neurodegenerative diseases; therapeutic applications
    DOI:  https://doi.org/10.3390/cells13070609
  21. bioRxiv. 2024 Mar 29. pii: 2024.03.26.586781. [Epub ahead of print]
    Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
    Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.
      Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanisms underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: 1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; 2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; 3) age is a dominant factor affecting mitochondrial activity, especially across different fat depots and skeletal muscle groups, and most brain regions; 4) age-effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and 5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
    DOI:  https://doi.org/10.1101/2024.03.26.586781
  22. Bioinformatics. 2024 Apr 11. pii: btae197. [Epub ahead of print]
    DrivR-Base: A Feature Extraction Toolkit For Variant Effect Prediction Model Construction.
    Amy Francis, Colin Campbell, Tom R Gaunt.
       MOTIVATION: Recent advancements in sequencing technologies have led to the discovery of numerous variants in the human genome. However, understanding their precise roles in diseases remains challenging due to their complex functional mechanisms. Various methodologies have emerged to predict the pathogenic significance of these genetic variants. Typically, these methods employ an integrative approach, leveraging diverse data sources that provide important insights into genomic function. Despite the abundance of publicly available data sources and databases, the process of navigating, extracting, and pre-processing features for machine learning models can be highly challenging and time-consuming. Furthermore, researchers often invest substantial effort in feature extraction, only to later discover that these features lack informativeness.
    RESULTS: In this paper, we introduce DrivR-Base, an innovative resource that efficiently extracts and integrates molecular information (features) related to single nucleotide variants. These features encompass information about the genomic positions and the associated protein positions of a variant. They are derived from a wide array of databases and tools, including structural properties obtained from AlphaFold, regulatory information sourced from ENCODE, and predicted variant consequences from Variant Effect Predictor. DrivR-Base is easily deployable via a Docker container to ensure reproducibility and ease of access across diverse computational environments. The resulting features can be used as input for machine learning models designed to predict the pathogenic impact of human genome variants in disease. Moreover, these feature sets have applications beyond this, including haploinsufficiency prediction and the development of drug repurposing tools. We describe the resource's development, practical applications, and potential for future expansion and enhancement.
    AVAILABILITY AND IMPLEMENTATION: DrivR-Base source code is available at https://github.com/amyfrancis97/DrivR-Base.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btae197
  23. Int J Biol Macromol. 2024 Apr 06. pii: S0141-8130(24)02260-8. [Epub ahead of print] 131455
    Order wrapped in chaos: On the roles of intrinsically disordered proteins and RNAs in the arrangement of the mitochondrial enzymatic machines.
    Semen V Nesterov, Nikolay S Ilyinsky, Konstantin S Plokhikh, Vladimir D Manuylov, Yuriy M Chesnokov, Raif G Vasilov, Irina M Kuznetsova, Konstantin K Turoverov, Valentin Ivanovich, Alexander V Fonin, Vladimir N Uversky.
      The analysis of cryo-electron tomography images of human and rat mitochondria revealed that the mitochondrial matrix is at least as crowded as the cytosol. To mitigate the crowding effects, metabolite transport in the mitochondria primarily occurs through the intermembrane space, which is significantly less crowded. The scientific literature largely ignores how enzyme systems and metabolite transport are organized in the crowded environment of the mitochondrial matrix. Under crowded conditions, multivalent interactions carried out by disordered protein regions (IDRs), may become extremely important. We analyzed the human mitochondrial proteome to determine the presence and physiological significance of IDRs. Despite mitochondrial proteins being generally more ordered than cytosolic or overall proteome proteins, disordered plays a significant role in certain mitochondrial compartments and processes. Even in highly ordered enzyme systems, there are proteins with long IDRs. Some IDRs act as binding elements between highly ordered subunits, while the roles of others are not yet established. Mitochondrial systems, like their bacterial ancestors, rely less on IDRs and more on RNA for LLPS compartmentalization. More evolutionarily advanced subsystems that enable mitochondria-cell interactions contain more IDRs. The study highlights the crucial and often overlooked role played by IDRs and non-coding RNAs in mitochondrial organization.
    Keywords:  Biomolecular condensates; Compartmentalization; Crowding; Cryo-electron tomography; Intrinsically disordered protein; Intrinsically disordered region; Liquid-liquid phase separation; Membrane-less organelles; Metabolon; Mitochondria; Multienzyme supercomplex; Protein-protein interaction
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.131455
  24. Nat Med. 2024 Apr 12.
    Designer antibiotics by generative AI.
    Karen O'Leary.
      
    Keywords:  Antibiotics; Drug discovery; Machine Learning
    DOI:  https://doi.org/10.1038/d41591-024-00025-1
  25. Dis Model Mech. 2024 Apr 11. pii: dmm.050471. [Epub ahead of print]
    Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.
    Jun-Yi Zhu, Joyce van de Leemput, Zhe Han.
      Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function, and molecular pathways between mammalian podocytes and Drosophila nephrocytes are highly conserved, therefore we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes of high-sucrose diet flies showed significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocytes filtration structure known as the slit diaphragm was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunction. Regulating mitochondrial dynamics by either genetic modification of the Pink1/Park (mammalian PINK1/PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1/Park-mediated mitophagy and associated control of mitochondrial dynamics, essential for function, in diabetic nephropathy; and demonstrate that targeting this pathway might provide therapeutic benefits in type 2 diabetic nephropathy.
    Keywords:   Drosophila ; Diabetes; Mitochondria; Nephrocyte; PINK1; PRKN
    DOI:  https://doi.org/10.1242/dmm.050471
  26. Annu Rev Biomed Data Sci. 2024 Apr 12.
    Human Genetics and Genomics for Drug Target Identification and Prioritization: Open Targets' Perspective.
    Ellen M McDonagh, Gosia Trynka, Mark McCarthy, Emily Rose Holzinger, Shameer Khader, Nikolina Nakic, Xinli Hu, Helena Cornu, Ian Dunham, David Hulcoop.
      Open Targets, a consortium among academic and industry partners, focuses on using human genetics and genomics to provide insights to key questions that build therapeutic hypotheses. Large-scale experiments generate foundational data, and open-source informatic platforms systematically integrate evidence for target-disease relationships and provide dynamic tooling for target prioritization. A locus-to-gene machine learning model uses evidence from genome-wide association studies (GWAS Catalog, UK BioBank, and FinnGen), functional genomic studies, epigenetic studies, and variant effect prediction to predict potential drug targets for complex diseases. These predictions are combined with genetic evidence from gene burden analyses, rare disease genetics, somatic mutations, perturbation assays, pathway analyses, scientific literature, differential expression, and mouse models to systematically build target-disease associations (https://platform.opentargets.org). Scored target attributes such as clinical precedence, tractability, and safety guide target prioritization. Here we provide our perspective on the value and impact of human genetics and genomics for generating therapeutic hypotheses.
    DOI:  https://doi.org/10.1146/annurev-biodatasci-102523-103838
  27. Free Radic Res. 2024 Apr 10. 1-40
    Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria.
    Danyang Mi, Izumi Yanatori, Hao Zheng, Yingyi Kong, Tasuku Hirayama, Shinya Toyokuni.
      Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Though direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.
    Keywords:  PCBP2; iron; mitochondria; sideroflexin-3
    DOI:  https://doi.org/10.1080/10715762.2024.2340711
  28. Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00040-0. [Epub ahead of print] 101882
    Machine learning-based 3D segmentation of mitochondria in polarized epithelial cells.
    Nan W Hultgren, Tianli Zhou, David S Williams.
      Mitochondria are dynamic organelles that alter their morphological characteristics in response to functional needs. Therefore, mitochondrial morphology is an important indicator of mitochondrial function and cellular health. Reliable segmentation of mitochondrial networks in microscopy images is a crucial initial step for further quantitative evaluation of their morphology. However, 3D mitochondrial segmentation, especially in cells with complex network morphology, such as in highly polarized cells, remains challenging. To improve the quality of 3D segmentation of mitochondria in super-resolution microscopy images, we took a machine learning approach, using 3D Trainable Weka, an ImageJ plugin. We demonstrated that, compared with other commonly used methods, our approach segmented mitochondrial networks effectively, with improved accuracy in different polarized epithelial cell models, including differentiated human retinal pigment epithelial (RPE) cells. Furthermore, using several tools for quantitative analysis following segmentation, we revealed mitochondrial fragmentation in bafilomycin-treated RPE cells.
    Keywords:  3D segmentation; ImageJ; Machine learning algorithm; Mitochondrial morphology; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.mito.2024.101882
  29. bioRxiv. 2024 Mar 29. pii: 2024.03.25.586603. [Epub ahead of print]
    MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN A DROSOPHILA MODEL OF NEURODEGENERATION.
    Andrew P K Wodrich, Brent T Harris, Edward Giniger.
      Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using a Drosophila model of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses, or whether they are simply covariates of pathology that do not alter viability. We find, surprisingly, that increasing mitochondrial H2O2 correlates with improved survival. We also find evidence that drugs that alter the mitochondrial glutathione redox potential modulate survival primarily through the compensatory effects they induce rather than through their direct effects on the final mitochondrial glutathione redox potential per se. We also find that the response to treatment with a redox-altering drug varies dramatically depending on the age at which the drug is administered, the duration of the treatment, and the genotype of the individual receiving the drug. These data have important implications for the design and interpretation of studies investigating the effect of redox state on health and disease as well as on efforts to modify the redox state to achieve therapeutic goals.
    Keywords:  Cdk5; Mitochondria; Neurodegeneration; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1101/2024.03.25.586603
  30. Biol Proced Online. 2024 Apr 09. 26(1): 9
    Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.
    Hongzhi Li, Jing Zhang, Yuqi Shen, Yifan Ye, Qingyou Jiang, Lan Chen, Bohao Sun, Zhuo Chen, Luxi Shen, Hezhi Fang, Jifeng Yang, Haihua Gu.
       BACKGROUND: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson's disease (PD) in human through its metabolite MPP+ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP+-treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice.
    RESULTS: The study in vitro showed NDI1 prevented MPP+-induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra.
    CONCLUSIONS: NDI1 compensates for the defective complex I in MPP+/MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance.
    Keywords:  MPTP; Parkinson’s disease; Respiratory chain complex; Therapy; Viral vector; Yeast NDI1 gene
    DOI:  https://doi.org/10.1186/s12575-024-00236-3
  31. Nat Neurosci. 2024 Apr 10.
    Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration.
    Raffaella De Pace, Saikat Ghosh, Veronica H Ryan, Mira Sohn, Michal Jarnik, Paniz Rezvan Sangsari, Nicole Y Morgan, Ryan K Dale, Michael E Ward, Juan S Bonifacino.
      In neurons, RNA granules are transported along the axon for local translation away from the soma. Recent studies indicate that some of this transport involves hitchhiking of RNA granules on lysosome-related vesicles. In the present study, we leveraged the ability to prevent transport of these vesicles into the axon by knockout of the lysosome-kinesin adaptor BLOC-one-related complex (BORC) to identify a subset of axonal mRNAs that depend on lysosome-related vesicles for transport. We found that BORC knockout causes depletion of a large group of axonal mRNAs mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This depletion results in mitochondrial defects and eventually leads to axonal degeneration in human induced pluripotent stem cell (iPSC)-derived and mouse neurons. Pathway analyses of the depleted mRNAs revealed a mechanistic connection of BORC deficiency with common neurodegenerative disorders. These results demonstrate that mRNA transport on lysosome-related vesicles is critical for the maintenance of axonal homeostasis and that its failure causes axonal degeneration.
    DOI:  https://doi.org/10.1038/s41593-024-01619-1
  32. J Mol Diagn. 2024 Apr 04. pii: S1525-1578(24)00063-1. [Epub ahead of print]
    Focused Exome Sequencing Gives a High Diagnostic Yield in the Indian Subcontinent.
    Arul Joseph Duraisamy, Ruby Liu, Shruti Sureshkumar, Rajiv Rose, Lakshmanan Jagannathan, Cristina da Silva, Adam Coovadia, Vinish Ramachander, Sathyapriya Chandrasekar, Indu Raja, Manisha Sajnani, Sreekanth Muthu Selvaraj, Bhuvandeep Narang, Katayoon Darvishi, Amar Chand Bhayal, Lavanya Katikala, Fen Guo, Xiangwen Chen-Deutsch, Jorune Balciuniene, Zeqiang Ma, Babi Ramesh Reddy Nallamilli, Lora Bean, Christin Collins, Madhuri Hegde.
      The genetically isolated yet heterogeneous and highly consanguineous Indian population has shown a higher prevalence of rare genetic disorders. However, there is a significant socioeconomic burden for genetic testing to be accessible to the general population. In the current study, we analyzed next-generation sequencing data generated through focused exome sequencing from individuals with different phenotypic manifestations referred for genetic testing to achieve a molecular diagnosis. We reported pathogenic or likely pathogenic variants in 280 of 833 cases with a diagnostic yield of 33.6%. Homozygous sequence and copy number variants were found as positive diagnostic findings in 131 cases (15.7%) because of the high consanguinity in the Indian population. No relevant findings related to reported phenotype were identified in 6.2% of the cases. Patients referred for testing due to metabolic disorder and neuromuscular disorder had higher diagnostic yields. Carrier testing of asymptomatic individuals with a family history of the disease, through focused exome sequencing, achieved positive diagnosis in 54 of 118 cases tested. We also reported copy number variants in trans with single-nucleotide variants and mitochondrial variants in a few of the cases. The diagnostic yield and the findings from this study signify that a focused exome test is a good lower-cost alternative for whole-exome and whole-genome sequencing and as a first-tier approach to genetic testing.
    DOI:  https://doi.org/10.1016/j.jmoldx.2024.03.005
  33. bioRxiv. 2024 Mar 27. pii: 2024.03.26.586828. [Epub ahead of print]
    Lysosomal storage disease proteo/lipidomic profiling using nMOST links ferritinophagy with mitochondrial iron deficiencies in cells lacking NPC2.
    Felix Kraus, Yuchen He, Sharan Swarup, Katherine A Overmyer, Yizhi Jiang, Johann Brenner, Cristina Capitanio, Anna Bieber, Annie Jen, Nicole M Nightingale, Benton J Anderson, Chan Lee, Joao A Paulo, Ian R Smith, Jürgen M Plitzko, Brenda A Schulman, Florian Wilfling, Joshua J Coon, J Wade Harper.
      Lysosomal storage diseases (LSDs) comprised ∼50 monogenic diseases characterized by the accumulation of cellular material in lysosomes and associated defects in lysosomal function, but systematic molecular phenotyping is lacking. Here, we develop a nanoflow-based multi-omic single-shot technology (nMOST) workflow allowing simultaneously quantify HeLa cell proteomes and lipidomes from more than two dozen LSD mutants, revealing diverse molecular phenotypes. Defects in delivery of ferritin and its autophagic receptor NCOA4 to lysosomes (ferritinophagy) were pronounced in NPC2 -/- cells, which correlated with increased lyso-phosphatidylcholine species and multi-lamellar membrane structures visualized by cryo-electron-tomography. Ferritinophagy defects correlated with loss of mitochondrial cristae, MICOS-complex components, and electron transport chain complexes rich in iron-sulfur cluster proteins. Strikingly, mitochondrial defects were alleviated when iron was provided through the transferrin system. This resource reveals how defects in lysosomal function can impact mitochondrial homeostasis in trans and highlights nMOST as a discovery tool for illuminating molecular phenotypes across LSDs.
    DOI:  https://doi.org/10.1101/2024.03.26.586828
  34. bioRxiv. 2024 Mar 25. pii: 2024.03.20.585932. [Epub ahead of print]
    Mitochondrial stress in GABAergic neurons non-cell autonomously regulates organismal health and aging.
    Laxmi Rathor, Shayla Curry, Youngyong Park, Taylor McElroy, Briana Robles, Yi Sheng, Wei-Wen Chen, Kisuk Min, Rui Xiao, Myon Hee Lee, Sung Min Han.
      Mitochondrial stress within the nervous system can trigger non-cell autonomous responses in peripheral tissues. However, the specific neurons involved and their impact on organismal aging and health have remained incompletely understood. Here, we demonstrate that mitochondrial stress in γ-aminobutyric acid-producing (GABAergic) neurons in Caenorhabditis elegans ( C. elegans ) is sufficient to significantly alter organismal lifespan, stress tolerance, and reproductive capabilities. This mitochondrial stress also leads to significant changes in mitochondrial mass, energy production, and levels of reactive oxygen species (ROS). DAF-16/FoxO activity is enhanced by GABAergic neuronal mitochondrial stress and mediates the induction of these non-cell-autonomous effects. Moreover, our findings indicate that GABA signaling operates within the same pathway as mitochondrial stress in GABAergic neurons, resulting in non-cell-autonomous alterations in organismal stress tolerance and longevity. In summary, these data suggest the crucial role of GABAergic neurons in detecting mitochondrial stress and orchestrating non-cell-autonomous changes throughout the organism.
    DOI:  https://doi.org/10.1101/2024.03.20.585932
  35. RNA. 2024 Apr 12. pii: rna.079925.123. [Epub ahead of print]
    Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2).
    Michelle Noble, Aindrila Chatterjee, Thileepan Sekaran, Thomas Schwarzl, Matthias W Hentze.
      Several enzymes of intermediary metabolism have been identified to bind RNA in 2 cells, with potential consequences for the bound RNAs and/or the enzyme. In this 3 study, we investigate the RNA-binding activity of the mitochondrial enzyme malate 4 dehydrogenase 2 (MDH2), which functions in the tricarboxylic acid (TCA) cycle and 5 the malate-aspartate shuttle. We confirmed in cellulo RNA-binding of MDH2 using 6 orthogonal biochemical assays and performed enhanced crosslinking and 7 immunoprecipitation (eCLIP) to identify the cellular RNAs associated with endogenous 8 MDH2. Surprisingly, MDH2 preferentially binds cytosolic over mitochondrial RNAs, 9 although the latter are abundant in the milieu of the mature protein. Subcellular 10 fractionation followed by RNA-binding assays revealed that MDH2-RNA interactions 11 occur predominantly outside of mitochondria. We also found that a cytosolically-12 retained N-terminal deletion mutant of MDH2 is competent to bind RNA, indicating that 13 mitochondrial targeting is dispensable for MDH2-RNA interactions. MDH2 RNA 14 binding increased when cellular NAD+ levels (MDH2's co-factor) was 15 pharmacologically diminished, suggesting that the metabolic state of cells affects RNA 16 binding. Taken together, our data implicate an as yet unidentified function of MDH2 17 binding RNA in the cytosol.
    Keywords:  MDH2; RNA-binding proteins; metabolic enzymes
    DOI:  https://doi.org/10.1261/rna.079925.123
  36. Cells. 2024 Apr 07. pii: 647. [Epub ahead of print]13(7):
    Miro GTPases at the Crossroads of Cytoskeletal Dynamics and Mitochondrial Trafficking.
    Pontus Aspenström.
      Miro GTPases are key components in the machinery responsible for transporting mitochondria and peroxisomes along microtubules, and also play important roles in regulating calcium homeostasis and organizing contact sites between mitochondria and the endoplasmic reticulum. Moreover, Miro GTPases have been shown to interact with proteins that actively regulate cytoskeletal organization and dynamics, suggesting that these GTPases participate in organizing cytoskeletal functions and organelle transport. Derailed mitochondrial transport is associated with neuropathological conditions such as Parkinson's and Alzheimer's diseases. This review explores our recent understanding of the diverse roles of Miro GTPases under cytoskeletal control, both under normal conditions and during the course of human diseases such as neuropathological disorders.
    Keywords:  Miro GTPases; Parkinson’s disease; microtubules; mitochondrial dynamics; neuropathology
    DOI:  https://doi.org/10.3390/cells13070647
  37. Gene. 2024 Apr 04. pii: S0378-1119(24)00318-4. [Epub ahead of print]916 148437
    Sudden cardiac death triggered by minimal alcohol consumption in the context of novel PPA2 mutations in 2 unrelated families.
    Cristina Gómez González, Iván Del Campo Cano, Ana Isabel Fernández-Avila, Maria Paz Suárez-Mier, María José Sagastizábal, Reyes Álvarez García-Rovés, Irene Méndez Fernández, Silvia Vilches, Miriam Centeno Jiménez, Ana Siles Sánchez-Manjavacas, Ana Usano Carrasco, Emiliano Gonzalez-Vioque, Juan Pablo Ochoa, Constancio Medrano, Esther González López, Pablo García-Pavía, Javier Bermejo, María Angeles Espinosa Castro.
      Biallelic variants in PPA2 gene cause a rare but lethal mitochondrial disorder. We describe the first four cases reported in Spain of PPA2 disease in two unrelated families. We have conducted a revision of the clinical history, necropsies, and postmortem genetic testing from probands, and clinical evaluation, genetic testing and blood transcript analysis in family members. All the cases harbored biallelic PPA2 variants in compound heterozygous status. Two brothers from family 1 suffered sudden death after a small first intake of alcohol in 2013 and 2022. The sister remains alive but affected with cardiomyopathy, extensive scar on cardiac imaging, and high sensitivity to alcohol intake. The three siblings carried PPA2 c.290A > G (p.Glu97Gly) novel missense variant and PPA2 c.513C > T (p.Cys171 = ) altering splicing site variant, both probably leading to mRNA degradation based on in-silico and transcript analyses. A teenager from family 2 suffered sudden death after a small intake of alcohol in 2018 and carried PPA2 c.683C > T (p.Pro228Leu) missense and PPA2 c.980_983del (p.Gln327fs) novel frameshift variant, both probably leading to abnormal protein structure. All cases were asymptomatic until adolescence. Furthermore, the sister in family 1 has survived as an asymptomatic adult. PPA2 disease can manifest as cardiac arrest in the young, especially after alcohol exposure. Our results show that PPA2 deficiency can be related to different pathogenicity mechanisms such as abnormal protein structure but also mRNA decay caused by synonymous or missense variants. Strict avoidance of alcohol consumption and early defibrillator implantation might prevent lethal arrhythmias in patients at risk.
    Keywords:  Mitochondrial disease; PPA2 gene; Sudden cardiac death
    DOI:  https://doi.org/10.1016/j.gene.2024.148437
  38. Bioorg Med Chem. 2024 Apr 03. pii: S0968-0896(24)00126-3. [Epub ahead of print]104 117712
    Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates.
    Patrick A Cardwell, Carlo Del Moro, Michael P Murphy, Adrian J Lapthorn, Richard C Hartley.
      Glutathione-S-transferases are key to the cellular detoxification of xenobiotics and products of oxidative damage. GSTs catalyse the reaction of glutathione (GSH) with electrophiles to form stable thioether adducts. GSTK1-1 is the main GST isoform in the mitochondrial matrix, but the GSTA1-1 and GSTA4-4 isoforms are also thought to be in the mitochondria with their distribution altering in transformed cells, thus potentially providing a cancer specific target. A mitochondria-targeted version of the GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), MitoCDNB, has been used to manipulate the mitochondrial GSH pool. To finesse this approach to target particular GST isoforms in the context of cancer, here we have determined the kcat/Km for the human isoforms of GSTK1-1, GSTA1-1 and GSTA4-4 with respect to GSH and CDNB. We show how the rate of the GST-catalysed reaction between GSH and CDNB analogues can be modified by both the electron withdrawing substituents, and by the position of the mitochondria-targeting triphenylphosphonium on the chlorobenzene ring to tune the activity of mitochondria-targeted substrates. These findings can now be exploited to selectively disrupt the mitochondrial GSH pools of cancer cells expressing particular GST isoforms.
    Keywords:  Cancer; Glutathione; Glutathione-S-transferase; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bmc.2024.117712
  39. Cell Rep Methods. 2024 Apr 06. pii: S2667-2375(24)00087-0. [Epub ahead of print] 100756
    Mutational rescue of the activity of high-fidelity Cas9 enzymes.
    Pascal D Vos, Andrianto P Gandadireja, Giulia Rossetti, Stefan J Siira, Jessica L Mantegna, Aleksandra Filipovska, Oliver Rackham.
      Programmable DNA endonucleases derived from bacterial genetic defense systems, exemplified by CRISPR-Cas9, have made it significantly easier to perform genomic modifications in living cells. However, unprogrammed, off-target modifications can have serious consequences, as they often disrupt the function or regulation of non-targeted genes and compromise the safety of therapeutic gene editing applications. High-fidelity mutants of Cas9 have been established to enable more accurate gene editing, but these are typically less efficient. Here, we merge the strengths of high-fidelity Cas9 and hyperactive Cas9 variants to provide an enzyme, which we dub HyperDriveCas9, that yields the desirable properties of both parents. HyperDriveCas9 functions efficiently in mammalian cells and introduces insertion and deletion mutations into targeted genomic regions while maintaining a favorable off-target profile. HyperDriveCas9 is a precise and efficient tool for gene editing applications in science and medicine.
    Keywords:  CP: Biotechnology; CP: Molecular biology; CRISPR; Cas9; HypaCas9; TurboCas9; gene editing; gene therapy; genome modification; off target; protein engineering; synthetic biology
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100756
  40. Can J Ophthalmol. 2024 Apr 06. pii: S0008-4182(24)00095-4. [Epub ahead of print]
    Poor visual prognosis of Asian patients with 3460 mitochondrial DNA mutation in Leber's hereditary optic neuropathy.
    Hee Kyung Yang, Moon-Woo Seong, Ji Yeon Kim, Sung Sup Park, Jeong-Min Hwang.
       BACKGROUND: Among the 3 primary mutations of Leber's hereditary optic neuropathy (LHON), the incidence of LHON with a mutation at nucleotide position 3460 is the lowest in Asians. Therefore, information about the clinical manifestations of LHON mutations in Asians with the 3460 mutation is limited.
    OBJECTIVE: To determine the clinical manifestations including visual prognosis of Asians with the LHON 3460 mutation.
    METHODS: We performed a retrospective study of 5 Korean LHON patients with the 3460 mutation.
    RESULTS: All patients were male, and the age of onset for visual impairment varied from 17 to 35 years, with an average of 25.4 ± 7.16 years. Among the 10 affected eyes, only 1 eye of 1 patient showed visual improvement to 20/50 at 2 years after onset. The remaining patients had a visual acuity of worse than 20/200.
    CONCLUSION: The visual prognosis of Korean patients with the LHON 3460 mutation was generally poor. Further studies regarding Asian patients with the LHON 3460 mutation are necessary.
    DOI:  https://doi.org/10.1016/j.jcjo.2024.03.013
  41. Cells. 2024 Apr 08. pii: 648. [Epub ahead of print]13(7):
    Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.
    Artyom Y Baev, Andrey Y Vinokurov, Elena V Potapova, Andrey V Dunaev, Plamena R Angelova, Andrey Y Abramov.
      Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated symptoms. Mitochondrial dysfunction has been shown to be involved in the pathogenesis of most the neurodegenerative disorders. The fast and transient permeability of mitochondria (the mitochondrial permeability transition, mPT) has been shown to be an initial step in the mechanism of apoptotic and necrotic cell death, which acts as a regulator of tissue regeneration for postmitotic neurons as it leads to the irreparable loss of cells and cell function. In this study, we review the role of the mitochondrial permeability transition in neuronal death in major neurodegenerative diseases, covering the inductors of mPTP opening in neurons, including the major ones-free radicals and calcium-and we discuss perspectives and difficulties in the development of a neuroprotective strategy based on the inhibition of mPTP in neurodegenerative disorders.
    Keywords:  astrocyte; cell death; mitochondrial permeability transition; neurodegeneration; neuron
    DOI:  https://doi.org/10.3390/cells13070648
  42. Cell Calcium. 2024 Apr 08. pii: S0143-4160(24)00045-9. [Epub ahead of print]120 102887
    A novel probe to monitor lysosome-mitochondria contact sites opens up a new path to study neurodegenerative diseases.
    Mai Makino, Shuhei Nakamura.
      
    DOI:  https://doi.org/10.1016/j.ceca.2024.102887
  43. Orphanet J Rare Dis. 2024 Apr 12. 19(1): 159
    Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods.
    Yupeng Liu, Xue Ma, Zhehui Chen, Ruxuan He, Yao Zhang, Hui Dong, Yanyan Ma, Tongfei Wu, Qiao Wang, Yuan Ding, Xiyuan Li, Dongxiao Li, Jinqing Song, Mengqiu Li, Ying Jin, Jiong Qin, Yanling Yang.
       BACKGROUND: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported.
    RESULTS: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR.
    CONCLUSIONS: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.
    Keywords:  Dual molecular diagnoses; Genetic disease; Methylmalonic acid; Whole-exome sequencing
    DOI:  https://doi.org/10.1186/s13023-024-03148-3
  44. Biochem Biophys Res Commun. 2024 Apr 04. pii: S0006-291X(24)00419-4. [Epub ahead of print]710 149883
    Cardiac-specific deletion of heat shock protein 60 induces mitochondrial stress and disrupts heart development in mice.
    Tao Shen, Shuting Wang, Can Huang, Siting Zhu, Xiangbin Zhu, Na Li, Hong Wang, Lei Huang, Mingming Ren, Zhen Han, Jianjun Ge, Ze'e Chen, Kunfu Ouyang.
      Congenital heart diseases are the most common birth defects around the world. Emerging evidence suggests that mitochondrial homeostasis is required for normal heart development. In mitochondria, a series of molecular chaperones including heat shock protein 60 (HSP60) are engaged in assisting the import and folding of mitochondrial proteins. However, it remains largely obscure whether and how these mitochondrial chaperones regulate cardiac development. Here, we generated a cardiac-specific Hspd1 deletion mouse model by αMHC-Cre and investigated the role of HSP60 in cardiac development. We observed that deletion of HSP60 in embryonic cardiomyocytes resulted in abnormal heart development and embryonic lethality, characterized by reduced cardiac cell proliferation and thinner ventricular walls, highlighting an essential role of cardiac HSP60 in embryonic heart development and survival. Our results also demonstrated that HSP60 deficiency caused significant downregulation of mitochondrial ETC subunits and induced mitochondrial stress. Analysis of gene expression revealed that P21 that negatively regulates cell proliferation is significantly upregulated in HSP60 knockout hearts. Moreover, HSP60 deficiency induced activation of eIF2α-ATF4 pathway, further indicating the underlying mitochondrial stress in cardiomyocytes after HSP60 deletion. Taken together, our study demonstrated that regular function of mitochondrial chaperones is pivotal for maintaining normal mitochondrial homeostasis and embryonic heart development.
    Keywords:  ATF4; Cardiomyocytes; Heart development; Heat shock protein 60; Mitochondrial stress
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149883
  45. J Med Internet Res. 2024 Apr 11. 26 e51138
    A Perspective on Crowdsourcing and Human-in-the-Loop Workflows in Precision Health.
    Peter Washington.
      Modern machine learning approaches have led to performant diagnostic models for a variety of health conditions. Several machine learning approaches, such as decision trees and deep neural networks, can, in principle, approximate any function. However, this power can be considered to be both a gift and a curse, as the propensity toward overfitting is magnified when the input data are heterogeneous and high dimensional and the output class is highly nonlinear. This issue can especially plague diagnostic systems that predict behavioral and psychiatric conditions that are diagnosed with subjective criteria. An emerging solution to this issue is crowdsourcing, where crowd workers are paid to annotate complex behavioral features in return for monetary compensation or a gamified experience. These labels can then be used to derive a diagnosis, either directly or by using the labels as inputs to a diagnostic machine learning model. This viewpoint describes existing work in this emerging field and discusses ongoing challenges and opportunities with crowd-powered diagnostic systems, a nascent field of study. With the correct considerations, the addition of crowdsourcing to human-in-the-loop machine learning workflows for the prediction of complex and nuanced health conditions can accelerate screening, diagnostics, and ultimately access to care.
    Keywords:  AI; artificial intelligence; crowdsourcing; digital medicine; human in the loop; human-AI collaboration; human-in-the-loop; machine learning; precision health
    DOI:  https://doi.org/10.2196/51138
  46. Mol Neurobiol. 2024 Apr 06.
    Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.
    Sarah Hui, Jimmy George, Minesh Kapadia, Hien Chau, Zahn Bariring, Rebecca Earnshaw, Kashfia Shafiq, Lorraine V Kalia, Suneil K Kalia.
      Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.
    Keywords:  Alpha-synuclein; Lysosomes; Mitochondria dysfunction; Mitophagy; Neurodegeneration; Parkinson’s disease; Substantia nigra pars compacta
    DOI:  https://doi.org/10.1007/s12035-024-04131-6
  47. Res Sq. 2024 Mar 29. pii: rs.3.rs-4087193. [Epub ahead of print]
    Oocyte mitochondria link maternal environment to offspring phenotype.
    Nick Burton, Jason Cooper, Kim Nguyen, Darrick Gates, Emily Wolfram, Colt Capan, Hyoungjoo Lee, Devia Williams, Chidozie Okoye, Andrew Wojtovich.
      During maturation oocytes undergo a recently discovered mitochondrial proteome remodeling event in flies 1 , frogs 1 , and humans 2 . This oocyte mitochondrial remodeling, which includes substantial changes in electron transport chain (ETC) subunit abundance 1,2 , is regulated by maternal insulin signaling 1 . Why oocytes undergo mitochondrial remodeling is unknown, with some speculating that it might be an evolutionarily conserved mechanism to protect oocytes from genotoxic damage by reactive oxygen species (ROS) 2 . In Caenorhabditis elegans , we previously found that maternal exposure to osmotic stress drives a 50-fold increase in offspring survival in response to future osmotic stress3. Like mitochondrial remodeling, we found that this intergenerational adaptation is also regulated by insulin signaling to oocytes 3 . Here, we used proteomics and genetic manipulations to show that insulin signaling to oocytes regulates offspring's ability to adapt to future stress via a mechanism that depends on ETC composition in maternal oocytes. Specifically, we found that maternally expressed mutant alleles of nduf-7 (complex I subunit) or isp -1 (complex III subunit) altered offspring's response to osmotic stress at hatching independently of offspring genotype. Furthermore, we found that expressing wild44 type isp -1 in germ cells (oocytes) was sufficient to restore offspring's normal response to osmotic stress. Chemical mutagenesis screens revealed that maternal ETC composition regulates offspring's response to stress by altering AMP kinase function in offspring which in turn regulates both ATP and glycerol metabolism in response to continued osmotic stress. To our knowledge, these data are the first to show that proper oocyte ETC composition is required to link a mother's environment to adaptive changes in offspring metabolism. The data also raise the possibility that the reason diverse animals exhibit insulin regulated remodeling of oocyte mitochondria is to tailor offspring metabolism to best match the environment of their mother.
    DOI:  https://doi.org/10.21203/rs.3.rs-4087193/v1
  48. J Cell Sci. 2024 Apr 08. pii: jcs.261612. [Epub ahead of print]
    GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.
    Xiumei He, Liang Wang, Hoi Ying Tsang, Xiaonan Liu, Xiaofeng Yang, Ziqi Guo, Cheng Yang, Qiong Wu, Zuping Zhou, Xiaobo Cen, Hongxia Zhao.
      Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the heightened phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. On the other hand, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 to mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.
    Keywords:  Drp1; Fission; GTPBP8; Mitochondria; Phosphorylation
    DOI:  https://doi.org/10.1242/jcs.261612
  49. bioRxiv. 2024 Mar 29. pii: 2023.12.01.567409. [Epub ahead of print]
    Ablation of Mitochondrial RCC1-L Induces Nigral Dopaminergic Neurodegeneration and Parkinsonian-like Motor Symptoms.
    Kaylin J Ellioff, Susan M K Osting, Alyssa Lentine, Ashley D Welper, Corinna Burger, Daniel S Greenspan.
      Mitochondrial dysfunction has been linked to both idiopathic and familial forms of Parkinson's disease (PD). We have previously identified RCC1-like (RCC1L) as a protein of the inner mitochondrial membrane important to mitochondrial fusion. Herein, to test whether deficits in RCC1L mitochondrial function might be involved in PD pathology, we have selectively ablated the Rcc1l gene in the dopaminergic (DA) neurons of mice. A PD-like phenotype resulted that includes progressive movement abnormalities, paralleled by progressive degeneration of the nigrostriatal tract. Experimental and control groups were examined at 2, 3-4, and 5-6 months of age. Animals were tested in the open field task to quantify anxiety, exploratory drive, locomotion, and immobility; and in the cylinder test to quantify rearing behavior. Beginning at 3-4 months, both female and male Rcc1l knockout mice show rigid muscles and resting tremor, kyphosis and a growth deficit compared with heterozygous or wild type littermate controls. Rcc1l knockout mice begin showing locomotor impairments at 3-4 months, which progress until 5-6 months of age, at which age the Rcc1l knockout mice die. The progressive motor impairments were associated with progressive and significantly reduced tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta (SNc), and dramatic loss of nigral DA projections in the striatum. Dystrophic spherical mitochondria are apparent in the soma of SNc neurons in Rcc1l knockout mice as early as 1.5-2.5 months of age and become progressively more pronounced until 5-6 months. Together, the results reveal the RCC1L protein to be essential to in vivo mitochondrial function in DA neurons. Further characterization of this mouse model will determine whether it represents a new model for in vivo study of PD, and the putative role of the human RCC1L gene as a risk factor that might increase PD occurrence and severity in humans.
    DOI:  https://doi.org/10.1101/2023.12.01.567409
  50. Int J Mol Sci. 2024 Mar 24. pii: 3629. [Epub ahead of print]25(7):
    Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?
    Camila D S Barros, Aryane Coutinho, Celia H Tengan.
      MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.
    Keywords:  MELAS; arginine; mitochondria; mitochondrial DNA; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.3390/ijms25073629
  51. medRxiv. 2024 Apr 03. pii: 2024.03.27.24304930. [Epub ahead of print]
    Longitudinal change in mitochondrial heteroplasmy exhibits positive selection for deleterious variants.
    Lieke M Kuiper, Wen Shi, Joost Verlouw, Yun Soo Hong, Pascal Arp, Daniela Puiu, Linda Broer, Jiaqi Xie, Charles Newcomb, Steve Rich, Kent Taylor, Jerome Rotter, Joel S Bader, Eliseo Guallar, Joyce Bj van Meurs, Dan E Arking.
      A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation due to their inefficient DNA repair and close proximity to reactive oxygen species, leading to a state of mitochondrial DNA heteroplasmy. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age, a phenomenon that has been attributed to genetic drift. In this first large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined n=1405) at two timepoints (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead demonstrating positive selection for predicted deleterious mutations at the cellular level, despite an negative impact on overall mortality.
    DOI:  https://doi.org/10.1101/2024.03.27.24304930
  52. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 04. pii: S0925-4439(24)00146-7. [Epub ahead of print] 167157
    Idebenone ameliorates statin-induced myotoxicity in atherosclerotic ApoE-/- mice by reducing oxidative stress and improving mitochondrial function.
    Wenfei Yu, Wenjing Wu, Dandan Zhao, Rui ZhangMD, Kai Shao, Haoyang Liu, Chuanzhu Yan, Pengfei Lin.
      Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE-/- mice and whether idebenone could counteract it. After administering simvastatin to ApoE-/- mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone's capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.
    Keywords:  Idebenone; Mitochondria; Myotoxicity; Oxidative stress; Statin
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167157
  53. Genet Med. 2024 Apr 07. pii: S1098-3600(24)00071-6. [Epub ahead of print] 101138
    Long-term Efficacy and Safety of Elamipretide in Patients with Barth Syndrome: 168-Week Open-label Extension Results of TAZPOWER.
    William R Thompson, Ryan Manuel, Anthony Abbruscato, Jim Carr, John Campbell, Brittany Hornby, Frédéric M Vaz, Hilary J Vernon.
       PURPOSE: Evaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS) .
    METHODS: TAZPOWER was a 28-week randomized, double-blind, placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed.
    RESULTS: Ten patients entered the OLE; 8 reached the Week 168 visit. Elamipretide was well tolerated, with injection site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE timepoints (cumulative 96.1 meters of improvement [Week 168, p=0.003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE timepoints. 3-D left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to Week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes.
    CONCLUSION: Elamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.
    Keywords:  Barth syndrome; MLCL/CL ratios; cardiolipin; cardiomyopathy; elamipretide; mitochondrial disease; skeletal muscle myopathy
    DOI:  https://doi.org/10.1016/j.gim.2024.101138
  54. Arch Plast Surg. 2024 Mar;51(2): 182-186
    Management of Ptosis in Kearns-Sayre Syndrome: A Case Report and Literature Review.
    Moulay O Moustaine, Zakaria Azemour, Frarchi Mohammed, Othman Benlanda, Hicham Nassik, Mehdi Karkouri.
      Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease that affects young adults, due to a deletion of mitochondrial DNA and characterized by the triad: age of onset lower than 20 years, chronic progressive external ophthalmoplegia, and an atypical pigmentary retinopathy. It is also characterized by other endocrine, neurological, and especially cardiac impairment with a very high risk of cardiac complications during surgical procedures under all types of anesthesia. We report a case of KSS revealed by severe bilateral ptosis and confirmed by a muscle biopsy with "ragged red fibers." The ptosis was surgically managed by cautious Frontal suspension under local anesthesia "Frontal nerve block." Through this case, we discuss challenges in the management of KSS patients.
    Keywords:  Frontal suspension; Kearns–Sayre syndrome; chronic progressive external ophthalmoplegia; ptosis
    DOI:  https://doi.org/10.1055/a-2207-7587
  55. Phenomics. 2024 Feb;4(1): 56-71
    Multimodal Omics Approaches to Aging and Age-Related Diseases.
    Qianzhao Ji, Xiaoyu Jiang, Minxian Wang, Zijuan Xin, Weiqi Zhang, Jing Qu, Guang-Hui Liu.
      Aging is associated with a progressive decline in physiological capacities and an increased risk of aging-associated disorders. An increasing body of experimental evidence shows that aging is a complex biological process coordinately regulated by multiple factors at different molecular layers. Thus, it is difficult to delineate the overall systematic aging changes based on single-layer data. Instead, multimodal omics approaches, in which data are acquired and analyzed using complementary omics technologies, such as genomics, transcriptomics, and epigenomics, are needed for gaining insights into the precise molecular regulatory mechanisms that trigger aging. In recent years, multimodal omics sequencing technologies that can reveal complex regulatory networks and specific phenotypic changes have been developed and widely applied to decode aging and age-related diseases. This review summarizes the classification and progress of multimodal omics approaches, as well as the rapidly growing number of articles reporting on their application in the field of aging research, and outlines new developments in the clinical treatment of age-related diseases based on omics technologies.
    Keywords:  Aging; Epigenome; Genome; Multimodal omics approaches
    DOI:  https://doi.org/10.1007/s43657-023-00125-x
  56. Biomed Hub. 2024 Jan-Dec;9(1):9(1): 38-44
    Redefining Rare Disease Care in the Digital Age: Insights and Key Takeaways from a Digital Health Symposium Focused on Empowering Rare Disease Communities.
    Emily Lewis, Anuradha Dayal, Ron Li.
      At the Stanford-UCB Rare Disease Digital Health Symposium held in Stanford, California, on September 8, 2023, researchers, clinicians, payers, thought leaders, and rare disease caregivers and advocates discussed the current state of care delivery and future perspectives of digitally-enabled care for rare disease patient populations. Digital health aims to improve healthcare delivery through novel ways of providing access to more precise diagnosis, monitoring of disease progression, treatment, prognosis, and care management for rare disease patients. The meeting focused on highlighting challenges and unmet needs, data infrastructure and analytics, the need for targeted and effective personalized therapies, and the importance of digital care transformation. The meeting also covered the social and ethical impact of access to digitally delivered, patient-centered care, as well as views on implementation and patient autonomy and empowerment.
    Keywords:  Digital health; Health technology; Patient-centered care; Precision medicine; Rare disease; Remote patient monitoring
    DOI:  https://doi.org/10.1159/000536274
  57. FEMS Yeast Res. 2024 Jan 09. pii: foae009. [Epub ahead of print]24
    Mitochondrial membrane transporters as attractive targets for the fermentative production of succinic acid from glycerol in Saccharomyces cerevisiae.
    Toni Rendulić, Andreea Perpelea, Juan Paulo Ragas Ortiz, Margarida Casal, Elke Nevoigt.
      Previously, we reported an engineered Saccharomyces cerevisiae CEN.PK113-1A derivative able to produce succinic acid (SA) from glycerol with net CO2 fixation. Apart from an engineered glycerol utilization pathway that generates NADH, the strain was equipped with the NADH-dependent reductive branch of the TCA cycle (rTCA) and a heterologous SA exporter. However, the results indicated that a significant amount of carbon still entered the CO2-releasing oxidative TCA cycle. The current study aimed to tune down the flux through the oxidative TCA cycle by targeting the mitochondrial uptake of pyruvate and cytosolic intermediates of the rTCA pathway, as well as the succinate dehydrogenase complex. Thus, we tested the effects of deletions of MPC1, MPC3, OAC1, DIC1, SFC1, and SDH1 on SA production. The highest improvement was achieved by the combined deletion of MPC3 and SDH1. The respective strain produced up to 45.5 g/L of SA, reached a maximum SA yield of 0.66 gSA/gglycerol, and accumulated the lowest amounts of byproducts when cultivated in shake-flasks. Based on the obtained data, we consider a further reduction of mitochondrial import of pyruvate and rTCA intermediates highly attractive. Moreover, the approaches presented in the current study might also be valuable for improving SA production when sugars (instead of glycerol) are the source of carbon.
    Keywords:  membrane transporter; metabolic engineering; mitochondria; mpc3; sdh1; succinate; yeast
    DOI:  https://doi.org/10.1093/femsyr/foae009
  58. J Inherit Metab Dis. 2024 Apr 09.
    Impaired coenzyme A homeostasis in cardiac dysfunction and benefits of boosting coenzyme A production with vitamin B5 and its derivatives in the management of heart failure.
    J J Wedman, O C M Sibon, E Mastantuono, A Iuso.
      Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too. In the current review, we will summarize our current knowledge on CoA and heart failure, with emphasis on two primary cardiomyopathies, phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency disorders biochemically characterized by a decreased level of CoA in patients' samples. Hence, we will discuss the potential benefits of CoA restoration in these diseases and, more generally, in heart failure, by vitamin B5 and its derivatives pantethine and 4'-phosphopantetheine.
    Keywords:  4′‐phosphopantetheine; PKAN; PPCDC DD; PPCS DD; TANGO2 DD; Type II 3‐methylglutaconic aciduria; cardiac dysfunction; coenzyme A (CoA); heart failure (HF); pantethine; vitamin B5 (or pantothenic acid)
    DOI:  https://doi.org/10.1002/jimd.12737
  59. Prog Neurobiol. 2024 Apr 09. pii: S0301-0082(24)00039-X. [Epub ahead of print] 102603
    The STRAT-PARK cohort: a personalized initiative to stratify Parkinson's disease.
    Kjersti Eline Stige, Simon Ulvenes Kverneng, Soumya Sharma, Geir-Olve Skeie, Erika Sheard, Mona Søgnen, Solveig Af Geijerstam, Therese Vetås, Anne Grete Wahlvåg, Haakon Berven, Sagar Buch, David Reese, Dina Babiker, Yekta Mahdi, Trevor Wade, Gala Prado Miranda, Jacky Ganguly, Yokhesh Krishnasamy Tamilselvam, Jia Ren Chai, Saurabh Bansal, Dorian Aur, Sima Soltani, Scott Adams, Christian Dölle, Fiona Dick, Erik Magnus Berntsen, Renate Grüner, Njål Brekke, Frank Riemer, Pål Erik Goa, Kristoffer Haugarvoll, E Mark Haacke, Mandar Jog, Charalampos Tzoulis.
      The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ~150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.
    Keywords:  Parkinson’s disease; mitochondria; progression; stratification; subtypes
    DOI:  https://doi.org/10.1016/j.pneurobio.2024.102603
  60. Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00036-9. [Epub ahead of print]76 101878
    The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.
    Gianmarco Borriello, Veronica Buonincontri, Antonio de Donato, Michele Della Corte, Ilenia Gravina, Pietro Iulianiello, Rashmi Joshi, Pasquale Mone, Giovanna Cacciola, Davide Viggiano.
      Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.
    Keywords:  Endothelium; Gliflozins; Proximal tubule; SGLT2; Sodium; Swelling
    DOI:  https://doi.org/10.1016/j.mito.2024.101878
  61. Cell Biosci. 2024 Apr 06. 14(1): 45
    Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease.
    Martin Grønbæk-Thygesen, Rasmus Hartmann-Petersen.
      Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype-phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease.
    Keywords:  NAA; NAAG; Neurodegeneration; Proteasome; Protein degradation; Protein folding; Protein misfolding; Protein quality control; Protein stability; VUS
    DOI:  https://doi.org/10.1186/s13578-024-01224-6
  62. bioRxiv. 2024 Mar 27. pii: 2024.03.24.584499. [Epub ahead of print]
    An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.
    Kai Chen, Patrick Ernst, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D Ringel, Xiaoguang Margaret Liu, Lufang Zhou.
      Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo .
    DOI:  https://doi.org/10.1101/2024.03.24.584499
  63. Cell. 2024 Mar 28. pii: S0092-8674(24)00252-6. [Epub ahead of print]
    A genome-wide spectrum of tandem repeat expansions in 338,963 humans.
    Ya Cui, Wenbin Ye, Jason Sheng Li, Jingyi Jessica Li, Eric Vilain, Tamer Sallam, Wei Li.
      The Genome Aggregation Database (gnomAD), widely recognized as the gold-standard reference map of human genetic variation, has largely overlooked tandem repeat (TR) expansions, despite the fact that TRs constitute ∼6% of our genome and are linked to over 50 human diseases. Here, we introduce the TR-gnomAD (https://wlcb.oit.uci.edu/TRgnomAD), a biobank-scale reference of 0.86 million TRs derived from 338,963 whole-genome sequencing (WGS) samples of diverse ancestries (39.5% non-European samples). TR-gnomAD offers critical insights into ancestry-specific disease prevalence using disparities in TR unit number frequencies among ancestries. Moreover, TR-gnomAD is able to differentiate between common, presumably benign TR expansions, which are prevalent in TR-gnomAD, from those potentially pathogenic TR expansions, which are found more frequently in disease groups than within TR-gnomAD. Together, TR-gnomAD is an invaluable resource for researchers and physicians to interpret TR expansions in individuals with genetic diseases.
    Keywords:  GWAS; TR-gnomAD; ancestries; expansion; genome aggregation; human genetics; missing heritability; rare diseases; tandem repeat; whole genome sequencing
    DOI:  https://doi.org/10.1016/j.cell.2024.03.004
  64. Mov Disord. 2024 Apr 08.
    A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.
    Karan Sharma, Asha Kishore, Anna Lechado-Terradas, Raffaele Passannanti, Francesco Raimondi, Marc Sturm, Ashwin Ashok Kumar Sreelatha, Divya Kalikavila Puthenveedu, Gangadhara Sarma, Nicolas Casadei, Rejko Krüger, Thomas Gasser, Philipp Kahle, Olaf Riess, Julia C Fitzgerald, Manu Sharma.
       BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research.
    OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family.
    METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment.
    RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved Deutsche Forschungsgemeinschaft (DFG) motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization.
    CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  PINK1; Parkinson's disease; genome sequencing; mitophagy; phosphorylation; ubiquitin
    DOI:  https://doi.org/10.1002/mds.29792
  65. Am J Hum Genet. 2024 Apr 03. pii: S0002-9297(24)00080-6. [Epub ahead of print]
    The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.
    Undiagnosed Diseases Network
      RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. The overall diagnostic yield was 25.4%. Over a quarter of the diagnostic findings benefited from transdifferentiation and could not be achieved by fibroblast RNA-seq alone. This iNeuron transcriptomic approach can be effectively integrated into diagnostic whole-transcriptome evaluation of individuals with genetic disorders.
    Keywords:  RNA sequencing; RNA-seq; clinically accessible tissue; fibroblast; genetic diagnosis; induced neuron; isoform; neurological disorder; transcriptome; transdifferentiation
    DOI:  https://doi.org/10.1016/j.ajhg.2024.03.007
  66. Science. 2024 Apr 11. eado0431
    Human telomere length is chromosome end-specific and conserved across individuals.
    Kayarash Karimian, Aljona Groot, Vienna Huso, Ramin Kahidi, Kar-Tong Tan, Samantha Sholes, Rebecca Keener, John F McDyer, Jonathan K Alder, Heng Li, Andreas Rechtsteiner, Carol W Greider.
      Short telomeres cause age-related disease and long telomeres predispose to cancer; however, the mechanisms regulating telomere length are unclear. We developed a nanopore-based method, Telomere Profiling, to determine telomere length at nearly single nucleotide resolution. Mapping telomere reads to chromosome ends showed chromosome end-specific length distributions that could differ by more than six kilobases. Telomere lengths in 147 individuals showed certain chromosome ends were consistently longer or shorter. The same rank order was found in newborn cord blood, suggesting that telomere length is determined at birth and chromosome end-specific telomere length differences are maintained as telomeres shorten with age. Telomere Profiling makes precision investigation of telomere length widely accessible for laboratory, clinical, and drug discovery efforts and will allow deeper insights into telomere biology.
    DOI:  https://doi.org/10.1126/science.ado0431
  67. Nat Commun. 2024 Apr 10. 15(1): 3110
    DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.
    Kian Hong Kock, Patrick K Kimes, Stephen S Gisselbrecht, Sachi Inukai, Sabrina K Phanor, James T Anderson, Gayatri Ramakrishnan, Colin H Lipper, Dongyuan Song, Jesse V Kurland, Julia M Rogers, Raehoon Jeong, Stephen C Blacklow, Rafael A Irizarry, Martha L Bulyk.
      Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and are the TF structural class with the largest number of disease-associated mutations in the Human Gene Mutation Database (HGMD). Despite numerous structural studies and large-scale analyses of HD DNA binding specificity, HD-DNA recognition is still not fully understood. Here, we analyze 92 human HD mutants, including disease-associated variants and variants of uncertain significance (VUS), for their effects on DNA binding activity. Many of the variants alter DNA binding affinity and/or specificity. Detailed biochemical analysis and structural modeling identifies 14 previously unknown specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibits different effects on DNA binding activity. Variant effect prediction tools perform moderately well in distinguishing variants with altered DNA binding affinity, but poorly in identifying those with altered binding specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and the development of clinical diagnostics and precision therapies.
    DOI:  https://doi.org/10.1038/s41467-024-47396-0
  68. Commun Biol. 2024 Apr 10. 7(1): 438
    Revealing myopathy spectrum: integrating transcriptional and clinical features of human skeletal muscles with varying health conditions.
    Huahua Zhong, Veronica Sian, Mridul Johari, Shintaro Katayama, Ali Oghabian, Per Harald Jonson, Peter Hackman, Marco Savarese, Bjarne Udd.
      Myopathy refers to a large group of heterogeneous, rare muscle diseases. Bulk RNA-sequencing has been utilized for the diagnosis and research of these diseases for many years. However, the existing valuable sequencing data often lack integration and clinical interpretation. In this study, we integrated bulk RNA-sequencing data from 1221 human skeletal muscles (292 with myopathies, 929 controls) from both databases and our local samples. By applying a method similar to single-cell analysis, we revealed a general spectrum of muscle diseases, ranging from healthy to mild disease, moderate muscle wasting, and severe muscle disease. This spectrum was further partly validated in three specific myopathies (97 muscles) through clinical features including trinucleotide repeat expansion, magnetic resonance imaging fat fraction, pathology, and clinical severity scores. This spectrum helped us identify 234 genuinely healthy muscles as unprecedented controls, providing a new perspective for deciphering the hallmark genes and pathways among different myopathies. The newly identified featured genes of general myopathy, inclusion body myositis, and titinopathy were highly expressed in our local muscles, as validated by quantitative polymerase chain reaction.
    DOI:  https://doi.org/10.1038/s42003-024-06143-3
  69. bioRxiv. 2024 Mar 29. pii: 2024.03.26.586745. [Epub ahead of print]
    Uncovering microstructural architecture from histology.
    Marios Georgiadis, Franca Auf der Heiden, Hamed Abbasi, Loes Ettema, Jeffrey Nirschl, Hossein Moein Taghavi, Moe Wakatsuki, Andy Liu, William Hai Dang Ho, Mackenzie Carlson, Michail Doukas, Sjors A Koppes, Stijn Keereweer, Raymond A Sobel, Kawin Setsompop, Congyu Liao, Katrin Amunts, Markus Axer, Michael Zeineh, Miriam Menzel.
      Microstructural tissue organization underlies the complex connectivity of the brain and controls properties of connective, muscle, and epithelial tissue. However, discerning microstructural architecture with high resolution for large fields of view remains prohibitive. We address this challenge with computational scattered light imaging (ComSLI), which exploits the anisotropic light scattering of aligned structures. Using a rotating lightsource and a high-resolution camera, ComSLI determines fiber architecture with micrometer resolution from histological sections across preparation and staining protocols. We show complex fiber architecture in brain and non-brain sections, including histological paraffin-embedded sections with various stains, and demonstrate its applicability on animal and human tissue, including disease cases with altered microstructure. ComSLI opens new avenues for investigating fiber architecture in new and archived sections across organisms, tissues, and diseases.
    One Sentence Summary: We uncover microstructural architecture of new or archived human and animal histological sections in health and disease.
    DOI:  https://doi.org/10.1101/2024.03.26.586745
  70. Orphanet J Rare Dis. 2024 Apr 06. 19(1): 148
    Identification and characterization of a new pathologic mutation in a large Leber hereditary optic neuropathy pedigree.
    Sonia Emperador, Mouna Habbane, Ester López-Gallardo, Alejandro Del Rio, Laura Llobet, Javier Mateo, Ana María Sanz-López, María José Fernández-García, Hortensia Sánchez-Tocino, Sol Benbunan-Ferreiro, María Calabuig-Goena, Carlos Narvaez-Palazón, Beatriz Fernández-Vega, Hector González-Iglesias, Roser Urreizti, Rafael Artuch, David Pacheu-Grau, Pilar Bayona-Bafaluy, Julio Montoya, Eduardo Ruiz-Pesini.
       BACKGROUND: Most patients suffering from Leber hereditary optic neuropathy carry one of the three classic pathologic mutations, but not all individuals with these genetic alterations develop the disease. There are different risk factors that modify the penetrance of these mutations. The remaining patients carry one of a set of very rare genetic variants and, it appears that, some of the risk factors that modify the penetrance of the classical pathologic mutations may also affect the phenotype of these other rare mutations.
    RESULTS: We describe a large family including 95 maternally related individuals, showing 30 patients with Leber hereditary optic neuropathy. The mutation responsible for the phenotype is a novel transition, m.3734A > G, in the mitochondrial gene encoding the ND1 subunit of respiratory complex I. Molecular-genetic, biochemical and cellular studies corroborate the pathogenicity of this genetic change.
    CONCLUSIONS: With the study of this family, we confirm that, also for this very rare mutation, sex and age are important factors modifying penetrance. Moreover, this pedigree offers an excellent opportunity to search for other genetic or environmental factors that additionally contribute to modify penetrance.
    Keywords:  Incomplete penetrance; Large pedigree; Leber hereditary optic neuropathy; Mitochondrial DNA; Pathologic mutation
    DOI:  https://doi.org/10.1186/s13023-024-03165-2
  71. medRxiv. 2024 Mar 26. pii: 2024.03.22.24304565. [Epub ahead of print]
    Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease.
    Undiagnosed Diseases Network
      Rare structural variants (SVs) - insertions, deletions, and complex rearrangements - can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore long-read genomes of 68 individuals from the Undiagnosed Disease Network (UDN) with no previously identified diagnostic mutations from short-read sequencing. Using our optimized SV detection pipelines and 571 control long-read genomes, we detected 716 long-read rare (MAF < 0.01) SV alleles per genome on average, achieving a 2.4x increase from short-reads. To characterize the functional effects of rare SVs, we assessed their relationship with gene expression from blood or fibroblasts from the same individuals, and found that rare SVs overlapping enhancers were enriched (LOR = 0.46) near expression outliers. We also evaluated tandem repeat expansions (TREs) and found 14 rare TREs per genome; notably these TREs were also enriched near overexpression outliers. To prioritize candidate functional SVs, we developed Watershed-SV, a probabilistic model that integrates expression data with SV-specific genomic annotations, which significantly outperforms baseline models that do not incorporate expression data. Watershed-SV identified a median of eight high-confidence functional SVs per UDN genome. Notably, this included compound heterozygous deletions in FAM177A1 shared by two siblings, which were likely causal for a rare neurodevelopmental disorder. Our observations demonstrate the promise of integrating long-read sequencing with gene expression towards improving the prioritization of functional SVs and TREs in rare disease patients.
    DOI:  https://doi.org/10.1101/2024.03.22.24304565
  72. bioRxiv. 2024 Mar 27. pii: 2024.03.26.582525. [Epub ahead of print]
    Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.
    Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Cagri G Besirli, Costas A Lyssiotis, Thomas J Wubben.
      The bioenergetic demand of photoreceptors rivals that of cancer cells, and numerous metabolic similarities exist between these cells. Glutamine (Gln) anaplerosis via the tricarboxylic acid (TCA) cycle provides biosynthetic intermediates and is a hallmark of cancer metabolism. In this process, Gln is first converted to glutamate via glutaminase (GLS), which is a crucial pathway in many cancer cells. To date, no study has been undertaken to examine the role of Gln metabolism in vivo in photoreceptors. Here, mice lacking GLS in rod photoreceptors were generated. Animals lacking GLS experienced rapid photoreceptor degeneration with concomitant functional loss. Gln has multiple roles in metabolism including redox balance, biosynthesis of nucleotides and amino acids, and supplementing the TCA cycle. Few alterations were noted in redox balance. Unlabeled targeted metabolomics demonstrated few changes in glycolytic and TCA cycle intermediates, which corresponded with a lack of significant changes in mitochondrial function. GLS deficiency in rod photoreceptors did decrease the fractional labelling of TCA cycle intermediates when provided uniformly labeled 13 C-Gln in vivo . However, supplementation with alpha-ketoglutarate provided only marginal rescue of photoreceptor degeneration. Nonessential amino acids, glutamate and aspartate, were decreased in the retina of mice lacking GLS in rod photoreceptors. In accordance with this amino acid deprivation, the integrated stress response (ISR) was found to be activated with decreased global protein synthesis. Importantly, supplementation with asparagine delayed photoreceptor degeneration to a greater degree than alpha-ketoglutarate. These data show that GLS-mediated Gln catabolism is essential for rod photoreceptor amino acid biosynthesis, function, and survival.
    Significance Statement: Glucose has been central in the study of photoreceptor cell metabolism. Recently, it was shown that fuel sources besides glucose can meet the metabolic needs of photoreceptors. Glutamine (Gln) is the most abundant circulating amino acid and has many biosynthetic and bioenergetic roles in cells. Glutaminolysis is the process by which Gln is metabolized into tricarboxylic acid cycle intermediates to provide biosynthetic precursors. Here, Gln is first converted to glutamate via the enzyme glutaminase (GLS). This research demonstrates that deletion of GLS in rod photoreceptors alters retinal metabolism, activates the integrated stress response (ISR), and results in rapid photoreceptor degeneration. As such, Gln is a critical fuel source that supports photoreceptor cell biomass, redox balance, and survival.
    DOI:  https://doi.org/10.1101/2024.03.26.582525
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