bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–04–07
seventy papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
  2. Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.
  3. mtDNA analysis using Mitopore.
  4. A novel mitochondrial DNA variant in MT-ND6: m.14430A>C p.(Trp82Gly) identified in a patient with Leigh syndrome and complex I deficiency.
  5. Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.
  6. Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
  7. Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.
  8. Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.
  9. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.
  10. Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
  11. MICU1's calcium sensing beyond mitochondrial calcium uptake.
  12. A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
  13. An inner mitochondrial membrane microprotein from the SLC35A4 upstream ORF regulates cellular metabolism.
  14. Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.
  15. Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.
  16. Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.
  17. A spatiotemporal proteomic map of human adipogenesis.
  18. PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
  19. Orthogonal analysis of mitochondrial function in Parkinson's disease patients.
  20. Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.
  21. Mitochondrial Targeted Therapies to Prevent Maternal Diabetes-Induced Congenital Heart Defects.
  22. Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.
  23. SRSF1 Is Required for Mitochondrial Homeostasis and Thermogenic Function in Brown Adipocytes Through its Control of Ndufs3 Splicing.
  24. Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.
  25. Closing the gap: Solving complex medically relevant genes at scale.
  26. Improved mitochondrial function in the heart of sarcolipin-deficient dystrophin and utrophin double knockout mice.
  27. Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
  28. The Roles of CircRNAs in Mitochondria.
  29. Mitofilin in Cardiovascular Diseases: Insights into the Pathogenesis and Potential Pharmacological Interventions.
  30. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).
  31. Mitochondrial remodeling underlying age-induced skeletal muscle wasting: let's talk about sex.
  32. Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes.
  33. Genetic and functional correction of argininosuccinate lyase deficiency using CRISPR adenine base editors.
  34. From powerhouse to regulator: The role of mitoepigenetics in mitochondrion-related cellular functions and human diseases.
  35. The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.
  36. Age-dependent loss of Crls1 causes myopathy and skeletal muscle regeneration failure.
  37. Letter to the editor on: prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume.
  38. Prioritizing disease-related rare variants by integrating gene expression data.
  39. Primary Coenzyme Q10 Deficiency-4 Causing Young Onset Ataxia-Dystonia.
  40. Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.
  41. Clinical and genetic analysis of essential hypertension with mitochondrial tRNAMet 4435A>G and YARS2 mutation.
  42. Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations.
  43. Insight from Wild Yeast Isolates into the Molecular Mechanisms of Lifespan Variation Mediated by Caloric Restriction.
  44. Membrane fission via transmembrane contact.
  45. FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA.
  46. Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae.
  47. Secondary follicles enable efficient germline mtDNA base editing at hard-to-edit site.
  48. The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis.
  49. Identification and structural characterization of small molecule inhibitors of PINK1.
  50. Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype.
  51. Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.
  52. Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.
  53. SCAF1 drives the compositional diversity of mammalian respirasomes.
  54. Tracing the lipidome in inborn errors of metabolism.
  55. Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes.
  56. Gut microbiota regulates the nutrient sensing enteroendocrine cell maturation and mitochondrial function.
  57. Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.
  58. Intertwined relationship of dynamin-related protein 1, mitochondrial metabolism and circadian rhythm.
  59. Prioritization of genes for translation: a computational approach.
  60. Mapping structural variants to rare disease genes using long-read whole genome sequencing and trait-relevant polygenic scores.
  61. AI in Cellular Engineering and Reprogramming.
  62. mRNA therapies: Pioneering a new era in rare genetic disease treatment.
  63. Drug discovery by AI trained on aging biology.
  64. Leber Hereditary Optic Neuropathy in 2 Sisters With Friedreich Ataxia.
  65. RedOx regulation of LRRK2 kinase activity by active site cysteines.
  66. Chaperone function in Fe-S protein biogenesis: Three possible scenarios.
  67. Parkinson's disease gene, Synaptojanin1, dysregulates the basal maintenance of the dopamine transporter.
  68. Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease.
  69. Sequencing technologies and hardware-accelerated parallel computing transform computational genomics research.
  70. Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery.
  1. EMBO Rep. 2024 Apr 02.
    The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
    Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.
      Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
    Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import
    DOI:  https://doi.org/10.1038/s44319-024-00113-w
  2. bioRxiv. 2024 Mar 22. pii: 2024.03.21.586162. [Epub ahead of print]
    Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.
    Alia R Edington, Olivia M Connor, Madeleine Marlar-Pavey, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that exist in a semi- continuous network. Mitochondrial morphology arises from the complex interplay of numerous processes, including opposing fission and fusion dynamics and the formation of highly organized cristae invaginations of the inner membrane. While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear how fission is coordinated across two membrane bilayers and how mitochondrial inner membrane organization is coupled with mitochondrial fission dynamics. Previously, the yeast protein Mdm33 was implicated in facilitating fission by coordinating with inner membrane homeostasis pathways. However, Mdm33 is not conserved outside fungal species and its precise mechanistic role remains unclear. Here, we use a bioinformatic approach to identify a putative structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK). We find that the mitochondrial phenotypes associated with altered CCDC51 levels implicate the protein in mitochondrial fission dynamics. Further, using timelapse microscopy, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 can partially rescue yeast Δ mdm33 cells, indicating the proteins are functionally analogous. Our data reveal that Mdm33/CCDC51 are conserved mediators of mitochondrial morphology and suggest the proteins play a crucial role in maintaining normal mitochondrial dynamics and organelle homeostasis.
    DOI:  https://doi.org/10.1101/2024.03.21.586162
  3. Mol Ther Methods Clin Dev. 2024 Jun 13. 32(2): 101231
    mtDNA analysis using Mitopore.
    Jochen Dobner, Thach Nguyen, Mario Gustavo Pavez-Giani, Lukas Cyganek, Felix Distelmaier, Jean Krutmann, Alessandro Prigione, Andrea Rossi.
      Mitochondrial DNA (mtDNA) analysis is crucial for the diagnosis of mitochondrial disorders, forensic investigations, and basic research. Existing pipelines are complex, expensive, and require specialized personnel. In many cases, including the diagnosis of detrimental single nucleotide variants (SNVs), mtDNA analysis is still carried out using Sanger sequencing. Here, we developed a simple workflow and a publicly available webserver named Mitopore that allows the detection of mtDNA SNVs, indels, and haplogroups. To simplify mtDNA analysis, we tailored our workflow to process noisy long-read sequencing data for mtDNA analysis, focusing on sequence alignment and parameter optimization. We implemented Mitopore with eliBQ (eliminate bad quality reads), an innovative quality enhancement that permits the increase of per-base quality of over 20% for low-quality data. The whole Mitopore workflow and webserver were validated using patient-derived and induced pluripotent stem cells harboring mtDNA mutations. Mitopore streamlines mtDNA analysis as an easy-to-use fast, reliable, and cost-effective analysis method for both long- and short-read sequencing data. This significantly enhances the accessibility of mtDNA analysis and reduces the cost per sample, contributing to the progress of mtDNA-related research and diagnosis.
    Keywords:  Mitopore; ONT; clinical mtDNA diagnosis; forensic mtDNA analysis; haplogroups; iPSCs quality control; long-read sequencing; mtDNA analysis; mtDNA heteroplasmy; webserver
    DOI:  https://doi.org/10.1016/j.omtm.2024.101231
  4. Mol Genet Metab Rep. 2024 Jun;39 101078
    A novel mitochondrial DNA variant in MT-ND6: m.14430A>C p.(Trp82Gly) identified in a patient with Leigh syndrome and complex I deficiency.
    Surita Meldau, Sally Ackermann, Gillian Riordan, George F van der Watt, Careni Spencer, Sharika Raga, Kashief Khan, Dee M Blackhurst, Francois H van der Westhuizen.
      Leigh syndrome is a severe progressive mitochondrial disorder mainly affecting children under the age of 5 years. It is caused by pathogenic variants in any one of more than 75 known genes in the nuclear or mitochondrial genomes. A 19-week-old male infant presented with lactic acidosis and encephalopathy following a 2-week history of irritability, neuroregression and poor weight gain. He was hypotonic with pathological reflexes, impaired vision, and nystagmus. Brain MRI showed extensive bilateral symmetrical T2 hyperintense lesions in basal ganglia, thalami, and brainstem. Metabolic workup showed elevated serum alanine, and heavy lactic aciduria with increased ketones, fumarate, malate, and alpha-ketoglutarate as well as reduced succinate on urine organic acid analysis. Lactic acidemia persisted, with only a marginally elevated lactate:pyruvate ratio (16.46, ref. 0-10). He demised at age 7 months due to respiratory failure. Exome sequencing followed by virtual gene panel analysis for pyruvate metabolism and mitochondrial defects could not identify any nuclear cause for Leigh syndrome. Mitochondrial DNA (mtDNA) genome sequencing revealed 88% heteroplasmy for a novel variant, NC_012920.1(MT-ND6):m.14430A>C p.(Trp82Gly), in blood DNA. This variant was absent from the unaffected mother's blood, fibroblast, and urine DNA, and detected at a level of 5% in her muscle DNA. Mitochondrial respiratory chain analysis revealed markedly reduced mitochondrial complex I activity in patient fibroblasts (34% of parent and control cells), and reduced NADH-linked respirometry (less than half of parental and control cells), while complex II driven respirometry remained intact. The combined clinical, genetic, and biochemical findings suggest that the novel MT-ND6 variant is the likely cause of Leigh syndrome in this patient. The mitochondrial ND6 protein is a subunit of complex I. An interesting finding was the absence of a significantly elevated lactate:pyruvate ratio in the presence of severe lactatemia, which directed initial diagnostic efforts towards excluding a pyruvate metabolism defect. This case highlights the value of a multidisciplinary approach and complete genetic workup to diagnosing mitochondrial disorders in South African patients.
    Keywords:  Complex I deficiency; Leigh syndrome; MT-DN6; Novel mtDNA variant
    DOI:  https://doi.org/10.1016/j.ymgmr.2024.101078
  5. PNAS Nexus. 2024 Apr;3(4): pgae116
    Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.
    Darren J Walsh, David J Bernard, Joanna L Fiddler, Faith Pangilinan, Madison Esposito, Denise Harold, Martha S Field, Anne Parle-McDermott, Lawrence C Brody.
      One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.
    Keywords:  cobalamin; folic acid; heteroplasmy; mitochondria; vitamin B12
    DOI:  https://doi.org/10.1093/pnasnexus/pgae116
  6. bioRxiv. 2024 Mar 20. pii: 2024.03.20.586011. [Epub ahead of print]
    Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
    Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Hao Zhang, Xianfeng Niu, Marissa A Laramie, Marion I Stunault, Jasmin Sponagel, Gary Patti, Leah Shriver, Vitaly Klyachko, Ghazaleh Ashrafi.
      Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals.
    HIGHLIGHTS: Serum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle.The mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism.Acetylation of the MPC complex modulates mitochondrial pyruvate uptake.MPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals.
    DOI:  https://doi.org/10.1101/2024.03.20.586011
  7. Trends Biochem Sci. 2024 Apr 01. pii: S0968-0004(24)00071-9. [Epub ahead of print]
    Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.
    Scott A Jones, Jonathan J Ruprecht, Paul G Crichton, Edmund R S Kunji.
      In mitochondria, the oxidation of nutrients is coupled to ATP synthesis by the generation of a protonmotive force across the mitochondrial inner membrane. In mammalian brown adipose tissue (BAT), uncoupling protein 1 (UCP1, SLC25A7), a member of the SLC25 mitochondrial carrier family, dissipates the protonmotive force by facilitating the return of protons to the mitochondrial matrix. This process short-circuits the mitochondrion, generating heat for non-shivering thermogenesis. Recent cryo-electron microscopy (cryo-EM) structures of human UCP1 have provided new molecular insights into the inhibition and activation of thermogenesis. Here, we discuss these structures, describing how purine nucleotides lock UCP1 in a proton-impermeable conformation and rationalizing potential conformational changes of this carrier in response to fatty acid activators that enable proton leak for thermogenesis.
    Keywords:  SLC25 mitochondrial carrier family; UCP1; bioenergetics; brown adipose tissue; non-shivering thermogenesis; thermogenin
    DOI:  https://doi.org/10.1016/j.tibs.2024.03.005
  8. Commun Biol. 2024 Mar 30. 7(1): 391
    Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.
    Paul Y Bi, Samuel A Killackey, Linus Schweizer, Damien Arnoult, Dana J Philpott, Stephen E Girardin.
      Mitochondrial stress inducers such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and oligomycin trigger the DELE1-HRI branch of the integrated stress response (ISR) pathway. Previous studies performed using epitope-tagged DELE1 showed that these stresses induced the cleavage of DELE1 to DELE1-S, which stimulates HRI. Here, we report that mitochondrial protein import stress (MPIS) is an overarching stress that triggers the DELE1-HRI pathway, and that endogenous DELE1 could be cleaved into two forms, DELE1-S and DELE1-VS, the latter accumulating only upon non-depolarizing MPIS. Surprisingly, while the mitochondrial protease OMA1 was crucial for DELE1 cleavage in HeLa cells, it was dispensable in HEK293T cells, suggesting that multiple proteases may be involved in DELE1 cleavage. In support, we identified a role for the mitochondrial protease, HtrA2, in mediating DELE1 cleavage into DELE1-VS, and showed that a Parkinson's disease (PD)-associated HtrA2 mutant displayed reduced DELE1 processing ability, suggesting a novel mechanism linking PD pathogenesis to mitochondrial stress. Our data further suggest that DELE1 is likely cleaved into DELE1-S in the cytosol, while the DELE1-VS form might be generated during halted translocation into mitochondria. Together, this study identifies MPIS as the overarching stress detected by DELE1 and identifies a novel role for HtrA2 in DELE1 processing.
    DOI:  https://doi.org/10.1038/s42003-024-06107-7
  9. Am J Hum Genet. 2024 Mar 27. pii: S0002-9297(24)00081-8. [Epub ahead of print]
    Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.
    Gabrielle Lemire, Alba Sanchis-Juan, Kathryn Russell, Samantha Baxter, Katherine R Chao, Moriel Singer-Berk, Emily Groopman, Isaac Wong, Eleina England, Julia Goodrich, Lynn Pais, Christina Austin-Tse, Stephanie DiTroia, Emily O'Heir, Vijay S Ganesh, Monica H Wojcik, Emily Evangelista, Hana Snow, Ikeoluwa Osei-Owusu, Jack Fu, Mugdha Singh, Yulia Mostovoy, Steve Huang, Kiran Garimella, Samantha L Kirkham, Jennifer E Neil, Diane D Shao, Christopher A Walsh, Emanuela Argilli, Carolyn Le, Elliott H Sherr, Joseph G Gleeson, Shirlee Shril, Ronen Schneider, Friedhelm Hildebrandt, Vijay G Sankaran, Jill A Madden, Casie A Genetti, Alan H Beggs, Pankaj B Agrawal, Kinga M Bujakowska, Emily Place, Eric A Pierce, Sandra Donkervoort, Carsten G Bönnemann, Lyndon Gallacher, Zornitza Stark, Tiong Yang Tan, Susan M White, Ana Töpf, Volker Straub, Mark D Fleming, Martin R Pollak, Katrin Õunap, Sander Pajusalu, Kirsten A Donald, Zandre Bruwer, Gianina Ravenscroft, Nigel G Laing, Daniel G MacArthur, Heidi L Rehm, Michael E Talkowski, Harrison Brand, Anne O'Donnell-Luria.
      Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.
    Keywords:  CNV; GATK-gCNV; copy number variant; diagnostic yield; exome; variant classification
    DOI:  https://doi.org/10.1016/j.ajhg.2024.03.008
  10. Sci Adv. 2024 Apr 05. 10(14): eadl0389
    Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
    Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.
      The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adl0389
  11. Biochim Biophys Acta Mol Cell Res. 2024 Mar 29. pii: S0167-4889(24)00057-0. [Epub ahead of print] 119714
    MICU1's calcium sensing beyond mitochondrial calcium uptake.
    Sarah D Kaye, Shanikumar Goyani, Dhanendra Tomar.
      The discovery of MICU1 as gatekeeper of mitochondrial calcium (mCa2+) entry has transformed our understanding of mCa2+ flux. Recent studies revealed an additional role of MICU1 as a Ca2+ sensor at MICOS (mitochondrial contact site and cristae organizing system). MICU1's presence at MICOS suggests its involvement in coordinating Ca2+ signaling and mitochondrial ultrastructure. Besides its role in Ca2+ regulation, MICU1 influences cellular signaling pathways including transcription, epigenetic regulation, metabolism, and cell death signaling pathways, thereby affecting human health. Here, we summarize recent findings on MICU1's canonical and noncanonical functions, and its relevance to human health and diseases.
    Keywords:  Calcium; MCU; MICOS; MICU1; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119714
  12. Res Sq. 2024 Mar 22. pii: rs.3.rs-4047706. [Epub ahead of print]
    A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
    Martin Picard, Eugene Mosharov, Ayelet Rosenberg, Anna Monzel, Corey Osto, Linsey Stiles, Gorazd Rosoklija, Andrew Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline Mariani, Mihran Bakalian, David Sulzer, Philip De Jager, Vilas Menon, Orian Shirihai, John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten.
      Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3x3x3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.
    DOI:  https://doi.org/10.21203/rs.3.rs-4047706/v1
  13. J Mol Biol. 2024 Apr 03. pii: S0022-2836(24)00154-2. [Epub ahead of print] 168559
    An inner mitochondrial membrane microprotein from the SLC35A4 upstream ORF regulates cellular metabolism.
    Andrea L Rocha, Victor Pai, Guy Perkins, Tina Chang, Jiao Ma, Qian Chu, Joan M Vaughan, Jolene K Diedrich, Mark H Ellisman, Alan Saghatelian.
      Upstream open reading frames (uORFs) are cis-acting elements that can dynamically regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing translation under stress conditions. Computational and empirical methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts, making uORFs one the largest regulatory elements known. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides and small proteins, or microproteins, encoded by uORFs are under studied. We hypothesized that a uORF in the SLC35A4 mRNA is producing a functionalmicroprotein (SLC35A4-MP) because of its conserved amino acid sequence. Through a series of biochemical and cellular experiments, we find that the 103-amino acid SLC35A4-MP is a single-pass transmembrane inner mitochondrial membrane (IMM) microprotein. The IMM contains the protein machinery crucial for cellular respiration and ATP generation, and loss of function studies with SLC35A4-MP significantly diminish maximal cellular respiration, indicating a vital role for this microprotein in cellular metabolism. The findings add to the growing list of functional microproteins and, more generally, indicate that uORFs that encode conserved microproteins are an untapped reservoir of functional microproteins.
    Keywords:  cellular metabolism; inner mitochondrial membrane; microprotein; mitochondria; upstream open reading frame (uORF)
    DOI:  https://doi.org/10.1016/j.jmb.2024.168559
  14. Brain. 2024 Apr 04. pii: awae089. [Epub ahead of print]
    Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.
    Thomas Paß, Konrad M Ricke, Pierre Hofmann, Roy S Chowdhury, Yu Nie, Patrick Chinnery, Heike Endepols, Bernd Neumaier, André Carvalho, Lionel Rigoux, Sophie M Steculorum, Julien Prudent, Trine Riemer, Markus Aswendt, Birgit Liss, Bent Brachvogel, Rudolf J Wiesner.
      Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations leading to mitochondrial dysfunction are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E-variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control.
    Keywords:  Parkinson’s disease; axonal sprouting; dopaminergic neurons; mitochondrial DNA; motor symptoms; neurodegeneration
    DOI:  https://doi.org/10.1093/brain/awae089
  15. J Physiol. 2024 Apr 02.
    Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.
    Hailey A Parry, T Bradley Willingham, Kevin A Giordano, Yuho Kim, Shureed Qazi, Jay R Knutson, Christian A Combs, Brian Glancy.
      Mitochondria within skeletal muscle cells are located either between the muscle contractile apparatus (interfibrillar mitochondria, IFM) or beneath the cell membrane (subsarcolemmal mitochondria, SSM), with several structural and functional differences reported between IFM and SSM. However, recent 3D imaging studies demonstrate that mitochondria are particularly concentrated in the proximity of capillaries embedded in sarcolemmal grooves rather than in proximity to the sarcolemma itself (paravascular mitochondria, PVM). To evaluate the impact of capillary vs. sarcolemmal proximity, we compared the structure and function of skeletal muscle mitochondria located either lateral to embedded capillaries (PVM), adjacent to the sarcolemma but not in PVM pools (SSM) or interspersed between sarcomeres (IFM). Mitochondrial morphology and interactions were assessed by 3D electron microscopy coupled with machine learning segmentation, whereas mitochondrial energy conversion was assessed by two-photon microscopy of mitochondrial membrane potential, content, calcium, NADH redox and flux in live, intact cells. Structurally, although PVM and SSM were similarly larger than IFM, PVM were larger, rounder and had more physical connections to neighbouring mitochondria compared to both IFM and SSM. Functionally, PVM had similar or greater basal NADH flux compared to SSM and IFM, respectively, despite a more oxidized NADH pool and a greater membrane potential, signifying a greater activation of the electron transport chain in PVM. Together, these data indicate that proximity to capillaries has a greater impact on resting mitochondrial energy conversion and distribution in skeletal muscle than the sarcolemma alone. KEY POINTS: Capillaries have a greater impact on mitochondrial energy conversion in skeletal muscle than the sarcolemma. Paravascular mitochondria are larger, and the outer mitochondrial membrane is more connected with neighbouring mitochondria. Interfibrillar mitochondria are longer and have greater contact sites with other organelles (i.e. sarcoplasmic reticulum and lipid droplets). Paravascular mitochondria have greater activation of oxidative phosphorylation than interfibrillar mitochondria at rest, although this is not regulated by calcium.
    Keywords:  energy function; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1113/JP286246
  16. Eur J Neurol. 2024 Apr 04. e16275
    Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.
    Michelangelo Mancuso, Maria T Papadopoulou, Yi Shiau Ng, Anna Ardissone, Marcello Bellusci, Enrico Bertini, Lidia Di Vito, Teresinha Evangelista, Carmen Fons, Omar Hikmat, Rita Horvath, Thomas Klopstock, Cornelia Kornblum, Costanza Lamperti, Laura Licchetta, Maria Judit Molnar, Kristin N Varhaug, Mar O'Callaghan, Ronit M Pressler, Manuel Schiff, Serenella Servidei, Nora Szabo, Gráinne S Gorman, J Helen Cross, Shamima Rahman.
       BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy.
    METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement.
    RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted.
    CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.
    Keywords:  consensus; epilepsy; management; mitochondrial diseases; recommendations
    DOI:  https://doi.org/10.1111/ene.16275
  17. Nat Metab. 2024 Apr 02.
    A spatiotemporal proteomic map of human adipogenesis.
    Felix Klingelhuber, Scott Frendo-Cumbo, Muhmmad Omar-Hmeadi, Lucas Massier, Pamela Kakimoto, Austin J Taylor, Morgane Couchet, Sara Ribicic, Martin Wabitsch, Ana C Messias, Arcangela Iuso, Timo D Müller, Mikael Rydén, Niklas Mejhert, Natalie Krahmer.
      White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.
    DOI:  https://doi.org/10.1038/s42255-024-01025-8
  18. Stem Cell Reports. 2024 Mar 26. pii: S2213-6711(24)00079-1. [Epub ahead of print]
    PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
    George Cairns, Madhavee Thumiah-Mootoo, Mah Rukh Abbasi, Melissa Gourlay, Jeremy Racine, Nikita Larionov, Alexandre Prola, Mireille Khacho, Yan Burelle.
      Maintenance of mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC), but the underlying mechanisms remain ill defined. In this study, we monitored mitophagy in MuSCS under various myogenic states and examined the role of PINK1 in maintaining regenerative capacity. Results indicate that quiescent MuSCs actively express mitophagy genes and exhibit a measurable mitophagy flux and prominent mitochondrial localization to autophagolysosomes, which become rapidly decreased during activation. Genetic disruption of Pink1 in mice reduces PARKIN recruitment to mitochondria and mitophagy in quiescent MuSCs, which is accompanied by premature activation/commitment at the expense of self-renewal and progressive loss of muscle regeneration, but unhindered proliferation and differentiation capacity. Results also show that impaired fate decisions in PINK1-deficient MuSCs can be restored by scavenging excess mitochondrial ROS. These data shed light on the regulation of mitophagy in MuSCs and position PINK1 as an important regulator of their mitochondrial properties and fate decisions.
    Keywords:  fate decision; mitochondria; mitochondrial quality control; mitophagy; muscle regeneration; muscle stem cells
    DOI:  https://doi.org/10.1016/j.stemcr.2024.03.004
  19. Cell Death Dis. 2024 Apr 03. 15(4): 243
    Orthogonal analysis of mitochondrial function in Parkinson's disease patients.
    Sander Barnhoorn, Chiara Milanese, Tracy Li, Lieke Dons, Mehrnaz Ghazvini, Martina Sette, Stefania Farina, Daisy Sproviero, Cesar Payan-Gomez, Pier G Mastroberardino.
      The etiopathology of Parkinson's disease has been associated with mitochondrial defects at genetic, laboratory, epidemiological, and clinical levels. These converging lines of evidence suggest that mitochondrial defects are systemic and causative factors in the pathophysiology of PD, rather than being mere correlates. Understanding mitochondrial biology in PD at a granular level is therefore crucial from both basic science and translational perspectives. In a recent study, we investigated mitochondrial alterations in fibroblasts obtained from PD patients assessing mitochondrial function in relation to clinical measures. Our findings demonstrated that the magnitude of mitochondrial alterations parallels disease severity. In this study, we extend these investigations to blood cells and dopamine neurons derived from induced pluripotent stem cells reprogrammed from PD patients. To overcome the inherent metabolic heterogeneity of blood cells, we focused our analyses on metabolically homogeneous, accessible, and expandable erythroblasts. Our results confirm the presence of mitochondrial anomalies in erythroblasts and induced dopamine neurons. Consistent with our previous findings in fibroblasts, we observed that mitochondrial alterations are reversible, as evidenced by enhanced mitochondrial respiration when PD erythroblasts were cultured in a galactose medium that restricts glycolysis. This observation indicates that suppression of mitochondrial respiration may constitute a protective, adaptive response in PD pathogenesis. Notably, this effect was not observed in induced dopamine neurons, suggesting their distinct bioenergetic behavior. In summary, we provide additional evidence for the involvement of mitochondria in the disease process by demonstrating mitochondrial abnormalities in additional cell types relevant to PD. These findings contribute to our understanding of PD pathophysiology and may have implications for the development of novel biomarkers and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-024-06617-6
  20. Neurotherapeutics. 2024 Apr 04. pii: S1878-7479(24)00041-2. [Epub ahead of print] e00355
    Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.
    Hyeyoon Eo, Shin-Hye Yu, Yujin Choi, Yujin Kim, Young Cheol Kang, Hanbyeol Lee, Jin Hee Kim, Kyuboem Han, Hong Kyu Lee, Mi-Yoon Chang, Myung Sook Oh, Chun-Hyung Kim.
      Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 ​mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.
    Keywords:  Mitochondria; Mitotherapy; Neuroprotective; Parkinson's disease; Transplantation
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00355
  21. JACC Basic Transl Sci. 2024 Mar;9(3): 319-321
    Mitochondrial Targeted Therapies to Prevent Maternal Diabetes-Induced Congenital Heart Defects.
    Sushma Reddy.
      
    Keywords:  congenital heart defects; fusion; maternal diabetes; mitochondria
    DOI:  https://doi.org/10.1016/j.jacbts.2024.01.016
  22. Biochem J. 2024 Apr 10. 481(7): 499-514
    Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.
    Amina Djurabekova, Jonathan Lasham, Oleksii Zdorevskyi, Volker Zickermann, Vivek Sharma.
      Respiratory complex I is a redox-driven proton pump. Several high-resolution structures of complex I have been determined providing important information about the putative proton transfer paths and conformational transitions that may occur during catalysis. However, how redox energy is coupled to the pumping of protons remains unclear. In this article, we review biochemical, structural and molecular simulation data on complex I and discuss several coupling models, including the key unresolved mechanistic questions. Focusing both on the quinone-reductase domain as well as the proton-pumping membrane-bound domain of complex I, we discuss a molecular mechanism of proton pumping that satisfies most experimental and theoretical constraints. We suggest that protonation reactions play an important role not only in catalysis, but also in the physiologically-relevant active/deactive transition of complex I.
    Keywords:  MD simulations; energy conversion; mitochondrial respiration; protein dynamics; proton pump
    DOI:  https://doi.org/10.1042/BCJ20240009
  23. Adv Sci (Weinh). 2024 Apr 03. e2306871
    SRSF1 Is Required for Mitochondrial Homeostasis and Thermogenic Function in Brown Adipocytes Through its Control of Ndufs3 Splicing.
    Ningyang Yuan, Lei Shen, Qian Peng, Rula Sha, Zhenzhen Wang, Zhiqi Xie, Xue You, Ying Feng.
      RNA splicing dysregulation and the involvement of specific splicing factors are emerging as common factors in both obesity and metabolic disorders. The study provides compelling evidence that the absence of the splicing factor SRSF1 in mature adipocytes results in whitening of brown adipocyte tissue (BAT) and impaired thermogenesis, along with the inhibition of white adipose tissue browning in mice. Combining single-nucleus RNA sequencing with transmission electron microscopy, it is observed that the transformation of BAT cell types is associated with dysfunctional mitochondria, and SRSF1 deficiency leads to degenerated and fragmented mitochondria within BAT. The results demonstrate that SRSF1 effectively binds to constitutive exon 6 of Ndufs3 pre-mRNA and promotes its inclusion. Conversely, the deficiency of SRSF1 results in impaired splicing of Ndufs3, leading to reduced levels of functional proteins that are essential for mitochondrial complex I assembly and activity. Consequently, this deficiency disrupts mitochondrial integrity, ultimately compromising the thermogenic capacity of BAT. These findings illuminate a novel role for SRSF1 in influencing mitochondrial function and BAT thermogenesis through its regulation of Ndufs3 splicing within BAT.
    Keywords:  dysregulatred splicing; impaired thermogenesis; mitochondria dysfunction; splicing regulator; whitening of brown adipocyte tissue
    DOI:  https://doi.org/10.1002/advs.202306871
  24. Nature. 2024 Apr 03.
    Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.
    Yilin Kang, Jussi Hepojoki, Rocio Sartori Maldonado, Takayuki Mito, Mügen Terzioglu, Tuula Manninen, Ravi Kant, Sachin Singh, Alaa Othman, Rohit Verma, Johanna Uusimaa, Kirmo Wartiovaara, Lauri Kareinen, Nicola Zamboni, Tuula Anneli Nyman, Anders Paetau, Anja Kipar, Olli Vapalahti, Anu Suomalainen.
      Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.
    DOI:  https://doi.org/10.1038/s41586-024-07260-z
  25. medRxiv. 2024 Mar 18. pii: 2024.03.14.24304179. [Epub ahead of print]
    Closing the gap: Solving complex medically relevant genes at scale.
    Medhat Mahmoud, John Harting, Holly Corbitt, Xiao Chen, Shalini Jhangiani, Harsha Doddapaneni, Qingchang Meng, Christine Lambert, Siyuan Zhang, Primo Baybayan, Geoff Henno, Tina Han, Han Yi, Casey Riegler, Ginger Metcalf, Chinn K Ivan, Michael A Eberle, Sarah Kingan, Tim Farinholt, Carvalho Claudia, Richard A Gibbs, Zev Kronenberg, Donna Muzny, Fritz J Sedlazeck.
      Comprehending the mechanism behind human diseases with an established heritable component represents the forefront of personalized medicine. Nevertheless, numerous medically important genes are inaccurately represented in short-read sequencing data analysis due to their complexity and repetitiveness or the so-called "dark regions" of the human genome. The advent of PacBio as a long-read platform has provided new insights, yet HiFi whole-genome sequencing (WGS) cost remains frequently prohibitive. We introduce a targeted sequencing and analysis framework, Twist Alliance Dark Genes Panel (TADGP), designed to offer phased variants across 389 medically important yet complex autosomal genes. We highlight TADGP accuracy across eleven control samples and compare it to WGS. This demonstrates that TADGP achieves variant calling accuracy comparable to HiFi-WGS data, but at a fraction of the cost. Thus, enabling scalability and broad applicability for studying rare diseases or complementing previously sequenced samples to gain insights into these complex genes. TADGP revealed several candidate variants across all cases and provided insight into LPA diversity when tested on samples from rare disease and cardiovascular disease cohorts. In both cohorts, we identified novel variants affecting individual disease-associated genes (e.g., IKZF1, KCNE1). Nevertheless, the annotation of the variants across these 389 medically important genes remains challenging due to their underrepresentation in ClinVar and gnomAD. Consequently, we also offer an annotation resource to enhance the evaluation and prioritization of these variants. Overall, we can demonstrate that TADGP offers a cost-efficient and scalable approach to routinely assess the dark regions of the human genome with clinical relevance.
    DOI:  https://doi.org/10.1101/2024.03.14.24304179
  26. JCI Insight. 2024 Apr 02. pii: e170185. [Epub ahead of print]
    Improved mitochondrial function in the heart of sarcolipin-deficient dystrophin and utrophin double knockout mice.
    Satvik Mareedu, Nadezhda Fefelova, Cristi L Galindo, Goutham Prakash, Risa Mukai, Junichi Sadoshima, Lai-Hua Xie, Gopal J Babu.
      Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD-cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin null (mdx:utrn-/-) mice in sarcolipin (SLN) heterozygous knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium. Germline reduction of SLN expression in mdx:utrn-/- mice improved cardiac sarco/endoplasmic reticulum (SR) Ca2+ cycling, reduced cardiac fibrosis, and improved cardiac function. At the cellular level, reducing SLN expression prevented mitochondrial Ca2+ overload, reduced mitochondrial membrane potential loss, and improved mitochondrial function. Transmission electron microscopy of myocardial tissues and proteomic analysis of mitochondria-associated membranes show that reducing SLN expression improved mitochondrial structure and SR-mitochondria interactions in dystrophic cardiac myocytes. These findings indicate that SLN upregulation plays a significant role in the pathogenesis of cardiomyopathy and that reducing SLN expression has clinical implications in the treatment of DMD-cardiomyopathy.
    Keywords:  Calcium; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.170185
  27. Sci Rep. 2024 Apr 03. 14(1): 7877
    Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
    Tsuyoshi Kawabata, Reiko Sekiya, Shinji Goto, Tao-Sheng Li.
      Replication stress is a major contributor to tumorigenesis because it provides a source of chromosomal rearrangements via recombination events. PARK2, which encodes parkin, a regulator of mitochondrial homeostasis, is located on one of the common fragile sites that are prone to rearrangement by replication stress, indicating that replication stress may potentially impact mitochondrial homeostasis. Here, we show that chronic low-dose replication stress causes a fixed reduction in parkin expression, which is associated with mitochondrial dysfunction, indicated by an increase in mtROS. Consistent with the major role of parkin in mitophagy, reduction in parkin protein expression was associated with a slight decrease in mitophagy and changes in mitochondrial morphology. In contrast, cells expressing ectopic PARK2 gene does not show mtROS increases and changes in mitochondrial morphology even after exposure to chronic replication stress, suggesting that intrinsic fragility at PARK2 loci associated with parkin reduction is responsible for mitochondrial dysfunction caused by chronic replication stress. As endogenous replication stress and mitochondrial dysfunction are both involved in multiple pathophysiology, our data support the therapeutic development of recovery of parkin expression in human healthcare.
    DOI:  https://doi.org/10.1038/s41598-024-58656-w
  28. J Cancer. 2024 ;15(9): 2759-2769
    The Roles of CircRNAs in Mitochondria.
    Donghong Liu, Xinyu Zhou, Yida He, Jun Zhao.
      Mitochondria participate in varieties of cellular events. It is widely accepted that human mitochondrial genome encodes 13 proteins, 2 rRNAs, and 22 tRNAs. Gene variation derived from human nuclear genome cannot completely explain mitochondrial diseases. The advent of high-throughput sequencing coupled with novel bioinformatic analyses decode the complexity of mitochondria-derived transcripts. Recently, circular RNAs (circRNAs) from both human mitochondrial genome and nuclear genome have been found to be located at mitochondria. Studies about the roles and molecular mechanisms underlying trafficking of the nucleus encoded circRNAs to mitochondria and mitochondria encoded circRNAs to the nucleus or cytoplasm in mammals are only beginning to emerge. These circRNAs have been associated with a variety of diseases, especially cancers. Here, we discuss the emerging field of mitochondria-located circRNAs by reviewing their identification, expression patterns, regulatory roles, and functional mechanisms. Mitochondria-located circRNAs have regulatory roles in cellular physiology and pathology. We also highlight future perspectives and challenges in studying mitochondria-located circRNAs, as well as their potential biomedical applications.
    Keywords:  circular RNAs; mitochondria; mitochondrial genome; noncoding RNAs; nuclear genome
    DOI:  https://doi.org/10.7150/jca.92111
  29. Pharmacol Res. 2024 Apr 01. pii: S1043-6618(24)00108-7. [Epub ahead of print] 107164
    Mitofilin in Cardiovascular Diseases: Insights into the Pathogenesis and Potential Pharmacological Interventions.
    Abdallah Iddy Chaurembo, Na Xing, Francis Chanda, Yuan Li, Hui-Juan Zhang, Li-Dan Fu, Jian-Yuan Huang, Yun-Jing Xu, Wen-Hui Deng, Hao-Dong Cui, Xin-Yue Tong, Chi Shu, Han-Bin Lin, Kai-Xuan Lin.
      The impact of mitochondrial dysfunction on the pathogenesis of cardiovascular disease is increasing. However, the precise underlying mechanism remains unclear. Mitochondria produce cellular energy through oxidative phosphorylation while regulating calcium homeostasis, cellular respiration, and the production of biosynthetic chemicals. Nevertheless, problems related to cardiac energy metabolism, defective mitochondrial proteins, mitophagy, and structural changes in mitochondrial membranes can cause cardiovascular diseases via mitochondrial dysfunction. Mitofilin is a critical inner mitochondrial membrane protein that maintains cristae structure and facilitates protein transport while linking the inner mitochondrial membrane, outer mitochondrial membrane, and mitochondrial DNA transcription. Researchers believe that mitofilin may be a therapeutic target for treating cardiovascular diseases, particularly cardiac mitochondrial dysfunctions. In this review, we highlight current findings regarding the role of mitofilin in the pathogenesis of cardiovascular diseases and potential therapeutic compounds targeting mitofilin.
    Keywords:  Bendavia (elamipretide) (PubChem CID: 11764719); Cardiovascular diseases; Cristae junction; Ginsenoside Rg1 (PubChem CID: 441923); Levosimendan (PubChem CID: 3033825); Malvidin 3-O-arabinoside (M3A) (PubChem CID: 91810654); Mito-Tempo (PubChem CID: 134828258); MitoQ (PubChem CID: 11388332); Mitochondrial dysfunction; Mitochondrial-targeted therapy; Mitochonic Acid-5 (PubChem CID: 76070959); Mitofilin; N-acetylcysteine (PubChem CID: 12035); Pyridostatin (PubChem CID: 25227847); Resveratrol (PubChem CID: 445154)
    DOI:  https://doi.org/10.1016/j.phrs.2024.107164
  30. Int J Mol Med. 2024 May;pii: 47. [Epub ahead of print]53(5):
    Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).
    Pei Qin, Ye Sun, Liya Li.
      Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation. In addition to providing energy to cells, mitochondria also participate in the immunoinflammatory response of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and epilepsy, by regulating processes such as cell death and inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, mitochondrial dynamics and calcium homeostasis imbalance may serve as underlying regulatory mechanisms for these diseases. Therefore, investigating mechanisms related to mitochondrial dysfunction may result in therapeutic strategies against chronic neuroinflammation and neurodegeneration. The present review summarizes the mechanisms of mitochondria in chronic neuroinflammatory diseases and the current treatment approaches that target mitochondrial dysfunction in these diseases.
    Keywords:  Alzheimer's disease; Parkinson's disease; chronic neuroinflammation; epilepsy; mitochondrial dysfunction; multiple sclerosis; neurodegeneration
    DOI:  https://doi.org/10.3892/ijmm.2024.5371
  31. Free Radic Biol Med. 2024 Apr 02. pii: S0891-5849(24)00170-9. [Epub ahead of print]
    Mitochondrial remodeling underlying age-induced skeletal muscle wasting: let's talk about sex.
    Alexandra Moreira-Pais, Rui Vitorino, Cláudia Sousa-Mendes, Maria João Neuparth, Alessandro Nuccio, Claudio Luparello, Alessandro Attanzio, Petr Novák, Dmitry Loginov, Rita Nogueira-Ferreira, Adelino Leite-Moreira, Paula A Oliveira, Rita Ferreira, José A Duarte.
      Sarcopenia is associated with reduced quality of life and premature mortality. The sex disparities in the processes underlying sarcopenia pathogenesis, which include mitochondrial dysfunction, are ill-understood and can be decisive for the optimization of sarcopenia-related interventions. To improve the knowledge regarding the sex differences in skeletal muscle aging, the gastrocnemius muscle of young and old female and male rats was analyzed with a focus on mitochondrial remodeling through the proteome profiling of mitochondria-enriched fractions. To the best of our knowledge, this is the first study analyzing sex differences in skeletal muscle mitochondrial proteome remodeling. Data demonstrated that age induced skeletal muscle atrophy and fibrosis in both sexes. In females, however, this adverse skeletal muscle remodeling was more accentuated than in males and might be attributed to an age-related reduction of 17beta-estradiol signaling through its estrogen receptor alpha located in mitochondria. The females-specific mitochondrial remodeling encompassed increased abundance of proteins involved in fatty acid oxidation, decreased abundance of the complexes subunits, and enhanced proneness to oxidative posttranslational modifications. This conceivable accretion of damaged mitochondria in old females might be ascribed to low levels of Parkin, a key mediator of mitophagy. Despite skeletal muscle atrophy and fibrosis, males maintained their testosterone levels throughout aging, as well as their androgen receptor content, and the age-induced mitochondrial remodeling was limited to increased abundance of pyruvate dehydrogenase E1 component subunit beta and electron transfer flavoprotein subunit beta. Herein, for the first time, it was demonstrated that age affects more severely the skeletal muscle mitochondrial proteome of females, reinforcing the necessity of sex-personalized approaches towards sarcopenia management, and the inevitability of the assessment of mitochondrion-related therapeutics.
    Keywords:  Fatty acid oxidation; Mitophagy; Oxidative phosphorylation; Sarcopenia; Sexual dimorphism
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.04.005
  32. JACC Basic Transl Sci. 2024 Mar;9(3): 303-318
    Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes.
    Guanglei Wang, Wenhui Lu, Wei-Bin Shen, Mariusz Karbowski, Sunjay Kaushal, Peixin Yang.
      Most congenital heart defect (CHD) cases are attributed to nongenetic factors; however, the mechanisms underlying nongenetic factor-induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors, and this study aimed to determine whether impaired mitochondrial fusion contributes to maternal diabetes-induced CHDs and if mitochondrial fusion activators, teriflunomide and echinacoside, could reduce CHD incidence in diabetic pregnancy. We demonstrated maternal diabetes-activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Two mitochondrial fusion activators are effective in preventing CHDs in diabetic pregnancy.
    Keywords:  congenital heart defect; maternal diabetes; microRNA; mitochondrial fusion; mitofusin 1; mitofusin 2
    DOI:  https://doi.org/10.1016/j.jacbts.2023.11.008
  33. Am J Hum Genet. 2024 Apr 04. pii: S0002-9297(24)00077-6. [Epub ahead of print]111(4): 714-728
    Genetic and functional correction of argininosuccinate lyase deficiency using CRISPR adenine base editors.
    Sami Jalil, Timo Keskinen, Juhana Juutila, Rocio Sartori Maldonado, Liliya Euro, Anu Suomalainen, Risto Lapatto, Emilia Kuuluvainen, Ville Hietakangas, Timo Otonkoski, Mervi E Hyvönen, Kirmo Wartiovaara.
      Argininosuccinate lyase deficiency (ASLD) is a recessive metabolic disorder caused by variants in ASL. In an essential step in urea synthesis, ASL breaks down argininosuccinate (ASA), a pathognomonic ASLD biomarker. The severe disease forms lead to hyperammonemia, neurological injury, and even early death. The current treatments are unsatisfactory, involving a strict low-protein diet, arginine supplementation, nitrogen scavenging, and in some cases, liver transplantation. An unmet need exists for improved, efficient therapies. Here, we show the potential of a lipid nanoparticle-mediated CRISPR approach using adenine base editors (ABEs) for ASLD treatment. To model ASLD, we first generated human-induced pluripotent stem cells (hiPSCs) from biopsies of individuals homozygous for the Finnish founder variant (c.1153C>T [p.Arg385Cys]) and edited this variant using the ABE. We then differentiated the hiPSCs into hepatocyte-like cells that showed a 1,000-fold decrease in ASA levels compared to those of isogenic non-edited cells. Lastly, we tested three different FDA-approved lipid nanoparticle formulations to deliver the ABE-encoding RNA and the sgRNA targeting the ASL variant. This approach efficiently edited the ASL variant in fibroblasts with no apparent cell toxicity and minimal off-target effects. Further, the treatment resulted in a significant decrease in ASA, to levels of healthy donors, indicating restoration of the urea cycle. Our work describes a highly efficient approach to editing the disease-causing ASL variant and restoring the function of the urea cycle. This method relies on RNA delivered by lipid nanoparticles, which is compatible with clinical applications, improves its safety profile, and allows for scalable production.
    Keywords:  ABE; ASL; CRISPR; LNP; argininosuccinic aciduria; genetic defect; genome editing; lipid nanoparticles; liver; mRNA
    DOI:  https://doi.org/10.1016/j.ajhg.2024.03.004
  34. Free Radic Biol Med. 2024 Mar 31. pii: S0891-5849(24)00162-X. [Epub ahead of print]
    From powerhouse to regulator: The role of mitoepigenetics in mitochondrion-related cellular functions and human diseases.
    Luigi Donato, Domenico Mordà, Concetta Scimone, Simona Alibrandi, Rosalia D'Angelo, Antonina Sidoti.
      Beyond their crucial role in energy production, mitochondria harbor a distinct genome subject to epigenetic regulation akin to that of nuclear DNA. This paper delves into the nascent but rapidly evolving fields of mitoepigenetics and mitoepigenomics, exploring the sophisticated regulatory mechanisms governing mitochondrial DNA (mtDNA). These mechanisms encompass mtDNA methylation, the influence of non-coding RNAs (ncRNAs), and post-translational modifications of mitochondrial proteins. Together, these epigenetic modifications meticulously coordinate mitochondrial gene transcription, replication, and metabolism, thereby calibrating mitochondrial function in response to the dynamic interplay of intracellular needs and environmental stimuli. Notably, the dysregulation of mitoepigenetic pathways is increasingly implicated in mitochondrial dysfunction and a spectrum of human pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and cardiovascular conditions. This comprehensive review synthesizes the current state of knowledge, emphasizing recent breakthroughs and innovations in the field. It discusses the potential of high-resolution mitochondrial epigenome mapping, the diagnostic and prognostic utility of blood or tissue mtDNA epigenetic markers, and the promising horizon of mitochondrial epigenetic drugs. Furthermore, it explores the transformative potential of mitoepigenetics and mitoepigenomics in precision medicine. Exploiting a theragnostic approach to maintaining mitochondrial allostasis, this paper underscores the pivotal role of mitochondrial epigenetics in charting new frontiers in medical science.
    Keywords:  Epigenetic biomarkers; Mitochondrial dysfunction; Mitochondrial therapy; Mitoepigenetics; Mitoepigenomics; Precision medicine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.025
  35. Acta Physiol (Oxf). 2024 Apr 05. e14143
    The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.
    Kristina Žuna, Tatyana Tyschuk, Taraneh Beikbaghban, Felix Sternberg, Jürgen Kreiter, Elena E Pohl.
       AIMS: Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2-oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons.
    METHODS: The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance (Gm) of planar lipid bilayers. OGC-mediated substrate transport was measured in proteoliposomes using 14C-malate.
    RESULTS: OGC increases proton Gm only in the presence of natural (long-chain fatty acids, FA) or chemical (2,4-dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism.
    CONCLUSION: OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.
    Keywords:  SLC25A11; long‐chain fatty acids; mitochondrial transport; planar bilayer membranes; proton transport; total membrane conductance
    DOI:  https://doi.org/10.1111/apha.14143
  36. Exp Mol Med. 2024 Apr 01.
    Age-dependent loss of Crls1 causes myopathy and skeletal muscle regeneration failure.
    Youngbum Yoo, MyeongHoon Yeon, Won-Kyung Kim, Hyeon-Bin Shin, Seung-Min Lee, Mee-Sup Yoon, Hyunju Ro, Young-Kyo Seo.
      Skeletal muscle aging results in the gradual suppression of myogenesis, leading to muscle mass loss. However, the specific role of cardiolipin in myogenesis has not been determined. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrated that cardiolipin and Crls1 are downregulated in aged skeletal muscle. Moreover, the knockdown of Crls1 in myoblasts reduced mitochondrial mass, activity, and OXPHOS complex IV expression and disrupted the structure of the mitochondrial cristae. AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas AAV9-mCrls1-mediated Crls1 overexpression improved regeneration. Overall, our results highlight that the age-dependent decrease in CRLS1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. Hence, modulating CRLS1 expression is a promising therapeutic strategy for mitigating muscle deterioration associated with aging, suggesting potential avenues for developing interventions to improve overall muscle health and quality of life in elderly individuals.
    DOI:  https://doi.org/10.1038/s12276-024-01199-x
  37. Acta Neuropathol Commun. 2024 Apr 05. 12(1): 53
    Letter to the editor on: prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume.
    Cinzia Bocca, Judith Kouassi-Nzoughet, Juan Manuel Chao de la Barca, Dominique Bonneau, Christophe Verny, Philippe Gohier, Christophe Orssaud, Pascal Reynier.
      
    Keywords:  Glaucoma; Leber hereditary optic neuropathy; Mitochondria; Nicotinamide; Optic neuropathy; Retinal ganglion cells; Vitamine B3
    DOI:  https://doi.org/10.1186/s40478-024-01768-1
  38. bioRxiv. 2024 Mar 21. pii: 2024.03.19.585836. [Epub ahead of print]
    Prioritizing disease-related rare variants by integrating gene expression data.
    Hanmin Guo, Alexander Eckehart Urban, Wing Hung Wong.
      Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.
    DOI:  https://doi.org/10.1101/2024.03.19.585836
  39. Mov Disord Clin Pract. 2024 Apr;11(4): 438-440
    Primary Coenzyme Q10 Deficiency-4 Causing Young Onset Ataxia-Dystonia.
    Divya M Radhakrishnan, Arti Saini, Saman Fatima, Anu Gupta, Venugopalan Y Vishnu, Mamta Bhushan Singh, Rohit Bhatia, M V Padma Srivastva, Achal K Srivastava, Roopa Rajan.
      
    DOI:  https://doi.org/10.1002/mdc3.13950
  40. Biochem Soc Trans. 2024 Apr 02. pii: BST20230191. [Epub ahead of print]
    Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.
    Elizaveta A Olkhova, Laura A Smith, Bethany H Dennis, Yi Shiau Ng, Fiona E N LeBeau, Gráinne S Gorman.
      Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.
    Keywords:  interneurons; mitochondrial dysfunction; molecular mechanisms; neurodegeneration; oscillations; parvalbumin
    DOI:  https://doi.org/10.1042/BST20230191
  41. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Mar 30. 1-10
    Clinical and genetic analysis of essential hypertension with mitochondrial tRNAMet 4435A>G and YARS2 mutation.
    Meili Guo, Yunfan He, Ade Chen, Zaishou Zhuang, Xiaoyong Pan, Minxin Guan.
       OBJECTIVES: To investigate the role of m.4435A>G and YARS2 c.572G>T (p.G191V) mutations in the development of essential hypertension.
    METHODS: A hypertensive patient with m.4435A>G and YARS2 p.G191V mutations was identified from the mitochondrial genome and exon sequencing data previously collected. Clinical data were collected, and the molecular genetic study was conducted in the proband and his family members. Peripheral venous blood was collected, and immortalized lymphocyte lines were constructed. The mitochondrial tRNA, mitochondrial protein, ATP, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) in the constructed lymphocyte cell lines were detected.
    RESULTS: Mitochondrial genome sequencing results showed that all maternal members carried a highly conserved m.4435A>G mutation. The m.4435A>G mutation might affect the secondary structure and folding free energy of mitochondrial tRNA and change its stability, which would affect the anticodon ring structure. Compared with the control group, the cell lines carrying m.4435A>G and YARS2 p.G191V mutations had decreased mitochondrial tRNA homeostasis, partial mitochondrial protein expression, ATP production, and MMP levels, and increased ROS levels. The differences were statistically significant (P<0.05).
    CONCLUSIONS: The YARS2 p.G191V mutation aggravates the changes in mitochondrial translation and mitochondrial function caused by m.4435A>G by affecting the steady-state level of mitochondrial tRNA and further leads to cell dysfunction, indicating that YARS2 p.G191V and m.4435A>G mutations have a synergistic effect in this family and jointly participate in the occurrence and development of essential hypertension.
    Keywords:  Essential hypertension; Gene mutation; Maternal inheritance; Mitochondrial DNA; Mitochondrial dysfunction; Respiratory chain
    DOI:  https://doi.org/10.3724/zdxbyxb-2023-0571
  42. Nat Commun. 2024 Apr 05. 15(1): 2957
    Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations.
    Nikhil Bharti, Leonardo Santos, Marcos Davyt, Stine Behrmann, Marie Eichholtz, Alejandro Jimenez-Sanchez, Jeong S Hong, Andras Rab, Eric J Sorscher, Suki Albers, Zoya Ignatova.
      Nonsense mutations - the underlying cause of approximately 11% of all genetic diseases - prematurely terminate protein synthesis by mutating a sense codon to a premature stop or termination codon (PTC). An emerging therapeutic strategy to suppress nonsense defects is to engineer sense-codon decoding tRNAs to readthrough and restore translation at PTCs. However, the readthrough efficiency of the engineered suppressor tRNAs (sup-tRNAs) largely varies in a tissue- and sequence context-dependent manner and has not yet yielded optimal clinical efficacy for many nonsense mutations. Here, we systematically analyze the suppression efficacy at various pathogenic nonsense mutations. We discover that the translation velocity of the sequence upstream of PTCs modulates the sup-tRNA readthrough efficacy. The PTCs most refractory to suppression are embedded in a sequence context translated with an abrupt reversal of the translation speed leading to ribosomal collisions. Moreover, modeling translation velocity using Ribo-seq data can accurately predict the suppression efficacy at PTCs. These results reveal previously unknown molecular signatures contributing to genotype-phenotype relationships and treatment-response heterogeneity, and provide the framework for the development of personalized tRNA-based gene therapies.
    DOI:  https://doi.org/10.1038/s41467-024-47258-9
  43. bioRxiv. 2024 Mar 17. pii: 2024.03.17.585422. [Epub ahead of print]
    Insight from Wild Yeast Isolates into the Molecular Mechanisms of Lifespan Variation Mediated by Caloric Restriction.
    Samantha McLean, Mitchell Lee, Weiqiang Liu, Rohil Hameed, Vikas Anil Gujjala, Xuming Zhou, Matt Kaeberlein, Alaattin Kaya.
      Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among closely related species or strains of a single species. Since mitochondrial mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect.
    Keywords:  Caloric restriction; aging; metabolism; mitochondria; yeast
    DOI:  https://doi.org/10.1101/2024.03.17.585422
  44. Nat Commun. 2024 Mar 30. 15(1): 2793
    Membrane fission via transmembrane contact.
    Russell K W Spencer, Isaac Santos-Pérez, Izaro Rodríguez-Renovales, Juan Manuel Martinez Galvez, Anna V Shnyrova, Marcus Müller.
      Division of intracellular organelles often correlates with additional membrane wrapping, e.g., by the endoplasmic reticulum or the outer mitochondrial membrane. Such wrapping plays a vital role in proteome and lipidome organization. However, how an extra membrane impacts the mechanics of the division has not been investigated. Here we combine fluorescence and cryo-electron microscopy experiments with self-consistent field theory to explore the stress-induced instabilities imposed by membrane wrapping in a simple double-membrane tubular system. We find that, at physiologically relevant conditions, the outer membrane facilitates an alternative pathway for the inner-tube fission through the formation of a transient contact (hemi-fusion) between both membranes. A detailed molecular theory of the fission pathways in the double membrane system reveals the topological complexity of the process, resulting both in leaky and leakless intermediates, with energies and topologies predicting physiological events.
    DOI:  https://doi.org/10.1038/s41467-024-47122-w
  45. Nat Commun. 2024 Mar 30. 15(1): 2790
    FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA.
    Yaping Liu, Sarah C Reed, Christopher Lo, Atish D Choudhury, Heather A Parsons, Daniel G Stover, Gavin Ha, Gregory Gydush, Justin Rhoades, Denisse Rotem, Samuel Freeman, David W Katz, Ravi Bandaru, Haizi Zheng, Hailu Fu, Viktor A Adalsteinsson, Manolis Kellis.
      Analysis of DNA methylation in cell-free DNA reveals clinically relevant biomarkers but requires specialized protocols such as whole-genome bisulfite sequencing. Meanwhile, millions of cell-free DNA samples are being profiled by whole-genome sequencing. Here, we develop FinaleMe, a non-homogeneous Hidden Markov Model, to predict DNA methylation of cell-free DNA and, therefore, tissues-of-origin, directly from plasma whole-genome sequencing. We validate the performance with 80 pairs of deep and shallow-coverage whole-genome sequencing and whole-genome bisulfite sequencing data.
    DOI:  https://doi.org/10.1038/s41467-024-47196-6
  46. Hum Mol Genet. 2024 Apr 01. pii: ddae057. [Epub ahead of print]
    Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae.
    Serena Aneli, Camilla Ceccatelli Berti, Alexandru Ionut Gilea, Giovanni Birolo, Giacomo Mutti, Angelo Pavesi, Enrico Baruffini, Paola Goffrini, Cristian Capelli.
      Neanderthal and Denisovan hybridisation with modern humans has generated a non-random genomic distribution of introgressed regions, the result of drift and selection dynamics. Cross-species genomic incompatibility and more efficient removal of slightly deleterious archaic variants have been proposed as selection-based processes involved in the post-hybridisation purge of archaic introgressed regions. Both scenarios require the presence of functionally different alleles across Homo species onto which selection operated differently according to which populations hosted them, but only a few of these variants have been pinpointed so far. In order to identify functionally divergent archaic variants removed in humans, we focused on mitonuclear genes, which are underrepresented in the genomic landscape of archaic humans. We searched for non-synonymous, fixed, archaic-derived variants present in mitonuclear genes, rare or absent in human populations. We then compared the functional impact of archaic and human variants in the model organism Saccharomyces cerevisiae. Notably, a variant within the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) gene exhibited a significant decrease in respiratory activity and a substantial reduction of Cox2 levels, a proxy for mitochondrial protein biosynthesis, coupled with the accumulation of the YARS2 protein precursor and a lower amount of mature enzyme. Our work suggests that this variant is associated with mitochondrial functionality impairment, thus contributing to the purging of archaic introgression in YARS2. While different molecular mechanisms may have impacted other mitonuclear genes, our approach can be extended to the functional screening of mitonuclear genetic variants present across species and populations.
    Keywords:  archaic introgression; archaic variants; functional variation; mitonuclear genes
    DOI:  https://doi.org/10.1093/hmg/ddae057
  47. Mol Ther Nucleic Acids. 2024 Jun 11. 35(2): 102170
    Secondary follicles enable efficient germline mtDNA base editing at hard-to-edit site.
    Qin Xie, Haibo Wu, Hui Long, Caiwen Xiao, Jiaxin Qiu, Weina Yu, Xueyi Jiang, Junbo Liu, Shuo Zhang, Qifeng Lyu, Lun Suo, Yanping Kuang.
      Efficient germline mtDNA editing is required to construct disease-related animal models and future gene therapy. Recently, the DddA-derived cytosine base editors (DdCBEs) have made mitochondrial genome (mtDNA) precise editing possible. However, there still exist challenges for editing some mtDNA sites in germline via zygote injection, probably due to the suspended mtDNA replication during preimplantation development. Here, we introduce a germline mtDNA base editing strategy: injecting DdCBEs into oocytes of secondary follicles, at which stage mtDNA replicates actively. With this method, we successfully observed efficient G-to-A conversion at a hard-to-edit site and also obtained live animal models. In addition, for those editable sites, this strategy can greatly improve the base editing efficiency up to 3-fold, which is more than that in zygotes. More important, editing in secondary follicles did not increase more the risk of off-target effects than that in zygotes. This strategy provides an option to efficiently manipulate mtDNA sites in germline, especially for hard-to-edit sites.
    Keywords:  DdCBEs; LHON; MT: RNA/DNA Editing; TALENs; follicle; gene editing; m.3733 G>A; mitochondrial genome; mtDNA
    DOI:  https://doi.org/10.1016/j.omtn.2024.102170
  48. J Nanobiotechnology. 2024 Apr 03. 22(1): 148
    The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis.
    E Wen, Yi Cao, Shiwen He, Yuezhou Zhang, Lanlan You, Tingqiu Wang, Zhigang Wang, Jun He, Yi Feng.
      Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM's active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy.
    Keywords:  Kaempferol; Mitochondrial homeostasis; Nanosystem; Severe acute pancreatitis; TK bond
    DOI:  https://doi.org/10.1186/s12951-024-02439-y
  49. Sci Rep. 2024 04 02. 14(1): 7739
    Identification and structural characterization of small molecule inhibitors of PINK1.
    Shafqat Rasool, Tara Shomali, Luc Truong, Nathalie Croteau, Simon Veyron, Bernardo A Bustillos, Wolfdieter Springer, Fabienne C Fiesel, Jean-François Trempe.
      Mutations in PINK1 and Parkin cause early-onset Parkinson's Disease (PD). PINK1 is a kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it phosphorylates ubiquitin, which in turn recruits and activates Parkin, an E3 ubiquitin ligase. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop therapeutics. In this study, we used a thermal shift assay with insect PINK1 to identify small molecules that inhibit ATP hydrolysis and ubiquitin phosphorylation. PRT062607, an SYK inhibitor, is the most potent inhibitor in our screen and inhibits both insect and human PINK1, with an IC50 in the 0.5-3 µM range in HeLa cells and dopaminergic neurons. The crystal structures of insect PINK1 bound to PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate and causes a destabilization of insert-2 at the autophosphorylation dimer interface. While PRT062607 is not selective for PINK1, it provides a scaffold for the development of more selective and potent inhibitors of PINK1 that could be used as chemical probes.
    Keywords:  Inhibitor; Kinase; Mitochondria; PTEN‐induced kinase 1 (PINK1); Parkinson disease; Ubiquitin
    DOI:  https://doi.org/10.1038/s41598-024-58285-3
  50. Nat Commun. 2024 Mar 30. 15(1): 2778
    Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype.
    Han-Yi Chen, Wan-Chen Hsieh, Yu-Chieh Liu, Huei-Ying Li, Po-Yo Liu, Yu-Ting Hsu, Shao-Chun Hsu, An-Chi Luo, Wei-Chen Kuo, Yi-Jhen Huang, Gan-Guang Liou, Meng-Yun Lin, Chun-Jung Ko, Hsing-Chen Tsai, Shu-Jung Chang.
      Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin, triggers the senescence-associated secretory phenotype (SASP) by damaging mitochondrial DNA. The actions of typhoid toxin disrupt mitochondrial DNA integrity, leading to mitochondrial dysfunction and disturbance of redox homeostasis. Consequently, it facilitates the release of damaged mitochondrial DNA into the cytosol, activating type I interferon via the cGAS-STING pathway. We also reveal that the GCN2-mediated integrated stress response plays a role in the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect on T cells, leading to senescence in these cells. These findings provide insights into how a bacterial genotoxin targets mitochondria to trigger a proinflammatory SASP, highlighting a potential therapeutic target for an anti-toxin intervention.
    DOI:  https://doi.org/10.1038/s41467-024-47190-y
  51. J Neuroinflammation. 2024 Apr 02. 21(1): 81
    Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.
    Min Wang, Tian Tian, Hong Zhou, Si-Yuan Jiang, Ying-Ying Jiao, Zhu Zhu, Jiang Xia, Jian-Hua Ma, Ren-Hong Du.
       BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
    METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD.
    RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration.
    CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.
    Keywords:  Astrocyte senescence; Metformin; Mitofusin 2; Parkinson’s disease; cGAS-STING
    DOI:  https://doi.org/10.1186/s12974-024-03072-0
  52. Mov Disord. 2024 Apr 04.
    Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.
    MDS Basic Science Special Interest Group Steering Committee
      Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Parkinson's disease; basic science; movement disorders; translational research
    DOI:  https://doi.org/10.1002/mds.29802
  53. Nat Struct Mol Biol. 2024 Apr 04.
    SCAF1 drives the compositional diversity of mammalian respirasomes.
    Irene Vercellino, Leonid A Sazanov.
      Supercomplexes of the respiratory chain are established constituents of the oxidative phosphorylation system, but their role in mammalian metabolism has been hotly debated. Although recent studies have shown that different tissues/organs are equipped with specific sets of supercomplexes, depending on their metabolic needs, the notion that supercomplexes have a role in the regulation of metabolism has been challenged. However, irrespective of the mechanistic conclusions, the composition of various high molecular weight supercomplexes remains uncertain. Here, using cryogenic electron microscopy, we demonstrate that mammalian (mouse) tissues contain three defined types of 'respirasome', supercomplexes made of CI, CIII2 and CIV. The stoichiometry and position of CIV differs in the three respirasomes, of which only one contains the supercomplex-associated factor SCAF1, whose involvement in respirasome formation has long been contended. Our structures confirm that the 'canonical' respirasome (the C-respirasome, CICIII2CIV) does not contain SCAF1, which is instead associated to a different respirasome (the CS-respirasome), containing a second copy of CIV. We also identify an alternative respirasome (A-respirasome), with CIV bound to the 'back' of CI, instead of the 'toe'. This structural characterization of mouse mitochondrial supercomplexes allows us to hypothesize a mechanistic basis for their specific role in different metabolic conditions.
    DOI:  https://doi.org/10.1038/s41594-024-01255-0
  54. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Mar 31. pii: S1388-1981(24)00041-6. [Epub ahead of print] 159491
    Tracing the lipidome in inborn errors of metabolism.
    Martina Zandl-Lang.
      Inborn errors of metabolism (IEM) represent a heterogeneous group of more than 1800 rare disorders, many of which are causing significant childhood morbidity and mortality. More than 100 IEM are linked to dyslipidaemia, but yet our knowledge in connecting genetic information with lipidomic data is limited. Stable isotope tracing studies of the lipid metabolism (STL) provide insights on the dynamic of cellular lipid processes and could thereby facilitate the delineation of underlying metabolic (patho)mechanisms. This mini-review focuses on principles as well as technical limitations of STL and describes potential clinical applications by discussing recently published STL focusing on IEM.
    Keywords:  Flux studies; Lipids; Mass spectrometry; Metabolism; Rare diseases
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159491
  55. J Neuromuscul Dis. 2024 Apr 03.
    Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes.
    Adela Della Marina, Andreas Hentschel, Artur Czech, Ulrike Schara-Schmidt, Corinna Preusse, Andreas Laner, Angela Abicht, Tobias Ruck, Joachim Weis, Catherine Choueiri, Hanns Lochmüller, Heike Kölbel, Andreas Roos.
       Background: NEFL encodes for the neurofilament light chain protein. Pathogenic variants in NEFL cause demyelinating, axonal and intermediate forms of Charcot-Marie-Tooth disease (CMT) which present with a varying degree of severity and somatic mutations have not been described yet. Currently, 34 different CMT-causing pathogenic variants in NEFL in 174 patients have been reported. Muscular involvement was also described in CMT2E patients mostly as a secondary effect. Also, there are a few descriptions of a primary muscle vulnerability upon pathogenic NEFL variants.
    Objectives: To expand the current knowledge on the genetic landscape, clinical presentation and muscle involvement in NEFL-related neurological diseases by retrospective case study and literature review.
    Methods: We applied in-depth phenotyping of new and already reported cases, molecular genetic testing, light-, electron- and Coherent Anti-Stokes Raman Scattering-microscopic studies and proteomic profiling in addition to in silico modelling of NEFL-variants.
    Results: We report on a boy with a muscular phenotype (weakness, myalgia and cramps, Z-band alterations and mini-cores in some myofibers) associated with the heterozygous p.(Phe104Val) NEFL-variant, which was previously described in a neuropathy case. Skeletal muscle proteomics findings indicated affection of cytoskeletal proteins. Moreover, we report on two further neuropathic patients (16 years old girl and her father) both carrying the heterozygous p.(Pro8Ser) variant, which has been identified as 15% somatic mosaic in the father. While the daughter presented with altered neurophysiology,neurogenic clump feet and gait disturbances, the father showed clinically only feet deformities. As missense variants affecting proline at amino acid position 8 are leading to neuropathic manifestations of different severities, in silico modelling of these different amino acid substitutions indicated variable pathogenic impact correlating with disease onset.
    Conclusions: Our findings provide new morphological and biochemical insights into the vulnerability of denervated muscle (upon NEFL-associated neuropathy) as well as novel genetic findings expanding the current knowledge on NEFL-related neuromuscular phenotypes and their clinical manifestations. Along this line, our data show that even subtle expression of somatic NEFL variants can lead to neuromuscular symptoms.
    Keywords:  CARS microscopy muscle; Neurofilament light chain; muscle proteomics; protein accumulation; somatic mutation
    DOI:  https://doi.org/10.3233/JND-230230
  56. Development. 2024 Apr 05. pii: dev.202544. [Epub ahead of print]
    Gut microbiota regulates the nutrient sensing enteroendocrine cell maturation and mitochondrial function.
    Alfahdah Alsudayri, Shane Perelman, Melissa Brewer, Annika Chura, Madelyn McDevitt, Catherine Drerup, Lihua Ye.
      Enteroendocrine cells (EECs) are crucial for sensing ingested nutrients and regulating feeding behavior. How gut microbiota regulates the nutrient-sensing EEC activity is unclear. Our transcriptomic analysis demonstrates that commensal microbiota colonization significantly increases the expression of many genes associated with mitochondrial function. Using new methods to image EECs' cytoplasmic and mitochondrial Ca2+ activity in live zebrafish, our data revealed that EECs' cytoplasmic and mitochondrial Ca2+ is dynamically regulated during EECs' development process. Mature EECs display an increased mitochondrial-to-cytoplasmic Ca2+ ratio. Mitochondria are evenly distributed in the cytoplasm of immature EECs. As EECs mature, their mitochondria are highly localized at the basal membrane where EEC vesicle secretion occurs. CV EECs, but not GF EECs, exhibit spontaneous low-amplitude Ca2+ fluctuation. The mitochondrial-to-cytoplasmic Ca2+ ratio is significantly higher in CV EECs. Nutrient stimulants like fatty acid increase cytoplasmic Ca2+ in a subset of EECs and promote a sustained mitochondrial Ca2+ and ATP increase. However, the nutrient induced EEC mitochondrial activation is nearly abolished in GF zebrafish. Together, our study reveals that commensal microbiota are critical in supporting EEC mitochondrial function and maturation.
    Keywords:  Enteroendocrine cells; Gut microbiota; Mitochodria; in vivo imaging
    DOI:  https://doi.org/10.1242/dev.202544
  57. JCI Insight. 2024 Apr 02. pii: e169213. [Epub ahead of print]
    Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.
    Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P Taddeo, Cynthia Shu, Orian S Shirihai, Etty Bachar-Wikstrom, Jakob D Wikstrom.
      Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation ihas been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired re-epithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, whilst its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif knockout mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.
    Keywords:  Collagens; Dermatology; Mitochondria; Skin
    DOI:  https://doi.org/10.1172/jci.insight.169213
  58. Mol Biol Rep. 2024 Apr 05. 51(1): 488
    Intertwined relationship of dynamin-related protein 1, mitochondrial metabolism and circadian rhythm.
    Indrani Paramasivan Latha Laxmi, Anica Tholath Job, Venkatraman Manickam, Ramasamy Tamizhselvi.
      In recent years, mitochondria have gained significant interest in the field of biomedical research due to their impact on human health and ageing. As mitochondrial dynamics are strongly controlled by clock genes, misalignment of the circadian rhythm leads to adverse metabolic health effects. In this review, by exploring various aspects of research and potential links, we hope to update the current understanding of the intricate relationship between DRP1-mediated mitochondrial dynamics and changes in circadian rhythmicity leading to health issues. Thus, this review addresses the potential bidirectional relationships between DRP1-linked mitochondrial function and circadian rhythm misalignment, their impact on different metabolic pathways, and the potential therapeutics for metabolic and systemic disorders.
    Keywords:  Brain and muscle ARNT-like 1; Circadian locomotor output cycles Kaput; Dynamin-related protein 1; Inflammation; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s11033-024-09430-8
  59. Expert Rev Proteomics. 2024 Apr 02.
    Prioritization of genes for translation: a computational approach.
    Simone C da Silva Rosa, Amir Barzegar Behrooz, Sofia Guedes, Rui Vitorino, Saeid Ghavami.
       INTRODUCTION: Gene identification for genetic diseases is critical for the development of new diagnostic approaches and personalized treatment options. Prioritization of gene translation is an important consideration in the molecular biology field, allowing researchers to focus on the most promising candidates for further investigation.
    AREAS COVERED: In this paper, we discussed different approaches to prioritize genes for translation, including the use of computational tools and machine learning algorithms, as well as experimental techniques such as knockdown and overexpression studies. We also explored the potential biases and limitations of these approaches and proposed strategies to improve the accuracy and reliability of gene prioritization methods. Although numerous computational methods have been developed for this purpose, there is a need for computational methods that incorporate tissue-specific information to enable more accurate prioritization of candidate genes. Such methods should provide tissue-specific predictions, insights into underlying disease mechanisms, and more accurate prioritization of genes.
    EXPERT OPINION: Using advanced computational tools and machine learning algorithms to prioritize genes, we can identify potential targets for therapeutic intervention of complex diseases. This represents an up-and-coming method for drug development and personalized medicine.
    Keywords:  Alzheimer’s disease; Computational approach; Deep learning; Glioblastoma; Machine learning; Parkinson’s disease; Potential diagnostic predictor
    DOI:  https://doi.org/10.1080/14789450.2024.2337004
  60. medRxiv. 2024 Mar 18. pii: 2024.03.15.24304216. [Epub ahead of print]
    Mapping structural variants to rare disease genes using long-read whole genome sequencing and trait-relevant polygenic scores.
    C LeMaster, C Schwendinger-Schreck, B Ge, W Cheung, J J Johnston, T Pastinen, C Smail.
      Recent studies have revealed the pervasive landscape of rare structural variants (rSVs) present in human genomes. rSVs can have extreme effects on the expression of proximal genes and, in a rare disease context, have been implicated in patient cases where no diagnostic single nucleotide variant (SNV) was found. Approaches for integrating rSVs to date have focused on targeted approaches in known Mendelian rare disease genes. This approach is intractable for rare diseases with many causal loci or patients with complex, multi-phenotype syndromes. We hypothesized that integrating trait-relevant polygenic scores (PGS) would provide a substantial reduction in the number of candidate disease genes in which to assess rSV effects. We further implemented a method for ranking PGS genes to define a set of core/key genes where a rSV has the potential to exert relatively larger effects on disease risk. Among a subset of patients enrolled in the Genomic Answers for Kids (GA4K) rare disease program (N=497), we used PacBio HiFi long-read whole genome sequencing (lrWGS) to identify rSVs intersecting genes in trait-relevant PGSs. Illustrating our approach in Autism (N=54 cases), we identified 1,827 deletions, 158 duplications, 619 insertions, and 14 inversions overlapping putative core/key PGS genes. Additionally, by integrating genomic constraint annotations from gnomAD, we observed that rare duplications overlapping putative core/key PGS genes were frequently in higher constraint regions compared to controls (P = 2×10 -04 ). This difference was not observed in the lowest-ranked gene set (P = 0.18). Overall, our study provides a framework for the annotation of long-read rSVs from lrWGS data and prioritization of disease-linked genomic regions for downstream functional validation of rSV impacts. To enable reuse by other researchers, we have made SV allele frequencies and gene associations freely available.
    DOI:  https://doi.org/10.1101/2024.03.15.24304216
  61. Biophys J. 2024 Apr 04. pii: S0006-3495(24)00245-5. [Epub ahead of print]
    AI in Cellular Engineering and Reprogramming.
    Sara Capponi, Shangying Wang.
      During the last decade, Artificial Intelligence (AI) has increasingly been applied in biophysics and related fields, including cellular engineering and reprogramming, offering novel approaches to understand, manipulate, and control cellular function. The potential of AI lies in its ability to analyze complex datasets and generate predictive models. AI algorithms can process large amounts of data from single-cell genomics and multiomic technologies, allowing researchers to gain mechanistic insights into the control of cell identity and function. By integrating and interpreting these complex datasets, AI can help identify key molecular events and regulatory pathways involved in cellular reprogramming. This knowledge can inform the design of precision engineering strategies, such as the development of new transcription factor and signaling molecule cocktails, to manipulate cell identity and drive authentic cell fate across lineage boundaries. Furthermore, when used in combination with computational methods, AI can accelerate and improve the analysis and understanding of the intricate relationships between genes, proteins, and cellular processes. In this review article we explore the current state of AI applications in biophysics with a specific focus on cellular engineering and reprogramming. Then, we showcase a couple of recent applications where we combined machine learning with experimental and computational techniques. Finally, we briefly discuss the challenges and prospects of AI in cellular engineering and reprogramming, emphasizing the potential of these technologies to revolutionize our ability to engineer cells for a variety of applications, from disease modeling and drug discovery to regenerative medicine and biomanufacturing.
    DOI:  https://doi.org/10.1016/j.bpj.2024.04.001
  62. J Control Release. 2024 Apr 03. pii: S0168-3659(24)00220-7. [Epub ahead of print]
    mRNA therapies: Pioneering a new era in rare genetic disease treatment.
    Guobo Shen, Jian Liu, Hanmei Yang, Na Xie, Yang Yang.
      Rare genetic diseases, often referred to as orphan diseases due to their low prevalence and limited treatment options, have long posed significant challenges to our medical system. In recent years, Messenger RNA (mRNA) therapy has emerged as a highly promising treatment approach for various diseases caused by genetic mutations. Chemically modified mRNA is introduced into cells using carriers like lipid-based nanoparticles (LNPs), producing functional proteins that compensate for genetic deficiencies. Given the advantages of precise dosing, biocompatibility, transient expression, and minimal risk of genomic integration, mRNA therapies can safely and effectively correct genetic defects in rare diseases and improve symptoms. Currently, dozens of mRNA drugs targeting rare diseases are undergoing clinical trials. This comprehensive review summarizes the progress of mRNA therapy in treating rare genetic diseases. It introduces the development, molecular design, and delivery systems of mRNA therapy, highlighting their research progress in rare genetic diseases based on protein replacement and gene editing. The review also summarizes research progress in various rare disease models and clinical trials. Additionally, it discusses the challenges and future prospects of mRNA therapy. Researchers are encouraged to join this field and collaborate to advance the clinical translation of mRNA therapy, bringing hope to patients with rare genetic diseases.
    Keywords:  Delivery system; Gene editing; Lipid-based nanoparticles (LNPs); Protein replacement therapy; Rare genetic disease; mRNA therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2024.03.056
  63. Nat Aging. 2024 Apr 05.
    Drug discovery by AI trained on aging biology.
    Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-024-00615-1
  64. J Neuroophthalmol. 2024 Apr 02.
    Leber Hereditary Optic Neuropathy in 2 Sisters With Friedreich Ataxia.
    Joshua Pasol, Mohammed Shan Uddin, Mustafa Tekin, Henry P Moore.
      
    DOI:  https://doi.org/10.1097/WNO.0000000000002143
  65. NPJ Parkinsons Dis. 2024 Apr 03. 10(1): 75
    RedOx regulation of LRRK2 kinase activity by active site cysteines.
    Chiara R Trilling, Jui-Hung Weng, Pallavi Kaila Sharma, Viktoria Nolte, Jian Wu, Wen Ma, Daniela Boassa, Susan S Taylor, Friedrich W Herberg.
      Mutations of the human leucine-rich repeat kinase 2 (LRRK2) have been associated with both, idiopathic and familial Parkinson's disease (PD). Most of these pathogenic mutations are located in the kinase domain (KD) or GTPase domain of LRRK2. In this study we describe a mechanism in which protein kinase activity can be modulated by reversible oxidation or reduction, involving a unique pair of adjacent cysteines, the "CC" motif. Among all human protein kinases, only LRRK2 contains this "CC" motif (C2024 and C2025) in the Activation Segment (AS) of the kinase domain. In an approach combining site-directed mutagenesis, biochemical analyses, cell-based assays, and Gaussian accelerated Molecular Dynamics (GaMD) simulations we could attribute a role for each of those cysteines. We employed reducing and oxidizing agents with potential clinical relevance to investigate effects on kinase activity and microtubule docking. We find that each cysteine gives a distinct contribution: the first cysteine, C2024, is essential for LRRK2 protein kinase activity, while the adjacent cysteine, C2025, contributes significantly to redox sensitivity. Implementing thiolates (R-S-) in GaMD simulations allowed us to analyse how each of the cysteines in the "CC" motif interacts with its surrounding residues depending on its oxidation state. From our studies we conclude that oxidizing agents can downregulate kinase activity of hyperactive LRRK2 PD mutations and may provide promising tools for therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41531-024-00683-5
  66. Biochim Biophys Acta Mol Cell Res. 2024 Apr 02. pii: S0167-4889(24)00060-0. [Epub ahead of print] 119717
    Chaperone function in Fe-S protein biogenesis: Three possible scenarios.
    Jaroslaw Marszalek, Elizabeth A Craig, Marcin Pitek, Rafal Dutkiewicz.
      Among the six known iron‑sulfur (FeS) cluster biogenesis machineries that function across all domains of life only one involves a molecular chaperone system. This machinery, called ISC for 'iron sulfur cluster', functions in bacteria and in mitochondria of eukaryotes including humans. The chaperone system - a dedicated J-domain protein co-chaperone termed Hsc20 and its Hsp70 partner - is essential for proper ISC machinery function, interacting with the scaffold protein IscU which serves as a platform for cluster assembly and subsequent transfer onto recipient apo-proteins. Despite many years of research, surprisingly little is known about the specific role(s) that the chaperones play in the ISC machinery. Here we review three non-exclusive scenarios that range from involvement of the chaperones in the cluster transfer to regulation of the cellular levels of IscU itself.
    Keywords:  Hsc20; Hsp70; Hsp70-substrate interaction cycle; IscU; J-domain protein; JDP
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119717
  67. Res Sq. 2024 Mar 13. pii: rs.3.rs-4021466. [Epub ahead of print]
    Parkinson's disease gene, Synaptojanin1, dysregulates the basal maintenance of the dopamine transporter.
    Ping-Yue Pan, Jacqueline Saenz, Elnaz Khezerlou, Meha Aggarwal, Amina Shaikh, Naga Ganti, Freja Herborg.
      Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion of evoked dopamine (DA) and altered maintenance of the axonal dopamine transporter (DAT) in the Synj1+/- neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we demonstrated that axons of cultured Synj1+/- neurons exhibit an increase of total DAT but a reduction of the surface DAT, which could be exacerbated by neuronal activity. We revealed that the loss of surface DAT is specifically associated with the impaired 5'-phosphatase activity of Synj1 and the hyperactive downstream PI(4,5)P2-PKCbeta pathway. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling in early parkinsonism.
    DOI:  https://doi.org/10.21203/rs.3.rs-4021466/v1
  68. Front Ophthalmol (Lausanne). 2024 ;pii: 1355379. [Epub ahead of print]4
    Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease.
    Michael Landowski, Purnima Gogoi, Sakae Ikeda, Akihiro Ikeda.
      Aging is the most significant risk factor for age-related diseases in general, which is true for age-related diseases in the eye including age-related macular degeneration (AMD). Therefore, in order to identify potential therapeutic targets for these diseases, it is crucial to understand the normal aging process and how its mis-regulation could cause age-related diseases at the molecular level. Recently, abnormal lipid metabolism has emerged as one major aspect of age-related symptoms in the retina. Animal models provide excellent means to identify and study factors that regulate lipid metabolism in relation to age-related symptoms. Central to this review is the role of transmembrane protein 135 (TMEM135) in the retina. TMEM135 was identified through the characterization of a mutant mouse strain exhibiting accelerated retinal aging and positional cloning of the responsible mutation within the gene, indicating the crucial role of TMEM135 in regulating the normal aging process in the retina. Over the past decade, the molecular functions of TMEM135 have been explored in various models and tissues, providing insights into the regulation of metabolism, particularly lipid metabolism, through its action in multiple organelles. Studies indicated that TMEM135 is a significant regulator of peroxisomes, mitochondria, and their interaction. Here, we provide an overview of the molecular functions of TMEM135 which is crucial for regulating mitochondria, peroxisomes, and lipids. The review also discusses the age-dependent phenotypes in mice with TMEM135 perturbations, emphasizing the importance of a balanced TMEM135 function for the health of the retina and other tissues including the heart, liver, and adipose tissue. Finally, we explore the potential roles of TMEM135 in human age-related retinal diseases, connecting its functions to the pathobiology of AMD.
    Keywords:  AMD; DHA; RPE; TMEM135; lipid; mitochondria; peroxisomes; photoreceptors
    DOI:  https://doi.org/10.3389/fopht.2024.1355379
  69. Front Bioinform. 2024 ;4 1384497
    Sequencing technologies and hardware-accelerated parallel computing transform computational genomics research.
    Michael Olbrich, Lennart Bartels, Inken Wohlers.
      
    Keywords:  computational genomics; genome references; genome sequencing; long-read sequencing; pangenomics; parallel computing; sequencing software; systems genetics
    DOI:  https://doi.org/10.3389/fbinf.2024.1384497
  70. Free Radic Biol Med. 2024 Apr 03. pii: S0891-5849(24)00161-8. [Epub ahead of print]
    Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery.
    Hernán H Dieguez, Horacio E Romeo, Agustina Alaimo, Nathaly A Bernal Aguirre, Juan S Calanni, Juan S Adán Aréan, Silvia Alvarez, Roberta Sciurano, Ruth E Rosenstein, Damián Dorfman.
      Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondria play a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, and mitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrial quality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervical ganglionectomy (SCGx), which progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters' regulation at the nasal and temporal RPE from control eyes and at an early stage of experimental NE-AMD (i.e., 4 weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function, which was higher at the temporal than at the nasal RPE in control eyes, was significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD.
    Keywords:  AMPK; Metformin; Mitochondria dynamics; Non-exudative age-related macular degeneration; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.024
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