bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–10–06
forty-nine papers selected by
Catalina Vasilescu, Helmholz Munich
  1. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
  2. The role of PINK1-Parkin in mitochondrial quality control.
  3. Temporal alterations of the nascent proteome in response to mitochondrial stress.
  4. Biogenesis of mitochondrial β-barrel membrane proteins.
  5. Mitochondrial Dysfunctions: Genetic and Cellular Implications Revealed by Various Model Organisms.
  6. Mitochondrial Dynamics and mRNA Translation: A Local Synaptic Tale.
  7. Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.
  8. Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.
  9. Differential Mobility Spectrometry-Based Cardiolipin Analysis.
  10. Mitochondria: the beating heart of the eukaryotic cell.
  11. New Insights into Mitochondria in Health and Diseases.
  12. Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
  13. Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
  14. p38α kinase governs muscle strength through PGC1α in mice.
  15. Leaving no patient behind! Expert recommendation in the use of innovative technologies for diagnosing rare diseases.
  16. Diet induced mitochondrial DNA replication instability in Rad51c mutant mice drives sex-bias in anemia of inflammation.
  17. Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.
  18. Prioritizing disease-related rare variants by integrating gene expression data.
  19. Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.
  20. NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.
  21. Reassessing kinetin's effect on PINK1 and mitophagy.
  22. Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.
  23. RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.
  24. Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in Axons.
  25. Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.
  26. Periodic Paralysis in a Child With Thermosensitive Mitochondrial Trifunctional Protein Deficiency.
  27. Targeting Mitochondrial Dysfunction for the Prevention and Treatment of Metabolic Disease by Bioactive Food Components.
  28. Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.
  29. High-coverage nanopore sequencing of samples from the 1000 Genomes Project to build a comprehensive catalog of human genetic variation.
  30. Local glycolysis supports injury-induced axonal regeneration.
  31. The GENESIS database and tools: A decade of discovery in Mendelian genomics.
  32. Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
  33. Dopamine neuron dysfunction and loss in the PrknR275W mouse model of juvenile parkinsonism.
  34. Type 2 Diabetes Mellitus and Neurodegenerative Disorders: The Mitochondrial Connection.
  35. Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.
  36. Rare Disease Innovation at the FDA-Opportunities for Implementation.
  37. Skeletal Muscle Involvement in Friedreich Ataxia.
  38. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy.
  39. TSG Extends the Longevity of Caenorhabditis elegans by Targeting the DAF-16/SKN-1/SIR-2.1-Mediated Mitochondrial Quality Control Process.
  40. 'The phenotypic conundrum of Trp748Ser variant in POLG gene: a report of two patients'.
  41. Maintaining mitochondrial DNA copy number mitigates ROS-induced oocyte decline and female reproductive aging.
  42. Favorable Outcome after Liver Transplantation in an Infant with Liver Failure Due to Deoxyguanosine Kinase Deficiency.
  43. Matrix stiffness regulates mitochondria-lysosome contacts to modulate the mitochondrial network, alleviate the senescence of MSCs.
  44. Nonfunctional coq10 mutants maintain the ERMES complex and reveal true phenotypes associated with the loss of the coenzyme Q chaperone protein Coq10.
  45. Biallelic Variants in COQ4 Cause Childhood-Onset Pure Hereditary Spastic Paraplegia.
  46. Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy.
  47. Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.
  48. Impact of O -GlcNAcylation elevation on mitophagy and glia in the dentate gyrus.
  49. Correction: eIF2B conformation and assembly state regulate the integrated stress response.
  1. Sci Adv. 2024 Oct 04. 10(40): eadq6223
    SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
    Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
    DOI:  https://doi.org/10.1126/sciadv.adq6223
  2. Nat Cell Biol. 2024 Oct 02.
    The role of PINK1-Parkin in mitochondrial quality control.
    Derek P Narendra, Richard J Youle.
      Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.
    DOI:  https://doi.org/10.1038/s41556-024-01513-9
  3. Cell Rep. 2024 Oct 02. pii: S2211-1247(24)01154-9. [Epub ahead of print]43(10): 114803
    Temporal alterations of the nascent proteome in response to mitochondrial stress.
    Tomasz M Stępkowski, Vanessa Linke, Dorota Stadnik, Maciej Zakrzewski, Anna E Zawada, Remigiusz A Serwa, Agnieszka Chacinska.
      Under stress, protein synthesis is attenuated to preserve energy and mitigate challenges to protein homeostasis. Here, we describe, with high temporal resolution, the dynamic landscape of changes in the abundance of proteins synthesized upon stress from transient mitochondrial inner membrane depolarization. This nascent proteome was altered when global translation was attenuated by stress and began to normalize as translation was recovering. This transition was associated with a transient desynchronization of cytosolic and mitochondrial translation and recovery of cytosolic and mitochondrial ribosomal proteins. Further, the elongation factor EEF1A1 was downregulated upon mitochondrial stress, and its silencing mimicked the stress-induced nascent proteome remodeling, including alterations in the nascent respiratory chain proteins. Unexpectedly, the stress-induced alterations in the nascent proteome were independent of physiological protein abundance and turnover. In summary, we provide insights into the physiological and pathological consequences of mitochondrial function and dysfunction.
    Keywords:  CP: Cell biology; CP: Metabolism; EEF1A; EEF1A1; cellular stress; elongation factor; mass spectrometry; mitochondria; nascent chain; protein synthesis; proteomics; translation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114803
  4. FEBS Open Bio. 2024 Oct;14(10): 1595-1609
    Biogenesis of mitochondrial β-barrel membrane proteins.
    Iniyan Ganesan, Jon V Busto, Nikolaus Pfanner, Nils Wiedemann.
      β-barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β-barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β-barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β-barrel protein. The β-strands of β-barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50-preprotein hybrid barrel. The assembled precursor β-barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β-barrel, termed the β-barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer-to-inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER-mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β-barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.
    Keywords:  Mco6; Mdm10; SAM; Sam35; Sam37; Sam50; mitochondria; outer membrane; sorting and assembly machinery; β‐barrel protein
    DOI:  https://doi.org/10.1002/2211-5463.13905
  5. Genes (Basel). 2024 Sep 01. pii: 1153. [Epub ahead of print]15(9):
    Mitochondrial Dysfunctions: Genetic and Cellular Implications Revealed by Various Model Organisms.
    Monika Stańczyk, Natalia Szubart, Roman Maslanka, Renata Zadrag-Tecza.
      Mitochondria play a crucial role in maintaining the energy status and redox homeostasis of eukaryotic cells. They are responsible for the metabolic efficiency of cells, providing both ATP and intermediate metabolic products. They also regulate cell survival and death under stress conditions by controlling the cell response or activating the apoptosis process. This functional diversity of mitochondria indicates their great importance for cellular metabolism. Hence, dysfunctions of these structures are increasingly recognized as an element of the etiology of many human diseases and, therefore, an extremely promising therapeutic target. Mitochondrial dysfunctions can be caused by mutations in both nuclear and mitochondrial DNA, as well as by stress factors or replication errors. Progress in knowledge about the biology of mitochondria, as well as the consequences for the efficiency of the entire organism resulting from the dysfunction of these structures, is achieved through the use of model organisms. They are an invaluable tool for analyzing complex cellular processes, leading to a better understanding of diseases caused by mitochondrial dysfunction. In this work, we review the most commonly used model organisms, discussing both their advantages and limitations in modeling fundamental mitochondrial processes or mitochondrial diseases.
    Keywords:  mitochondria; mitochondrial dysfunction; model organisms
    DOI:  https://doi.org/10.3390/genes15091153
  6. Biology (Basel). 2024 Sep 23. pii: 746. [Epub ahead of print]13(9):
    Mitochondrial Dynamics and mRNA Translation: A Local Synaptic Tale.
    Marta Zaninello, Pedro Baptista, Filipe V Duarte.
      Mitochondria are dynamic organelles that can adjust and respond to different stimuli within a cell. This plastic ability allows them to effectively coordinate several cellular functions in cells and becomes particularly relevant in highly complex cells such as neurons. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular function and ultimately to a range of diseases, including neurodegenerative disorders. Regulation of mRNA transport and local translation inside neurons is crucial for maintaining the proteome of distal mitochondria, which is vital for energy production and synaptic function. A significant portion of the axonal transcriptome is dedicated to mRNAs for mitochondrial proteins, emphasizing the importance of local translation in sustaining mitochondrial function in areas far from the cell body. In neurons, local translation and the regulation of mRNAs encoding mitochondrial-shaping proteins could be essential for synaptic plasticity and neuronal health. The dynamics of these mRNAs, including their transport and local translation, may influence the morphology and function of mitochondria, thereby affecting the overall energy status and responsiveness of synapses. Comprehending the mitochondria-related mRNA regulation and local translation, as well as its influence on mitochondrial morphology near the synapses will help to better understand neuronal physiology and neurological diseases where mitochondrial dysfunction and impaired synaptic plasticity play a central role.
    Keywords:  mRNA; mRNA trafficking; mitochondria; mitochondrial morphology; neuron; synapse
    DOI:  https://doi.org/10.3390/biology13090746
  7. bioRxiv. 2024 Sep 22. pii: 2024.09.20.614152. [Epub ahead of print]
    Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.
    Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.
      Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have high and others low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic activities in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mtDNA density were correlated between tissues (median r = -0.01-0.16), indicating that animals with high mitochondrial capacity in one tissue can have low capacity in other tissues. Similarly, the multi-tissue correlation structure of RNAseq-based indices of mitochondrial gene expression across 45 tissues from 948 women and men (GTEx) showed small to moderate coherence between only some tissues (regions of the same brain), but not between brain-body tissue pairs in the same person (median r = 0.01). Mitochondrial DNA copy number (mtDNAcn) also lacked coherence across organs and tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were attributable in part to i) tissue-specific activation of canonical energy sensing pathways including the transcriptional coactivator PGC-111 and the integrated stress response (ISR), and ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with high mitochondrial gene expression in some tissues (e.g., heart) but low expression in others (e.g., skeletal muscle) who display different clinical phenotypic patterns. Taken together, these data raise the possibility that tissue-specific energy sensing pathways may contribute to the idiosyncratic mitochondrial distribution patterns associated with the inter-organ heterogeneity and phenotypic diversity among individuals.
    DOI:  https://doi.org/10.1101/2024.09.20.614152
  8. Biomedicines. 2024 Sep 09. pii: 2050. [Epub ahead of print]12(9):
    Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.
    María J Esteban-Amo, Patricia Jiménez-Cuadrado, Pablo Serrano-Lorenzo, Miguel Á de la Fuente, María Simarro.
      Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations.
    Keywords:  complex II; disease; mitochondria; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/biomedicines12092050
  9. Methods Mol Biol. 2025 ;2855 373-385
    Differential Mobility Spectrometry-Based Cardiolipin Analysis.
    Fabien Riols, Michael Witting, Mark Haid.
      Cardiolipins (CL) are special lipids in many respects. First of all, CL are composed of four fatty acids linked by two phosphatidic acids, which provide CL a unique molecular structure. Secondly, in eukaryotic cells they are specific to a single organelle, mitochondria, where they are also synthetized. CL are one of the most abundant lipid classes in mitochondria, mainly localized in the inner membrane. They are key determinants of mitochondrial health and homeostasis by modulating membrane integrity and fluidity, mitochondrial shapes, and metabolic pathways. Disturbances in mitochondrial CL composition can lead to tissue malfunction and diseases. It is therefore important to develop analytical tools to study the mitochondrial lipidome, and more particularly the CL. The method described here allows the quantification of cardiolipins at the sum composition level in isolated mitochondria or in liver tissue by flow injection analysis coupled to differential mobility spectrometry (FIA-DMS), also known as DMS-based shotgun lipidomics.
    Keywords:  Cardiolipins; Differential mobility spectrometry; Flow injection analysis; Mass spectrometry; Mitochondria
    DOI:  https://doi.org/10.1007/978-1-0716-4116-3_22
  10. FEBS Open Bio. 2024 Oct;14(10): 1588-1590
    Mitochondria: the beating heart of the eukaryotic cell.
    Johannes M Herrmann.
      Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of proteins, which are synthesized in the cytosol and imported into mitochondria via different targeting routes. In addition, a small number of proteins are encoded by the organellar genome and synthesized by mitochondrial ribosomes. In this 'In the Limelight' special issue of FEBS Open Bio, five review articles describe these different biogenesis routes of mitochondrial proteins and provide a comprehensive overview of the structures and mechanisms by which mitochondrial proteins are synthesized and transported to their respective location within the organelle. These reviews, written by leading experts, provide a general overview, but also highlight current developments in the field of mitochondrial biogenesis.
    DOI:  https://doi.org/10.1002/2211-5463.13884
  11. Int J Mol Sci. 2024 Sep 16. pii: 9975. [Epub ahead of print]25(18):
    New Insights into Mitochondria in Health and Diseases.
    Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Ziyuan Wen, Mohan Su, Bing Li, Lina Yang.
      Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
    Keywords:  ROS; aging; bioenergetics; mitochondrial; mitochondrial dysfunction; mitochondrial targeted therapy; mtDNA; mutations
    DOI:  https://doi.org/10.3390/ijms25189975
  12. Clin Proteomics. 2024 Sep 30. 21(1): 57
    Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
    Andrea Ramirez-Sagredo, Anju Teresa Sunny, Kellye A Cupp-Sutton, Trishika Chowdhury, Zhitao Zhao, Si Wu, Ying Ann Chiao.
       BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying proteoform sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging.
    METHODS: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified.
    RESULTS: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N-terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. Data are available via ProteomeXchange with the identifier PXD051505.
    CONCLUSION: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart.
    Keywords:  Cardiac aging; Label-free quantitation; Mitochondria; Post-translational modifications; Top-down proteomics
    DOI:  https://doi.org/10.1186/s12014-024-09509-1
  13. EMBO J. 2024 Oct 04.
    Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
    Anna Rappe, Helena A Vihinen, Fumi Suomi, Antti J Hassinen, Homa Ehsan, Eija S Jokitalo, Thomas G McWilliams.
      Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.
    Keywords:  Aging; Autophagy; Brain; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1038/s44318-024-00241-y
  14. Acta Physiol (Oxf). 2024 Oct 03. e14234
    p38α kinase governs muscle strength through PGC1α in mice.
    Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A Dumesic, Sarah E Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio.
       AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.
    METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
    RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
    CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; muscle strength; p38α; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.14234
  15. Orphanet J Rare Dis. 2024 Sep 27. 19(1): 357
    Leaving no patient behind! Expert recommendation in the use of innovative technologies for diagnosing rare diseases.
    Clara D M van Karnebeek, Anne O'Donnell-Luria, Gareth Baynam, Anaïs Baudot, Tudor Groza, Judith J M Jans, Timo Lassmann, Mary Catherine V Letinturier, Stephen B Montgomery, Peter N Robinson, Stefaan Sansen, Ruty Mehrian-Shai, Charles Steward, Kenjiro Kosaki, Patricia Durao, Bekim Sadikovic.
      Genetic diagnosis plays a crucial role in rare diseases, particularly with the increasing availability of emerging and accessible treatments. The International Rare Diseases Research Consortium (IRDiRC) has set its primary goal as: "Ensuring that all patients who present with a suspected rare disease receive a diagnosis within one year if their disorder is documented in the medical literature". Despite significant advances in genomic sequencing technologies, more than half of the patients with suspected Mendelian disorders remain undiagnosed. In response, IRDiRC proposes the establishment of "a globally coordinated diagnostic and research pipeline". To help facilitate this, IRDiRC formed the Task Force on Integrating New Technologies for Rare Disease Diagnosis. This multi-stakeholder Task Force aims to provide an overview of the current state of innovative diagnostic technologies for clinicians and researchers, focusing on the patient's diagnostic journey. Herein, we provide an overview of a broad spectrum of emerging diagnostic technologies involving genomics, epigenomics and multi-omics, functional testing and model systems, data sharing, bioinformatics, and Artificial Intelligence (AI), highlighting their advantages, limitations, and the current state of clinical adaption. We provide expert recommendations outlining the stepwise application of these innovative technologies in the diagnostic pathways while considering global differences in accessibility. The importance of FAIR (Findability, Accessibility, Interoperability, and Reusability) and CARE (Collective benefit, Authority to control, Responsibility, and Ethics) data management is emphasized, along with the need for enhanced and continuing education in medical genomics. We provide a perspective on future technological developments in genome diagnostics and their integration into clinical practice. Lastly, we summarize the challenges related to genomic diversity and accessibility, highlighting the significance of innovative diagnostic technologies, global collaboration, and equitable access to diagnosis and treatment for people living with rare disease.
    Keywords:  Genomics; IRDiRC; Innovative technologies; Molecular diagnostics; Rare disease; Rare disease diagnosis; Rare disease research
    DOI:  https://doi.org/10.1186/s13023-024-03361-0
  16. bioRxiv. 2024 Sep 21. pii: 2024.09.21.613572. [Epub ahead of print]
    Diet induced mitochondrial DNA replication instability in Rad51c mutant mice drives sex-bias in anemia of inflammation.
    Karl-Heinz Tomaszowski, Yue Chen, Sunetra Roy, Momo Harris, Jianhua Zhang, Chi-Lin Tsai, Katharina Schlacher.
      Anemia of inflammation (AI) is a common comorbidity associated with obesity, diabetes, cardiac disease, aging, and during anti-cancer therapies. Mounting evidence illustrates that males are disproportionally affected by AI, but not why. Here we demonstrate a molecular cause for a sex-bias in inflammation. The data shows that mitochondrial DNA (mtDNA) instability induced by dietary stress causes anemia associated with inflamed macrophages and improper iron recycling in mice. These phenotypes are enhanced in mice with mutations in Fanco/Rad51c , which predisposes to the progeroid disease Fanconi Anemia. The data reveals a striking sex-bias whereby females are protected. We find that estrogen acts as a mitochondrial antioxidant that reduces diet-induced oxidative stress, mtDNA replication instability and the distinctively mtDNA-dependent unphosphorylated STAT1 response. Consequently, treatment of male Rad51c mutant mice with estrogen or mitochondrial antioxidants suppresses the inflammation-induced anemia. Collectively, this study uncovers estrogen-responsive mtDNA replication instability as a cause for sex-specific inflammatory responses and molecular driver for AI.
    DOI:  https://doi.org/10.1101/2024.09.21.613572
  17. Front Neurol. 2024 ;15 1466275
    Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.
    Chiara La Morgia, Maria Lucia Cascavilla, Anna Maria De Negri, Marcello Romano, Fabrizio Canalini, Silvia Rossi, Diego Centonze, Massimo Filippi.
      Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases.
    Keywords:  Leber’s Hereditary Optic Neuropathy; Optical Coherence Tomography; optic nerve; retinal ganglion cell; visual field
    DOI:  https://doi.org/10.3389/fneur.2024.1466275
  18. PLoS Genet. 2024 Sep 30. 20(9): e1011412
    Prioritizing disease-related rare variants by integrating gene expression data.
    Hanmin Guo, Alexander Eckehart Urban, Wing Hung Wong.
      Rare variants, comprising the vast majority of human genetic variations, are likely to have more deleterious impact in the context of 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 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. We also found strong excess of rare variants among the top prioritized genes in patients compared to that in healthy individuals. 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/10.1371/journal.pgen.1011412
  19. Mitochondrion. 2024 Sep 30. pii: S1567-7249(24)00129-6. [Epub ahead of print] 101971
    Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.
    Chinmay Pal.
      Parkinson's disease (PD), a neurodegenerative disorder, is one of the most significant challenges confronting modern societies, affecting millions of patients globally each year. The pathophysiology of PD is significantly influenced by mitochondrial dysfunction, as evident by the contribution of altered mitochondrial dynamics, bioenergetics, and increased oxidative stress to neuronal death. This review examines the potential use of small molecules that target mitochondria as a therapeutic approach for treating PD. Progress in mitochondrial biology has revealed various mitochondrial targets that can be modulated to restore function and mitigate neurodegeneration. Small molecules that promote mitochondrial biogenesis, enhance mitochondrial dynamics, decrease oxidative stress, and prevent the opening of the mitochondrial permeability transition pore (mPTP) have shown promise in preclinical models. Additionally, targeting mitochondrial quality control mechanisms, such as mitophagy, provides another therapeutic approach. This review explores recent research on small molecules targeting mitochondria, examines their mechanisms of action, and assesses their potential efficacy and safety profiles. By highlighting the most promising candidates and addressing the challenges and future directions in this field, this review aims to offer a comprehensive overview of current and future prospects for mitochondrial-targeted therapies in PD. Ultimately, treating mitochondrial dysfunction holds significant promise for developing disease-modifying PD medications, giving patients hope for better outcomes and improved quality of life.
    Keywords:  Mitochondrial dysfunction; Oxidative Stress; Parkinson’s disease; Reactive oxygen species; Small molecule
    DOI:  https://doi.org/10.1016/j.mito.2024.101971
  20. Gene. 2024 Oct 01. pii: S0378-1119(24)00857-6. [Epub ahead of print] 148976
    NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.
    Run Yan, Liting Chen, Zimu Cai, Jiyao Tang, Yanlin Zhu, Yanping Li, Xuemin Wang, Yu Ruan, Qi Han.
      Mitochondria are essential for cell metabolism and survival as they produce the majority of cellular ATP through oxidative phosphorylation as well as regulate critical processes such as cell proliferation and apoptosis. NIPSNAP family of proteins are predominantly mitochondrial matrix proteins. However, the molecular and cellular functions of the NIPSNAPs, particularly NIPSNAP3A, have remained elusive. Here, we demonstrated that NIPSNAP3A knockdown in HeLa cells inhibited their proliferation and migration and attenuated apoptosis induced by Actinomycin D (Act-D). These findings suggested a complex relationship between cellular processes and mitochondrial functions, mediated by NIPSNAP3A. Further investigations revealed that NIPSNAP3A knockdown not only inhibited mitochondrial fission through reduction of DRP1-S616, but also suppressed cytochrome c release in apoptosis. Collectively, our findings highlight the critical role of NIPSNAP3A in coordinating cellular processes, likely through its influence on mitochondrial dynamics.
    Keywords:  Apoptosis; Drp1; Fission; Mitochodnria; NIPSNAP3A; Proliferation
    DOI:  https://doi.org/10.1016/j.gene.2024.148976
  21. Autophagy. 2024 Sep 29. 1-2
    Reassessing kinetin's effect on PINK1 and mitophagy.
    Zhong Yan Gan, David Komander, Sylvie Callegari.
      Substantial evidence indicates that a decline in mitochondrial health contributes to the development of Parkinson disease. Accordingly, therapeutic stimulation of mitophagy, the autophagic turnover of dysfunctional mitochondria, is a promising approach to treat Parkinson disease. An attractive target in such a setting is PINK1, a protein kinase that initiates the mitophagy cascade. Previous reports suggest that PINK1 kinase activity can be enhanced by kinetin triphosphate (KTP), an enlarged ATP analog that acts as an alternate phosphate donor for PINK1 during phosphorylation. However, the mechanism of how KTP could exert such an effect on PINK1 was unclear. In a recent study, we demonstrate that contrary to previous thinking, KTP cannot be used by PINK1. Nucleotide-bound PINK1 structures indicate that KTP would clash with the back of PINK1's ATP binding pocket, and enlarging this pocket by mutagenesis is required to enable PINK1 to use KTP. Strikingly, mutation shifts PINK1's nucleotide preference from ATP to KTP. Similar results could be demonstrated in cells with kinetin, a membrane-permeable precursor of KTP. These results overturn the previously accepted mechanism of how kinetin enhances mitophagy and indicate that kinetin and its derivatives instead function through a currently unidentified mechanism.
    Keywords:  Mitophagy; PINK1; parkin; parkinson’s disease; protein kinase; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2024.2395144
  22. Brain Sci. 2024 Sep 05. pii: 899. [Epub ahead of print]14(9):
    Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.
    Adaleiz Ore, James M Angelastro, Cecilia Giulivi.
      The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.
    Keywords:  cell therapy; ethical concerns; exosomes; extracellular vesicles; mitochondrial dysfunction; mitochondrial medicine; neurodegenerative diseases; stem cells
    DOI:  https://doi.org/10.3390/brainsci14090899
  23. Nat Commun. 2024 Sep 29. 15(1): 8434
    RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.
    Xingjian Li, Hanwen Zhu, Bik Tzu Huang, Xianting Li, Heesoo Kim, Haiyan Tan, Yuanxi Zhang, Insup Choi, Junmin Peng, Pingyi Xu, Ji Sun, Zhenyu Yue.
      The leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and their phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the LRRK2-regulated RAB GTPase in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brain through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting RILPL1, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 activity. Furthermore, the ciliary and centrosome defects caused by the PD-linked LRRK2-G2019S mutation are prevented by Rab12 deletion in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.
    DOI:  https://doi.org/10.1038/s41467-024-52723-6
  24. Mol Neurobiol. 2024 Oct 01.
    Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in Axons.
    Christina Antoniou, Andrea Loreto, Jonathan Gilley, Elisa Merlini, Giuseppe Orsomando, Michael P Coleman.
      Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an endogenous axon survival factor that maintains axon health by blocking activation of the downstream pro-degenerative protein SARM1 (sterile alpha and TIR motif containing protein 1). While complete absence of NMNAT2 in mice results in extensive axon truncation and perinatal lethality, the removal of SARM1 completely rescues these phenotypes. Reduced levels of NMNAT2 can be compatible with life; however, they compromise axon development and survival. Mice born expressing sub-heterozygous levels of NMNAT2 remain overtly normal into old age but develop axonal defects in vivo and in vitro as well as behavioural phenotypes. Therefore, it is important to examine the effects of constitutively low NMNAT2 expression on SARM1 activation and disease susceptibility. Here we demonstrate that chronically low NMNAT2 levels reduce prenatal viability in mice in a SARM1-dependent manner and lead to sub-lethal SARM1 activation in morphologically intact axons of superior cervical ganglion (SCG) primary cultures. This is characterised by a depletion in NAD(P) and compromised neurite outgrowth. We also show that chronically low NMNAT2 expression reverses the NAD-enhancing effect of nicotinamide riboside (NR) in axons in a SARM1-dependent manner. These data indicate that low NMNAT2 levels can trigger sub-lethal SARM1 activation which is detectable at the molecular level and could predispose to human axonal disorders.
    Keywords:  NAD; NMNAT2; Programmed axon death; SARM1
    DOI:  https://doi.org/10.1007/s12035-024-04480-2
  25. Biomolecules. 2024 Aug 30. pii: 1089. [Epub ahead of print]14(9):
    Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.
    Azra Hasan, Brian E Staveley.
      The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.
    Keywords:  Amyotrophic Lateral Sclerosis; Buffy; Debcl; Drosophila melanogaster; Drp1; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fission
    DOI:  https://doi.org/10.3390/biom14091089
  26. Am J Med Genet A. 2024 Oct 03. e63900
    Periodic Paralysis in a Child With Thermosensitive Mitochondrial Trifunctional Protein Deficiency.
    Fatema Al-Amrani, Jos P N Ruiter, Mirjam Doolaard, Alok Kumar, Sacha Ferdinandusse, Khalid Al-Thihli.
      Mitochondrial trifunctional protein (MTP) deficiency is a fatty acid oxidation disorder associated with a spectrum of phenotypes. Patients with high residual enzyme activity tend to have milder phenotypes, and recently, fever-induced episodic myopathy was reported in association with a thermosensitive form of MTP deficiency. We report a 10-year-old male with recurrent episodes of acute flaccid paralysis involving upper and lower extremities in association with bulbar muscle weakness in the context of febrile illness, a phenotype reminiscent of recurrent periodic paralysis. The episodes started at the age of 3 years and have always been followed by full recovery within 1-2 weeks with no residual weakness. Whole exome sequencing revealed a homozygous c.2132C > T, p.(Pro711Leu) variant in HADHA. The variant leads to mildly reduced long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain ketoacyl-CoA thiolase (LCKAT) enzyme activities and reduced MTP protein expression in patient's fibroblasts when cultured at 37°C. Enzyme activities and MTP protein expression diminished when fibroblasts were cultured at 40°C. This is the first published report of confirmed recurrent periodic paralysis as a manifestation of a thermosensitive form of MTP deficiency, and it calls for this condition to be considered when evaluating patients with recurrent periodic paralysis given therapeutic implications.
    Keywords:  HADHA gene; LCHAD; MTP; bulbar involvement; long‐chain 3‐hydroxyacyl‐CoA dehydrogenase; mitochondrial trifunctional protein deficiency; periodic paralysis; thermosensitivity
    DOI:  https://doi.org/10.1002/ajmg.a.63900
  27. J Lipid Atheroscler. 2024 Sep;13(3): 306-327
    Targeting Mitochondrial Dysfunction for the Prevention and Treatment of Metabolic Disease by Bioactive Food Components.
    Mi-Bo Kim, Jaeeun Lee, Ji-Young Lee.
      Dysfunctional mitochondria have been linked to the pathogenesis of obesity-associated metabolic diseases. Excessive energy intake impairs mitochondrial biogenesis and function, decreasing adenosine-5'-triphosphate production and negatively impacting metabolically active tissues such as adipose tissue, skeletal muscle, and the liver. Compromised mitochondrial function disturbs lipid metabolism and increases reactive oxygen species production in these tissues, contributing to the development of insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease. Recent studies have demonstrated the therapeutic potential of bioactive food components, such as resveratrol, quercetin, coenzyme Q10, curcumin, and astaxanthin, by enhancing mitochondrial function. This review provides an overview of the current understanding of how these bioactive compounds ameliorate mitochondrial dysfunction to mitigate obesity-associated metabolic diseases.
    Keywords:  Metabolic diseases; Mitochondrial dysfunction; NAFLD; Obesity; Type 2 diabetes
    DOI:  https://doi.org/10.12997/jla.2024.13.3.306
  28. J Cachexia Sarcopenia Muscle. 2024 Oct 02.
    Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.
    Juan Diego Hernández-Camacho, Cristina Vicente-García, Lorena Ardila-García, Ana Padilla-Campos, Guillermo López-Lluch, Carlos Santos-Ocaña, Peter S Zammit, Jaime J Carvajal, Plácido Navas, Daniel J M Fernández-Ayala.
       BACKGROUND: ADCK genes encode aarF domain-containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult-onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β-oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention.
    METHODS: We used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests.
    RESULTS: We demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in 'aged' mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05).
    CONCLUSIONS: Our work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.
    Keywords:  ageing; coenzyme Q; development; mitochondria; satellite cell; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13574
  29. Genome Res. 2024 Oct 02. pii: gr.279273.124. [Epub ahead of print]
    High-coverage nanopore sequencing of samples from the 1000 Genomes Project to build a comprehensive catalog of human genetic variation.
    1000 Genomes ONT Sequencing Consortium
      Fewer than half of individuals with a suspected Mendelian or monogenic condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control datasets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project ONT Sequencing Consortium aims to generate LRS data from at least 800 of the 1000 Genomes Project samples. Our goal is to use LRS to identify a broader spectrum of variation so we may improve our understanding of normal patterns of human variation. Here, we present data from analysis of the first 100 samples, representing all 5 superpopulations and 19 subpopulations. These samples, sequenced to an average depth of coverage of 37x and sequence read N50 of 54 kbp, have high concordance with previous studies for identifying single nucleotide and indel variants outside of homopolymer regions. Using multiple structural variant (SV) callers, we identify an average of 24,543 high-confidence SVs per genome, including shared and private SVs likely to disrupt gene function as well as pathogenic expansions within disease-associated repeats that were not detected using short reads. Evaluation of methylation signatures revealed expected patterns at known imprinted loci, samples with skewed X-inactivation patterns, and novel differentially methylated regions. All raw sequencing data, processed data, and summary statistics are publicly available, providing a valuable resource for the clinical genetics community to discover pathogenic SVs.
    DOI:  https://doi.org/10.1101/gr.279273.124
  30. J Cell Biol. 2024 Dec 02. pii: e202402133. [Epub ahead of print]223(12):
    Local glycolysis supports injury-induced axonal regeneration.
    Luca Masin, Steven Bergmans, Annelies Van Dyck, Karl Farrow, Lies De Groef, Lieve Moons.
      Successful axonal regeneration following injury requires the effective allocation of energy. How axons withstand the initial disruption in mitochondrial energy production caused by the injury and subsequently initiate regrowth is poorly understood. Transcriptomic data showed increased expression of glycolytic genes after optic nerve crush in retinal ganglion cells with the co-deletion of Pten and Socs3. Using retinal cultures in a multicompartment microfluidic device, we observed increased regrowth and enhanced mitochondrial trafficking in the axons of Pten and Socs3 co-deleted neurons. While wild-type axons relied on mitochondrial metabolism, after injury, in the absence of Pten and Socs3, energy production was supported by local glycolysis. Specific inhibition of lactate production hindered injury survival and the initiation of regrowth while slowing down glycolysis upstream impaired regrowth initiation, axonal elongation, and energy production. Together, these observations reveal that glycolytic ATP, combined with sustained mitochondrial transport, is essential for injury-induced axonal regrowth, providing new insights into the metabolic underpinnings of axonal regeneration.
    DOI:  https://doi.org/10.1083/jcb.202402133
  31. Exp Neurol. 2024 Sep 30. pii: S0014-4886(24)00304-2. [Epub ahead of print] 114978
    The GENESIS database and tools: A decade of discovery in Mendelian genomics.
    Matt C Danzi, Eric Powell, Adriana P Rebelo, Maike F Dohrn, Danique Beijer, Sarah Fazal, Isaac R L Xu, Jessica Medina, Sitong Chen, Yeisha Arcia de Jesus, Jacquelyn Schatzman, Ray E Hershberger, Mario Saporta, Jonathan Baets, Marni Falk, David N Herrmann, Steven S Scherer, Mary M Reilly, Andrea Cortese, Wilson Marques, Mario R Carnejo-Olivas, Oranee Sanmaneechai, Marina L Kennerson, Albena Jordanova, Thiago Y T Silva, Jose Luiz Pedroso, Luca Schierbaum, Darius Ebrahimi-Fakhari, Stojan Peric, Yi-Chung Lee, Matthis Synofzik, Mustafa Tekin, Gianina Ravenscroft, Mike Shy, Nazli Basak, Rebecca Schule, Stephan Zuchner.
      In the past decade, human genetics research saw an acceleration of disease gene discovery and further dissection of the genetic architectures of many disorders. Much of this progress was enabled via data aggregation projects, collaborative data sharing among researchers, and the adoption of sophisticated and standardized bioinformatics analyses pipelines. In 2012, we launched the GENESIS platform, formerly known as GEM.app, with the aims to 1) empower clinical and basic researchers without bioinformatics expertise to analyze and explore genome level data and 2) facilitate the detection of novel pathogenic variation and novel disease genes by leveraging data aggregation and genetic matchmaking. The GENESIS database has grown to over 20,000 datasets from rare disease patients, which were provided by multiple academic research consortia and many individual investigators. Some of the largest global collections of genome-level data are available for Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and cerebellar ataxia. A number of rare disease consortia and networks are archiving their data in this database. Over the past decade, more than 1500 scientists have registered and used this resource and published over 200 papers on gene and variant identifications, which garnered >6000 citations. GENESIS has supported >100 gene discoveries and contributed to approximately half of all gene identifications in the fields of inherited peripheral neuropathies and spastic paraplegia in this time frame. Many diagnostic odysseys of rare disease patients have been resolved. The concept of genomes-to-therapy has borne out for a number of such discoveries that let to rapid clinical trials and expedited natural history studies. This marks GENESIS as one of the most impactful data aggregation initiatives in rare monogenic diseases.
    Keywords:  Data aggregation; Data sharing; Genome sequencing; Monogenic diseases; Neuromuscular diseases
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114978
  32. Cell Rep. 2024 Sep 28. pii: S2211-1247(24)01145-8. [Epub ahead of print]43(10): 114794
    Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
    Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.
      Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.
    Keywords:  CP: Cell biology; CP: Metabolism; Ca(2+); ER-mitochondrial contact; LBR; VDAC2; cell cycle; cell division; energy generation; metaphase-anaphase transition; mitochondria; mitosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114794
  33. Brain. 2024 Oct 01. pii: awae276. [Epub ahead of print]
    Dopamine neuron dysfunction and loss in the PrknR275W mouse model of juvenile parkinsonism.
    Maria Regoni, Letizia Zanetti, Martina Sevegnani, Chiara Domenicale, Stefano Magnabosco, Jyoti C Patel, Megan K Fernandes, Ryan M Feeley, Elena Monzani, Cecilia Mini, Stefano Comai, Laura Cherchi, Danilo De Gregorio, Isabella Soliman, Fabio Ruto, Laura Croci, Giacomo Consalez, Simona Rodighiero, Andrea Ciammola, Flavia Valtorta, Michele Morari, Giovanni Piccoli, Margaret E Rice, Jenny Sassone.
      Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies.
    Keywords:  PARKIN; mouse model; neurodegeneration
    DOI:  https://doi.org/10.1093/brain/awae276
  34. Pharmacol Res. 2024 Sep 30. pii: S1043-6618(24)00384-0. [Epub ahead of print] 107439
    Type 2 Diabetes Mellitus and Neurodegenerative Disorders: The Mitochondrial Connection.
    Isabella R Baduini, Jose E Castro Vildosola, Sheida Kavehmoghaddam, Fatmanur Kilic, S Aiman Nadeem, Juan J Nizama, Marietta A Rowand, Dileep Annapureddy, Chris-Ann Bryan, Lisa H Do, Samuel Hsiao, Sai A Jonnalagadda, Akhila Kasturi, Nikhila Mandava, Sachin Muppavaram, Bryan Ramirez, Aleece Siner, Christina N Suoto, Nasira Tamajal, Ernest R Scoma, Renata T Da Costa, Maria E Solesio.
      The incidence of type 2 diabetes mellitus (T2DM) has increased in our society in recent decades as the population ages, and this trend is not expected to revert. This is the same for the incidence of the main neurodegenerative disorders, including the two most common ones, which are, Alzheimer's and Parkinson's disease. Currently, no pharmacological therapies have been developed to revert or cure any of these pathologies. Interestingly, in recent years, an increased number of studies have shown a high co-morbidity between T2DM and neurodegeneration, as well as some common molecular pathways that are affected in both types of diseases. For example, while the etiopathology of T2DM and neurodegenerative disorders is highly complex, mitochondrial dysfunction has been broadly described in the early steps of both diseases; accordingly, this dysfunction has emerged as a plausible molecular link between them. In fact, the prominent role played by mitochondria in the mammalian metabolism of glucose places the physiology of the organelle in a central position to regulate many cellular processes that are affected in both T2DM and neurodegenerative disorders. In this collaborative review, we critically describe the relationship between T2DM and neurodegeneration; making a special emphasis on the mitochondrial mechanisms that link these diseases. A better understanding of the role of mitochondria on the etiopathology of T2DM and neurodegeneration could pave the way for the development of new pharmacological therapies focused on the regulation of the physiology of the organelle. These therapies could, ultimately, contribute to increase health span.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; Type 2 diabetes mellitus; mitochondria; neurodegenerative disorders
    DOI:  https://doi.org/10.1016/j.phrs.2024.107439
  35. bioRxiv. 2024 Sep 20. pii: 2024.09.19.613929. [Epub ahead of print]
    Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.
    Romane Manceau, Danie Majeur, Celena M Cherian, Colin J Miller, Lianna W Wat, Jasper D Fisher, Audrey Labarre, Serena Hollman, Sanjana Prakash, Sébastien Audet, Charlotte F Chao, Lewis Depaauw-Holt, Benjamin Rogers, Anthony Bosson, Joyce J Y Xi, Catrina A S Callow, Niyoosha Yoosefi, Niki Shahraki, Yi Han Xia, Alisa Hui, Jared VanderZwaag, Khalil Bouyakdan, Demetra Rodaros, Pavel Kotchetkov, Caroline Daneault, Ghazal Fallahpour, Martine Tetreault, Marie-Ève Tremblay, Matthieu Ruiz, Baptiste Lacoste, J A Parker, Ciaran Murphy-Royal, Tao Huan, Stephanie Fulton, Elizabeth J Rideout, Thierry Alquier.
      Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo . We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease.
    HIGHLIGHTS: Lipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene networkNeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasisLD regulation supports ER and mitochondrial function in hunger-activated neurons.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.1101/2024.09.19.613929
  36. JAMA. 2024 Oct 02.
    Rare Disease Innovation at the FDA-Opportunities for Implementation.
    Carolyn K Shore, Tequam L Worku, Jeffrey Kahn.
      
    DOI:  https://doi.org/10.1001/jama.2024.20358
  37. Int J Mol Sci. 2024 Sep 13. pii: 9915. [Epub ahead of print]25(18):
    Skeletal Muscle Involvement in Friedreich Ataxia.
    Elisabetta Indelicato, Julia Wanschitz, Wolfgang Löscher, Sylvia Boesch.
      Friedreich Ataxia (FRDA) is an inherited neuromuscular disorder triggered by a deficit of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency results in insufficient iron-sulfur cluster biosynthesis and impaired mitochondrial function and adenosine triphosphate production. The main clinical manifestation is a progressive balance and coordination disorder which depends on the involvement of peripheral and central sensory pathways as well as of the cerebellum. Besides the neurological involvement, FRDA affects also the striated muscles. The most prominent manifestation is a hypertrophic cardiomyopathy, which also represents the major determinant of premature mortality. Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.
    Keywords:  Friedreich Ataxia; biomarker; frataxin; mitochondria; proteomics; skeletal muscle; transcriptomics
    DOI:  https://doi.org/10.3390/ijms25189915
  38. Commun Biol. 2024 Oct 03. 7(1): 1250
    Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy.
    Lili Salinas, Claire B Montgomery, Francisco Figueroa, Phung N Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena N Dedkova.
      Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxnflox/null::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.
    DOI:  https://doi.org/10.1038/s42003-024-06962-4
  39. Antioxidants (Basel). 2024 Sep 04. pii: 1086. [Epub ahead of print]13(9):
    TSG Extends the Longevity of Caenorhabditis elegans by Targeting the DAF-16/SKN-1/SIR-2.1-Mediated Mitochondrial Quality Control Process.
    Menglu Sun, Congmin Wei, Yehui Gao, Xinyan Chen, Kaixin Zhong, Yingzi Li, Zhou Yang, Yihuai Gao, Hongbing Wang.
      The improvement of mitochondrial function is described as a strategy for alleviating oxidative stress and intervening in the aging process. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the major bioactive components isolated from Polygonum multiflorum Thunb, and it exhibits multiple activities, including antioxidant and anti-inflammatory effects. In this study, we found that 200 μM TSG significantly extended the mean lifespan of Caenorhabditis elegans by 16.48% and improved health status by delaying age-associated physiological decline in worms. The longevity prolongation effect of TSG depended on the regulation of the mitochondrial quality control process mediated by DAF-16/FOXO, SKN-1/Nrf2 and SIR-2.1/SIRT1 to improve mitochondrial function. Moreover, TSG treatment obviously alleviated the proteotoxicity of β-amyloid and tau proteins in worms. Our findings indicated that TSG is a promising natural product for preventing aging and treating aging-associated neurodegenerative diseases by regulating the mitochondrial quality control process to improve mitochondrial function.
    Keywords:  2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside; Caenorhabditis elegans; aging; mitochondrial function; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/antiox13091086
  40. Acta Neurol Belg. 2024 Sep 28.
    'The phenotypic conundrum of Trp748Ser variant in POLG gene: a report of two patients'.
    Abhishek Rathore, Gautham Arunachal, Rohan R Mahale, Hansashree Padmanabha, Pooja Mailankody.
      We present two cases of a 23-years and 32-years old female respectively, who presented with recurrent seizures, ataxia, dysarthria, psychomotor slowing. Magnetic resonance imaging (MRI) of the brain in the first patient revealed T2/FLAIR hyperintensity in the bilateral thalamus and cerebellar white matter with diffusion restriction, with no contrast enhancement. In the second patient, magnetic resonance imaging of brain showed FLAIR hyperintensity in precuneus while CSF showed raised HSV IgG titre on first presentation leading to suspicion of infective etiology. The initial differential diagnosis included autoimmune, metabolic and demyelinating causes. However, routine laboratory investigations, cerebrospinal fluid analysis, and autoimmune panel and demyelination workup were inconclusive. Considering the possibility of a genetic-mediated metabolic disorder, genetic testing was carried out leading to the identification of the Trp748Ser variation in POLG gene associated with mitochondrial DNA depletion syndrome. These cases highlight the diagnostic challenges and complexities in identifying rare metabolic encephalopathy, emphasizing the importance of a multidisciplinary approach in such cases.
    Keywords:   POLG variant; Autoimmune encephalopathy; Genetic testing; Metabolic encephalopathy; Mitochondrial DNA depletion syndrome
    DOI:  https://doi.org/10.1007/s13760-024-02640-8
  41. Commun Biol. 2024 Oct 01. 7(1): 1229
    Maintaining mitochondrial DNA copy number mitigates ROS-induced oocyte decline and female reproductive aging.
    Shiyun Long, Yunchao Zheng, Xiaoling Deng, Jing Guo, Zhe Xu, Karin Scharffetter-Kochanek, Yanmei Dou, Min Jiang.
      Oocytes play a crucial role in transmitting maternal mitochondrial DNA (mtDNA), essential for the continuation of species. However, the effects of mitochondrial reactive oxygen species (ROS) on mammalian oocyte maturation and mtDNA maintenance remain unclear. We investigated this by conditionally knocking out the Sod2 gene in primordial follicles, elevating mitochondrial matrix ROS levels from early oocyte stages. Our data indicates that reproductive aging in Sod2 conditional knockout females begins at 6 months, with oxidative stress impairing oocyte quality, particularly affecting OXPHOS complex II and mtDNA-encoded mRNA levels. Despite unchanged mtDNA mutation load, mtDNA copy numbers exhibited significant variations. Strikingly, reducing mtDNA copy numbers by reducing mtSSB protein, crucial for mtDNA replication, accelerated reproductive aging onset to three months, underscoring the critical role of mtDNA copy number maintenance under oxidative stress conditions. This research provides new insights into the relationship among mitochondrial ROS, mtDNA, and reproductive aging, offering potential strategies for delaying aging-related fertility decline.
    DOI:  https://doi.org/10.1038/s42003-024-06888-x
  42. J Clin Med. 2024 Sep 10. pii: 5356. [Epub ahead of print]13(18):
    Favorable Outcome after Liver Transplantation in an Infant with Liver Failure Due to Deoxyguanosine Kinase Deficiency.
    Alina Grama, Gabriel Benţa, Alexandru Stefan Niculae, Alexandra Mititelu, Claudia Simu, Otilia Fufezan, Xavier Stephenne, Raymond Reding, Catherine de Magnee, Roberto Tambucci, Etienne Sokal, Tudor Lucian Pop.
      Introduction: Deoxyguanosine Kinase (DGUOK) deficiency is a very rare disorder characterized by liver dysfunction, neurological manifestations, and metabolic disorders secondary to severely reduced mitochondrial DNA content. These patients develop early-onset liver failure, and their liver transplantation (LT) indication remains debatable due to the possibility of neurological involvement. Case Report: We present the case of a 6-month-old female diagnosed with DGUOK deficiency who developed liver failure. At 9 months, she underwent a living-related LT with an initial favorable evolution under immunosuppression therapy with tacrolimus. Four months after LT, she presented two prolonged bacterial and Rotavirus enteritis episodes. She developed classical post-transplant complications (severe renal tubular acidosis type IV, secondary to the high tacrolimus level, and post-transplant lymphoproliferative disease) during these episodes. Her condition deteriorated progressively, with reversible hypotonia and significant weight loss. However, the neurological evaluation did not reveal any signs suggestive of the progression of the underlying disease. A few months later, her clinical features and laboratory parameters improved considerably. Conclusions: This case highlights the unpredictable evolution of children with LT for liver failure due to DGUOK deficiency.
    Keywords:  children; deoxyguanosine kinase deficiency; liver transplantation; mitochondrial disorder; outcome
    DOI:  https://doi.org/10.3390/jcm13185356
  43. Cell Prolif. 2024 Oct 01. e13746
    Matrix stiffness regulates mitochondria-lysosome contacts to modulate the mitochondrial network, alleviate the senescence of MSCs.
    Kang Wang, Chingchun Ho, Xiangyu Li, Jianfeng Hou, Qipei Luo, Jiahong Wu, Yuxin Yang, Xinchun Zhang.
      The extracellular microenvironment encompasses the extracellular matrix, neighbouring cells, cytokines, and fluid components. Anomalies in the microenvironment can trigger aging and a decreased differentiation capacity in mesenchymal stem cells (MSCs). MSCs can perceive variations in the firmness of the extracellular matrix and respond by regulating mitochondrial function. Diminished mitochondrial function is intricately linked to cellular aging, and studies have shown that mitochondria-lysosome contacts (M-L contacts) can regulate mitochondrial function to sustain cellular equilibrium. Nonetheless, the influence of M-L contacts on MSC aging under varying matrix stiffness remains unclear. In this study, utilizing single-cell RNA sequencing and atomic force microscopy, we further demonstrate that reduced matrix stiffness in older individuals leads to MSC aging and subsequent decline in osteogenic ability. Mechanistically, augmented M-L contacts under low matrix stiffness exacerbate MSC aging by escalating mitochondrial oxidative stress and peripheral division. Moreover, under soft matrix stiffness, cytoskeleton reorganization facilitates rapid movement of lysosomes. The M-L contacts inhibitor ML282 ameliorates MSC aging by reinstating mitochondrial network and function. Overall, our findings confirm that MSC aging is instigated by disruption of the mitochondrial network and function induced by matrix stiffness, while also elucidating the potential mechanism by which M-L Contact regulates mitochondrial homeostasis. Crucially, this presents promise for cellular anti-aging strategies centred on mitochondria, particularly in the realm of stem cell therapy.
    DOI:  https://doi.org/10.1111/cpr.13746
  44. J Biol Chem. 2024 Sep 27. pii: S0021-9258(24)02322-6. [Epub ahead of print] 107820
    Nonfunctional coq10 mutants maintain the ERMES complex and reveal true phenotypes associated with the loss of the coenzyme Q chaperone protein Coq10.
    Noelle Alexa Novales, Kelsey J Feustel, Kevin L He, Guillaume F Chanfreau, Catherine F Clarke.
      Coenzyme Q (CoQ) is a redox-active lipid molecule that acts as an electron carrier in the mitochondrial electron transport chain. In Saccharomyces cerevisiae, CoQ is synthesized in the mitochondrial matrix by a multi-subunit protein-lipid complex termed the CoQ synthome, the spatial positioning of which is coordinated by the Endoplasmic Reticulum-Mitochondria Encounter Structure (ERMES). The MDM12 gene encoding the cytosolic subunit of ERMES, is co-expressed with COQ10, which encodes the putative CoQ chaperone Coq10, via a shared bidirectional promoter. Deletion of COQ10 results in respiratory deficiency, impaired CoQ biosynthesis, and reduced spatial coordination between ERMES and the CoQ Synthome. While Coq10 protein content is maintained upon deletion of MDM12, we show that deletion of COQ10 by replacement with a HIS3 marker results in diminished Mdm12 protein content. Since deletion of individual ERMES subunits prevents ERMES formation, we asked whether some or all of the phenotypes associated with COQ10 deletion result from ERMES dysfunction. To identify the phenotypes resulting solely due to the loss of Coq10, we constructed strains expressing a functionally impaired (coq10-L96S) or truncated (coq10-R147*) Coq10 isoform using CRISPR-Cas9. We show that both coq10 mutants preserve Mdm12 protein content and exhibit impaired respiratory capacity like the coq10Δ mutant, indicating that Coq10's function is vital for respiration regardless of ERMES integrity. Moreover, the maintenance of CoQ synthome stability and efficient CoQ biosynthesis observed for the coq10-R147* mutant suggests these deleterious phenotypes in the coq10Δ mutant result from ERMES disruption. Overall, this study clarifies the role of Coq10 in modulating CoQ biosynthesis.
    Keywords:  CoQ synthome; Coq10; Endoplasmic Reticulum-Mitochondria Encounter Structure; Mdm12; START domain; Saccharomyces cerevisiae; coenzyme Q; lipid; mitochondrial metabolism; ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107820
  45. Mov Disord Clin Pract. 2024 Oct 05.
    Biallelic Variants in COQ4 Cause Childhood-Onset Pure Hereditary Spastic Paraplegia.
    Luca Schierbaum, Vicente Quiroz, Amy Tam, Umar Zubair, Laura Tochen, Rasha Srouji, Kathryn Yang, Darius Ebrahimi-Fakhari.
      
    Keywords:  coenzyme Q; hereditary spastic paraplegia; inborn error of metabolism; mitochondrial disease; spastic paraplegia
    DOI:  https://doi.org/10.1002/mdc3.14226
  46. Mol Genet Metab. 2024 Sep 28. pii: S1096-7192(24)00465-7. [Epub ahead of print]143(3): 108581
    Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy.
    Camille Moreau, Adrien Paquot, Gustavo Soto Ares, Anne-Frédérique Dessein, Benoit Deprez, Terence Beghyn, Dries Dobbelaere.
      Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.
    Keywords:  ACOX1; Drug repurposing; High-throughput screening; Individualized medicine; Peroxisomal disorder
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108581
  47. Nutrients. 2024 Sep 15. pii: 3114. [Epub ahead of print]16(18):
    Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.
    Marilena Briglia, Fabio Allia, Rosanna Avola, Cinzia Signorini, Venera Cardile, Giovanni Luca Romano, Giovanni Giurdanella, Roberta Malaguarnera, Maria Bellomo, Adriana Carol Eleonora Graziano.
      Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects.
    Keywords:  dietary pattern; neurodegenerative disease; nutritional compounds; orphan disease; rare leukodystrophy; rare neurological disorders; rare tumors
    DOI:  https://doi.org/10.3390/nu16183114
  48. bioRxiv. 2024 Sep 20. pii: 2024.09.19.613771. [Epub ahead of print]
    Impact of O -GlcNAcylation elevation on mitophagy and glia in the dentate gyrus.
    Joshua Kramer, John C Chatham, Martin E Young, Victor Darley-Usmar, Jianhua Zhang.
      O -GlcNAcylation is a dynamic and reversible protein post-translational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O -GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative disease. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of OGA with thiamet G which leads to elevation of protein O -GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP positive astrocytes and is significantly decreased in response to elevated O -GlcNAcylation. Furthermore, with increased O -GlcNAcylation, the levels of astrocyte makers GFAP and S100B, and microglial cell marker IBA1 were decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O -GlcNAc pathway.
    DOI:  https://doi.org/10.1101/2024.09.19.613771
  49. Elife. 2024 Oct 03. pii: e103865. [Epub ahead of print]13
    Correction: eIF2B conformation and assembly state regulate the integrated stress response.
    Michael Schoof, Morgane Boone, Lan Wang, Rosalie Lawrence, Adam Frost, Peter Walter.
      
    Keywords:  biochemistry; cell biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.103865
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:23.