bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024‒07‒14
forty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.
  2. Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
  3. Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
  4. Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes.
  5. PINK1 regulated mitophagy is evident in skeletal muscles.
  6. BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease.
  7. Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.
  8. PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
  9. MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes.
  10. Exploring haematopoietic stem cell dynamics through mitochondrial mutation profiling.
  11. A roadmap for ribosome assembly in human mitochondria.
  12. The Changes of Mitochondria during Aging and Regeneration.
  13. New variants expand the neurological phenotype of COQ7 deficiency.
  14. Mitochondrial DNA D-loop variants correlate with a primary open-angle glaucoma subgroup.
  15. Leber's hereditary optic neuropathy: Update on current diagnosis and treatment.
  16. Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.
  17. Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.
  18. Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven by PRKN knockout.
  19. Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
  20. Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
  21. Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.
  22. Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.
  23. Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.
  24. Isolation of Mitochondria from Murine Skeletal Muscle.
  25. Extracellular Microvesicles vs. Mitochondria: Competing for the Top Spot in Cardiovascular Regenerative Medicine.
  26. Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.
  27. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
  28. Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import.
  29. Dietary linoleic acid supplementation fails to rescue established cardiomyopathy in Barth syndrome.
  30. Adult presentation of a rare mitochondrial tRNA Val gene mutation-an expanding clinical phenotype.
  31. Investigating mitochondrial remodelling in Arrhythmogenic Cardiomyopathy.
  32. Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.
  33. Lipid Droplet-Mitochondria Contacts in Health and Disease.
  34. Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.
  35. Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.
  36. Transient response to high-dose niacin therapy in a patient with NAXE deficiency.
  37. Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency.
  38. Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role.
  39. Unsupervised representation learning on high-dimensional clinical data improves genomic discovery and prediction.
  40. MRS2 missense variation at Asp216 abrogates inhibitory Mg2+ binding, potentiating cell migration and apoptosis resistance.
  41. ChatGPT for digital pathology research.
  42. Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.
  43. A diverse proteome is present and enzymatically active in metabolite extracts.
  44. Mitochondrial Structure, Dynamics, and Physiology: Light Microscopy to Disentangle the Network.
  45. Strategies for modeling aging and age-related diseases.
  46. Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.
  1. bioRxiv. 2024 Jun 24. pii: 2024.05.12.593764. [Epub ahead of print]
    The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.
    Sijie Tan, Alisa Susan Dengler, Rami Zahi Darawsheh, Nora Kory.
      Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1101/2024.05.12.593764
  2. Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00386-1. [Epub ahead of print]
    Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
    Daisuke Murata, Shubhrajit Roy, Svetlana Lutsenko, Miho Iijima, Hiromi Sesaki.
      Following the Goldilocks principle, mitochondria size must be "just right." Mitochondria balance division and fusion to avoid becoming too big or too small. Defects in this balance produce dysfunctional mitochondria in human diseases. Mitochondrial safeguard (MitoSafe) is a defense mechanism that protects mitochondria against extreme enlarging by suppressing fusion in mammalian cells. In MitoSafe, hyperfused mitochondria elicit flickering-short pulses of mitochondrial depolarization. Flickering activates an inner membrane protease, Oma1, which in turn proteolytically inactivates a mitochondrial fusion protein, Opa1. The mechanisms underlying flickering are unknown. Using a live-imaging screen, we identified Slc25a3 (a mitochondrial carrier transporting phosphate and copper) as necessary for flickering and Opa1 cleavage. Remarkably, copper, but not phosphate, is critical for flickering. Furthermore, we found that two copper-containing mitochondrial enzymes, superoxide dismutase 1 and cytochrome c oxidase, regulate flickering. Our data identify an unforeseen mechanism linking copper, redox homeostasis, and membrane flickering in mitochondrial defense against deleterious fusion.
    Keywords:  division; fusion; mitochondria; stress response; transporter
    DOI:  https://doi.org/10.1016/j.devcel.2024.06.008
  3. Life Sci Alliance. 2024 Sep;pii: e202402765. [Epub ahead of print]7(9):
    Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
    Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Keri-Lyn Kozul, Merima Forny, Jonathan R Friedman, Natalie M Niemi.
      PPTC7 is a mitochondrial-localized phosphatase that suppresses BNIP3- and NIX-mediated mitophagy, but the mechanisms underlying this regulation remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. Loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels, which requires an intact catalytic motif but is surprisingly independent of its targeting to mitochondria. Consistently, we find that PPTC7 is dual-localized to the outer mitochondrial membrane and the matrix. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments demonstrate that PPTC7 dynamically associates with BNIP3 and NIX within the native cellular environment. Collectively, these data reveal that a fraction of PPTC7 localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX, limiting basal mitophagy.
    DOI:  https://doi.org/10.26508/lsa.202402765
  4. Biol Lett. 2024 Jul;20(7): 20240147
    Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes.
    Giorgio Muneretto, Federico Plazzi, Marco Passamonti.
      The nucleus interacts with the other organelles to perform essential functions of the eukaryotic cell. Mitochondria have their own genome and communicate back to the nucleus in what is known as mitochondrial retrograde response. Information is transferred to the nucleus in many ways, leading to wide-ranging changes in nuclear gene expression and culminating with changes in metabolic, regulatory or stress-related pathways. RNAs are emerging molecules involved in this signalling. RNAs encode precise information and are involved in highly target-specific signalling, through a wide range of processes known as RNA interference. RNA-mediated mitochondrial retrograde response requires these molecules to exit the mitochondrion, a process that is still mostly unknown. We suggest that the proteins/complexes translocases of the inner membrane, polynucleotide phosphorylase, mitochondrial permeability transition pore, and the subunits of oxidative phosphorylation complexes may be responsible for RNA export.
    Keywords:  mito-nuclear interactions; mitochondrial export; mitochondrial retrograde response; regulatory RNAs; small mitochondrial highly transcribed RNAs
    DOI:  https://doi.org/10.1098/rsbl.2024.0147
  5. Autophagy Rep. 2024 Mar 11. 3(1): 2326402
    PINK1 regulated mitophagy is evident in skeletal muscles.
    Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.
      PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
    Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator
    DOI:  https://doi.org/10.1080/27694127.2024.2326402
  6. J Biol Chem. 2024 Jul 09. pii: S0021-9258(24)02044-1. [Epub ahead of print] 107543
    BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease.
    Yi Wang, Siyuan Luo, Huili Su, Zhimeng Wang, Ling Chu, Conggang Zhang.
      The pathogenesis of Parkinson's disease (PD) has been associated with mitochondrial dysfunction. Given that the PINK1/Parkin pathway governs mitochondrial quality control by inducing mitophagy to remove damaged mitochondria, therapeutic approaches to activate PINK1/Parkin-mediated mitophagy have the potential in the treatment of PD. Here, we have identified a new small molecule, BL-918, as an inducer of mitophagy via activating the PINK1/Parkin pathway. BL-918 triggers PINK1 accumulation and Parkin mitochondrial translocation to initiate PINK1/Parkin-mediated mitophagy. We found that mitochondrial membrane potential and mitochondrial permeability transition (mPT) pore were involved in BL-918-induced PINK1/Parkin pathway activation. Moreover, we showed that BL-918 mitigated PD progression in MPTP-induced PD mice in a PINK1-dependent manner. Our results unravel a new activator of the PINK1/Parkin signaling pathway and provide a potential strategy for the treatment of PD and other diseases with dysfunctional mitochondria.
    Keywords:  Mitochondrial quality control; Mitophagy; PINK1; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.jbc.2024.107543
  7. J Neurogenet. 2024 Jul 08. 1-8
    Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.
    Shivani Sharma, Anita Mahadevan, Gayathri Narayanappa, Monojit Debnath, Periyasamy Govindaraj, Sumanth Shivaram, Doniparthi V Seshagiri, Ramesh Siram, Akhilesh Shroti, Parayil S Bindu, Yasha T Chickabasaviah, Arun B Taly, Madhu Nagappa.
      Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.
    Keywords:  Deafness; mitochondria; optic atrophy; tropical ataxic neuropathy
    DOI:  https://doi.org/10.1080/01677063.2024.2373363
  8. EMBO Rep. 2024 Jul 11.
    PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
    Giang Thanh Nguyen-Dien, Brendan Townsend, Prajakta Gosavi Kulkarni, Keri-Lyn Kozul, Soo Siang Ooi, Denaye N Eldershaw, Saroja Weeratunga, Meihan Liu, Mathew Jk Jones, S Sean Millard, Dominic Ch Ng, Michele Pagano, Alexis Bonfim-Melo, Tobias Schneider, David Komander, Michael Lazarou, Brett M Collins, Julia K Pagan.
      Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.
    Keywords:  BNIP3; FBXL4; Mitophagy; NIX; PPTC7
    DOI:  https://doi.org/10.1038/s44319-024-00181-y
  9. bioRxiv. 2024 Jul 03. pii: 2024.06.20.599846. [Epub ahead of print]
    MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes.
    Zer Vue, Alexandria Murphy, Han Le, Kit Neikirk, Edgar Garza-Lopez, Andrea G Marshall, Margaret Mungai, Brenita Jenkins, Larry Vang, Heather K Beasley, Mariaassumpta Ezedimma, Sasha Manus, Aaron Whiteside, Maria Fernanda Forni, Chanel Harris, Amber Crabtree, Claude F Albritton, Sydney Jamison, Mert Demirci, Praveena Prasad, Ashton Oliver, Ky'Era V Actkins, Jianqiang Shao, Elma Zaganjor, Estevão Scudese, Benjamin Rodriguez, Alice Koh, Izabella Rabago, Johnathan E Moore, Desiree Nguyen, Muhammad Aftab, Benjamin Kirk, Yahang Li, Nelson Wandira, Taseer Ahmad, Mohammad Saleem, Ashlesha Kadam, Prasanna Katti, Ho-Jin Koh, Chantell Evans, Young Do Koo, Eric Wang, Quinton Smith, Dhanendra Tomar, Clintoria R Williams, Mariya T Sweetwyne, Anita M Quintana, Mark A Phillips, David Hubert, Annet Kirabo, Chandravanu Dash, Pooja Jadiya, André Kinder, Olujimi A Ajijola, Tyne W Miller-Fleming, Melanie R McReynolds, Antentor Hinton.
      The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.
    DOI:  https://doi.org/10.1101/2024.06.20.599846
  10. Mol Biomed. 2024 Jul 10. 5(1): 26
    Exploring haematopoietic stem cell dynamics through mitochondrial mutation profiling.
    Yongming Xia, Ruixiu Chen, Shiwei Duan.
      
    Keywords:  Blood disorders; Clonal dynamics; Haematopoietic stem cells; Lineage reconstruction; Mitochondrial DNA mutations; Single-cell sequencing
    DOI:  https://doi.org/10.1186/s43556-024-00190-2
  11. Nat Struct Mol Biol. 2024 Jul 11.
    A roadmap for ribosome assembly in human mitochondria.
    Elena Lavdovskaia, Elisa Hanitsch, Andreas Linden, Martin Pašen, Venkatapathi Challa, Yehor Horokhovskyi, Hanna P Roetschke, Franziska Nadler, Luisa Welp, Emely Steube, Marleen Heinrichs, Mandy Mong-Quyen Mai, Henning Urlaub, Juliane Liepe, Ricarda Richter-Dennerlein.
      Mitochondria contain dedicated ribosomes (mitoribosomes), which synthesize the mitochondrial-encoded core components of the oxidative phosphorylation complexes. The RNA and protein components of mitoribosomes are encoded on two different genomes (mitochondrial and nuclear) and are assembled into functional complexes with the help of dedicated factors inside the organelle. Defects in mitoribosome biogenesis are associated with severe human diseases, yet the molecular pathway of mitoribosome assembly remains poorly understood. Here, we applied a multidisciplinary approach combining biochemical isolation and analysis of native mitoribosomal assembly complexes with quantitative mass spectrometry and mathematical modeling to reconstitute the entire assembly pathway of the human mitoribosome. We show that, in contrast to its bacterial and cytosolic counterparts, human mitoribosome biogenesis involves the formation of ribosomal protein-only modules, which then assemble on the appropriate ribosomal RNA moiety in a coordinated fashion. The presence of excess protein-only modules primed for assembly rationalizes how mitochondria cope with the challenge of forming a protein-rich ribonucleoprotein complex of dual genetic origin. This study provides a comprehensive roadmap of mitoribosome biogenesis, from very early to late maturation steps, and highlights the evolutionary divergence from its bacterial ancestor.
    DOI:  https://doi.org/10.1038/s41594-024-01356-w
  12. Adv Biol (Weinh). 2024 Jul 09. e2300445
    The Changes of Mitochondria during Aging and Regeneration.
    Anqi Li, Yuan Qin, Guohua Gong.
      Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.
    Keywords:  mitochondrial homeostasis; mitochondrial oxidative respiration; mtROS; regeneration; senescence
    DOI:  https://doi.org/10.1002/adbi.202300445
  13. J Inherit Metab Dis. 2024 Jul 08.
    New variants expand the neurological phenotype of COQ7 deficiency.
    María Alcázar Fabra, Abraham J Paredes-Fuentes, Manuel Torralba Carnerero, Daniel J Moreno Férnandez de Ayala, Antonio Arroyo Luque, Ana Sánchez Cuesta, Carmine Staiano, Paula Sanchez-Pintos, María Luz Couce, Miguel Tomás, Ana Victoria Marco-Hernández, Carmen Orellana, Francisco Martínez, Mónica Roselló, Alfonso Caro, Juan Silvestre Oltra Soler, Sandra Monfort, Alejandro Sánchez, Dolores Rausell, Isidro Vitoria, Mireia Del Toro, Angels Garcia-Cazorla, Natalia A Julia-Palacios, Cristina Jou, Delia Yubero, Luis Carlos López, Juan Diego Hernández Camacho, Guillermo López Lluch, Manuel Ballesteros Simarro, Juan Carlos Rodríguez Aguilera, Gloria Brea Calvo, María Victoria Cascajo Almenara, Rafael Artuch, Carlos Santos-Ocaña.
      The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.
    Keywords:  COQ7; CoQ10; mitochondrial diseases; neurological disorders
    DOI:  https://doi.org/10.1002/jimd.12776
  14. Front Ophthalmol (Lausanne). 2023 ;3 1309836
    Mitochondrial DNA D-loop variants correlate with a primary open-angle glaucoma subgroup.
    Antoni Vallbona-Garcia, Patrick J Lindsey, Rick Kamps, Alphons P M Stassen, Nhan Nguyen, Florence H J van Tienen, Ilse H J Hamers, Rianne Hardij, Marike W van Gisbergen, Birke J Benedikter, Irenaeus F M de Coo, Carroll A B Webers, Theo G M F Gorgels, Hubert J M Smeets.
      Introduction: Primary open-angle glaucoma (POAG) is a characteristic optic neuropathy, caused by degeneration of the optic nerve-forming neurons, the retinal ganglion cells (RGCs). High intraocular pressure (IOP) and aging have been identified as major risk factors; yet the POAG pathophysiology is not fully understood. Since RGCs have high energy requirements, mitochondrial dysfunction may put the survivability of RGCs at risk. We explored in buffy coat DNA whether mtDNA variants and their distribution throughout the mtDNA could be risk factors for POAG.Methods: The mtDNA was sequenced from age- and sex-matched study groups, being high tension glaucoma (HTG, n=71), normal tension glaucoma patients (NTG, n=33), ocular hypertensive subjects (OH, n=7), and cataract controls (without glaucoma; n=30), all without remarkable comorbidities.
    Results: No association was found between the number of mtDNA variants in genes encoding proteins, tRNAs, rRNAs, and in non-coding regions in the different study groups. Next, variants that controls shared with the other groups were discarded. A significantly higher number of exclusive variants was observed in the D-loop region for the HTG group (~1.23 variants/subject), in contrast to controls (~0.35 variants/subject). In the D-loop, specifically in the 7S DNA sub-region within the Hypervariable region 1 (HV1), we found that 42% of the HTG and 27% of the NTG subjects presented variants, while this was only 14% for the controls and OH subjects. As we have previously reported a reduction in mtDNA copy number in HTG, we analysed if specific D-loop variants could explain this. While the majority of glaucoma patients with the exclusive D-loop variants m.72T>C, m.16163 A>G, m.16186C>T, m.16298T>C, and m.16390G>A presented a mtDNA copy number below controls median, no significant association between these variants and low copy number was found and their possible negative role in mtDNA replication remains uncertain. Approximately 38% of the HTG patients with reduced copy number did not carry any exclusive D-loop or other mtDNA variants, which indicates that variants in nuclear-encoded mitochondrial genes, environmental factors, or aging might be involved in those cases.
    Conclusion: In conclusion, we found that variants in the D-loop region may be a risk factor in a subgroup of POAG, possibly by affecting mtDNA replication.
    Keywords:  D-loop (control region); POAG; glaucoma; mitochondria; mtDNA; mtDNA replication
    DOI:  https://doi.org/10.3389/fopht.2023.1309836
  15. Front Ophthalmol (Lausanne). 2022 ;2 1077395
    Leber's hereditary optic neuropathy: Update on current diagnosis and treatment.
    Ali Esmaeil, Ali Ali, Raed Behbehani.
      Leber's hereditary optic neuropathy (LHON) is a fairly prevalent mitochondrial disorder (1:50,000) arising from the dysfunction of the mitochondrial respiratory chain, which eventually leads to apoptosis of retinal ganglion cells. The usual presentation is that of a young male with a sequential reduction in visual acuity. OCT has been used to study the pattern of optic nerve involvement in LHON, showing early thickening of the inferior and superior retinal nerve fibre layer and ganglion cell layer thinning corresponding with the onset of symptoms. Of the three primary mutations for LHON, the m.14484T>C mutation has the best visual prognosis. Recent emerging therapeutic options for LHON include idebenone and the introduction of genetic vector therapy, which is currently in phase III clinical trials. Screening of family members and adequate advice to avoid environmental triggers, such as smoking and alcohol consumption, are also cornerstones in the management of LHON.
    Keywords:  Leber’s hereditary optic neuropathy; diagnostics; genetic vector therapy; idebenone; mitochondrial disorder
    DOI:  https://doi.org/10.3389/fopht.2022.1077395
  16. Genome Med. 2024 Jul 11. 16(1): 88
    Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.
    SHaRe Investigators
      BACKGROUND: One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as "genetic constraint". Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes.METHODS: We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues.
    RESULTS: We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism.
    CONCLUSIONS: Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.
    Keywords:  Clinical interpretation; Developmental disorders; Genetic constraint; Missense variant interpretation; Protein domains
    DOI:  https://doi.org/10.1186/s13073-024-01358-9
  17. Curr Nutr Rep. 2024 Jul 08.
    Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.
    Lauren Jun, Ya-Xiong Tao, Thangiah Geetha, Jeganathan Ramesh Babu.
      PURPOSE OF REVIEW: The global obesity epidemic has become a major public health concern, necessitating comprehensive research into its adverse effects on various tissues within the human body. Among these tissues, skeletal muscle has gained attention due to its susceptibility to obesity-related alterations. Mitochondria are primary source of energy production in the skeletal muscle. Healthy skeletal muscle maintains constant mitochondrial content through continuous cycle of synthesis and degradation. However, obesity has been shown to disrupt this intricate balance. This review summarizes recent findings on the impact of obesity on skeletal muscle mitochondria structure and function. In addition, we summarize the molecular mechanism of mitochondrial quality control systems and how obesity impacts these systems. RECENT FINDINGS: Recent findings show various interventions aimed at mitigating mitochondrial dysfunction in obese model, encompassing strategies including caloric restriction and various dietary compounds. Obesity has deleterious effect on skeletal muscle mitochondria by disrupting mitochondrial biogenesis and dynamics. Caloric restriction, omega-3 fatty acids, resveratrol, and other dietary compounds enhance mitochondrial function and present promising therapeutic opportunities.
    Keywords:  Metabolic disease; Mitochondrial biogenesis; Mitochondrial dynamics; Omega-3 fatty acids; Resveratrol; Skeletal muscle fiber type
    DOI:  https://doi.org/10.1007/s13668-024-00555-7
  18. bioRxiv. 2024 Jun 29. pii: 2024.05.21.594886. [Epub ahead of print]
    Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven by PRKN knockout.
    Camille Goldman, Tatyana Kareva, Lily Sarrafha, Braxton R Schuldt, Abhishek Sahasrabudhe, Tim Ahfeldt, Joel W Blanchard.
      Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosoesl is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (Genetically Encoded and Modular SubCellular Organelle Probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN- knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provide critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.
    DOI:  https://doi.org/10.1101/2024.05.21.594886
  19. Nat Commun. 2024 Jul 10. 15(1): 5818
    Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
    Kazuhiro Yamada, Claudette St Croix, Donna B Stolz, Yulia Y Tyurina, Vladimir A Tyurin, Laura R Bradley, Alexander A Kapralov, Yanhan Deng, Xiuxia Zhou, Qi Wei, Bo Liao, Nobuhiko Fukuda, Mara Sullivan, John Trudeau, Anuradha Ray, Valerian E Kagan, Jinming Zhao, Sally E Wenzel.
      A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.
    DOI:  https://doi.org/10.1038/s41467-024-50222-2
  20. Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]
    Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
    Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.
      Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.
    Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
  21. Int J Mol Sci. 2024 Jun 30. pii: 7240. [Epub ahead of print]25(13):
    Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.
    Marta García-López, Lydia Jiménez-Vicente, Raquel González-Jabardo, Helena Dorado, Irene Gómez-Manjón, Miguel Ángel Martín, Carmen Ayuso, Joaquín Arenas, María Esther Gallardo.
      Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action.
    Keywords:  ADOA; CRISPR/Cas9; OPA1; RGCs; autosomal dominant optic atrophy; disease modeling; iPSCs; isogenic control; retinal ganglion cells
    DOI:  https://doi.org/10.3390/ijms25137240
  22. Mitochondrion. 2024 Jul 08. pii: S1567-7249(24)00091-6. [Epub ahead of print]78 101933
    Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.
    Harpreet Kaur, Omar Carrillo, Iraselia Garcia, Isaiah Ramos, Shaynah St Vallier, Patrick De La Torre, Alma Lopez, Megan Keniry, Daniel Bazan, Jorge Elizondo, K C Grishma, Lee Ann MacMillan-Crow, Robert Gilkerson.
      Mitochondrial optic atrophy-1 (OPA1) plays key roles in adapting mitochondrial structure to bioenergetic function. When transmembrane potential across the inner membrane (Δψm) is intact, long (L-OPA1) isoforms shape the inner membrane through membrane fusion and the formation of cristal junctions. When Δψm is lost, however, OPA1 is cleaved to short, inactive S-OPA1 isoforms by the OMA1 metalloprotease, disrupting mitochondrial structure and priming cellular stress responses such as apoptosis. Previously, we demonstrated that L-OPA1 of H9c2 cardiomyoblasts is insensitive to loss of Δψm via challenge with the protonophore carbonyl cyanide chlorophenyl hydrazone (CCCP), but that CCCP-induced OPA1 processing is activated upon differentiation in media with low serum supplemented with all-trans retinoic acid (ATRA). Here, we show that this developmental induction of OPA1 processing in H9c2 cells is independent of ATRA; moreover, pretreatment of undifferentiated H9c2s with chloramphenicol (CAP), an inhibitor of mitochondrial protein synthesis, recapitulates the Δψm-sensitive OPA1 processing observed in differentiated H9c2s. L6.C11 and C2C12 myoblast lines display the same developmental and CAP-sensitive induction of OPA1 processing, demonstrating a general mechanism of OPA1 regulation in mammalian myoblast cell settings. Restoration of CCCP-induced OPA1 processing correlates with increased apoptotic sensitivity. Moreover, OPA1 knockdown indicates that intact OPA1 is necessary for effective myoblast differentiation. Taken together, our results indicate that a novel developmental mechanism acts to regulate OMA1-mediated OPA1 processing in myoblast cell lines, in which differentiation engages mitochondrial stress sensing.
    Keywords:  Differentiation; Mitochondria; OMA1; OPA1; Transmembrane potential
    DOI:  https://doi.org/10.1016/j.mito.2024.101933
  23. Front Cell Neurosci. 2024 ;18 1403734
    Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.
    Raquel Coronel, Enrique García-Moreno, Emilio Siendones, Maria J Barrero, Beatriz Martínez-Delgado, Carlos Santos-Ocaña, Isabel Liste, M V Cascajo-Almenara.
      Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases. Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.
    Keywords:  3D cultures; drug repurposing; high-throughput screening; mitochondrial diseases; neurodevelopmental disorders; organoid; spheroids
    DOI:  https://doi.org/10.3389/fncel.2024.1403734
  24. Methods Mol Biol. 2024 ;2816 77-85
    Isolation of Mitochondria from Murine Skeletal Muscle.
    Li Dong, Xuejun Li, Ang Li, Jianxun Yi, Jingsong Zhou.
      Skeletal muscle is one of the largest tissues in human body. Besides enabling voluntary movements and maintaining body's metabolic homeostasis, skeletal muscle is also a target of many pathological conditions. Mitochondria occupy 10-15% volume of a muscle myofiber and regulate many cellular processes, which often determine the fate of the cell. Isolation of mitochondria from skeletal muscle provides opportunities for various multi-omics studies with a focus on mitochondria in biomedical research field. Here we describe a protocol to efficiently isolate mitochondria with high quality and purity from skeletal muscle of mice using Nycodenz density gradient ultracentrifugation.
    Keywords:  Mitochondria isolation; Nycodenz density gradient ultracentrifugation; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-3902-3_8
  25. Stem Cell Rev Rep. 2024 Jul 08.
    Extracellular Microvesicles vs. Mitochondria: Competing for the Top Spot in Cardiovascular Regenerative Medicine.
    David M Smadja.
      Regenerative medicine aims to restore, replace, and regenerate human cells, tissues, and organs. Despite significant advancements, many cell therapy trials for cardiovascular diseases face challenges like cell survival and immune compatibility, with benefits largely stemming from paracrine effects. Two promising therapeutic tools have been recently emerged in cardiovascular diseases: extracellular vesicles (EVs) and mitochondrial transfer. Concerning EVs, the first pivotal study with EV-enriched secretome derived from cardiovascular progenitor cells has been done treating heart failure. This first in man demonstrated the safety and feasibility of repeated intravenous infusions and highlighted significant clinical improvements, including enhanced cardiac function and reduced symptoms in heart failure patients. The second study uncovered a novel mechanism of endothelial regeneration through mitochondrial transfer via tunneling nanotubes (TNTs). This research showed that mesenchymal stromal cells (MSCs) transfer mitochondria to endothelial cells, significantly enhancing their bioenergetics and vessel-forming capabilities. This mitochondrial transfer was crucial for endothelial cell engraftment and function, offering a new strategy for vascular regeneration without the need for additional cell types. Combining EV and mitochondrial strategies presents new clinical opportunities. These approaches could revolutionize regenerative medicine, offering new hope for treating cardiovascular and other degenerative diseases. Continued research and clinical trials will be crucial in optimizing these therapies, potentially leading to personalized medicine approaches that enhance patient outcomes.
    Keywords:  ECFCs; Extracellular vesicles; Heart failure; Mitochondria; Regeneration; Stem cells
    DOI:  https://doi.org/10.1007/s12015-024-10758-8
  26. Appl Physiol Nutr Metab. 2024 Jul 09.
    Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.
    Yifan Chen, Tianzheng Yu, Patricia Deuster.
      Mitochondrial dysfunction is implicated in heat-induced skeletal muscle injury and its underlying mechanisms remain unclear. Evidence suggests that cellular ions and molecules, including divalent cations and adenine nucleotides, are involved in the regulation of mitochondrial function. In this study, we examined Ca2+, Mg2+, and NAD+ levels in mouse C2C12 myoblasts and skeletal muscle in response to heat exposure. During heat exposure, mitochondrial Ca2+ levels increased significantly, whereas cytosolic C2+ levels remained unaltered. The mitochondrial Ca2+ levels in the skeletal muscle of heat-exposed mice were 28% higher, compared to control mice. No changes in cytosolic Ca2+ were detected between the two groups. Following heat exposure, cytosolic and mitochondrial Mg2+ levels were reduced by 47% and 23% in C2C12 myoblasts, and by 51% and 44% in mouse skeletal muscles, respectively. In addition, heat exposure decreased mitochondrial NAD+ levels by 32% and 26% in C2C12 myoblasts and mouse skeletal muscles, respectively. Treatment with the NAD+ precursor nicotinamide riboside (NR) partially prevented heat-induced depletion of NAD+. Additionally, NR significantly reduced heat-increased mitochondrial fission, mitochondrial depolarization, and apoptosis in C2C12 myoblasts and mouse skeletal muscles. No effects of NR on heat-induced changes in intracellular Ca2+ and Mg2+ levels were observed. This study provides the in vitro and in vivo evidence that acute heat stress causes alterations in mitochondrial Ca2+, Mg2+, and NAD+ homeostasis. Our results suggest mitochondrial NAD+> homeostasis as a therapeutic target for the prevention of heat-induced skeletal muscle injury.
    DOI:  https://doi.org/10.1139/apnm-2024-0157
  27. Nature. 2024 Jul 11.
    De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
    Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Alicia Ljungdahl, Sarah L Stenton, Susan Walker, Jenny Lord, Gabrielle Lemire, Alexandra C Martin-Geary, Vijay S Ganesh, Jialan Ma, Jamie M Ellingford, Erwan Delage, Elston N D'Souza, Shan Dong, David R Adams, Kirsten Allan, Madhura Bakshi, Erin E Baldwin, Seth I Berger, Jonathan A Bernstein, Ishita Bhatnagar, Ed Blair, Natasha J Brown, Lindsay C Burrage, Kimberly Chapman, David J Coman, Alison G Compton, Chloe A Cunningham, Precilla D'Souza, Petr Danecek, Emmanuèle C Délot, Kerith-Rae Dias, Ellen R Elias, Frances Elmslie, Care-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L Fraser, Lyndon Gallacher, Casie A Genetti, Anne Goriely, Christina L Grant, Tobias Haack, Jenny E Higgs, Anjali G Hinch, Matthew E Hurles, Alma Kuechler, Katherine L Lachlan, Seema R Lalani, François Lecoquierre, Elsa Leitão, Anna Le Fevre, Richard J Leventer, Jan E Liebelt, Sarah Lindsay, Paul J Lockhart, Alan S Ma, Ellen F Macnamara, Sahar Mansour, Taylor M Maurer, Hector R Mendez, Kay Metcalfe, Stephen B Montgomery, Mariya Moosajee, Marie-Cécile Nassogne, Serena Neumann, Michael O'Donoghue, Melanie O'Leary, Elizabeth E Palmer, Nikhil Pattani, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L Rehm, Chloe M Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A Rosenfeld, Rani Sachdev, Charles J Shaw-Smith, Cas Simons, Sanjay M Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Helen S Stewart, Tiong Yang Tan, Natalie B Tan, Suzanna E L Temple, David R Thorburn, Cynthia J Tifft, Eloise Uebergang, Grace E VanNoy, Pradeep Vasudevan, Eric Vilain, David H Viskochil, Laura Wedd, Matthew T Wheeler, Susan M White, Monica Wojcik, Lynne A Wolfe, Zoe Wolfenson, Caroline F Wright, Changrui Xiao, David Zocche, John L Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M Fica, Diana Baralle, Christel Depienne, Daniel G MacArthur, Joanna M M Howson, Stephan J Sanders, Anne O'Donnell-Luria, Nicola Whiffin.
      Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5' splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
    DOI:  https://doi.org/10.1038/s41586-024-07773-7
  28. Nat Genet. 2024 Jul 08.
    Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import.
    Artem Khan, Gokhan Unlu, Phillip Lin, Yuyang Liu, Ece Kilic, Timothy C Kenny, Kıvanç Birsoy, Eric R Gamazon.
      Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Association Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions and even pinpoint genes that are distant from the variants implicated by GWAS. In particular, our analysis identified solute carrier family 25 member 48 (SLC25A48) as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite betaine. Integrative rare variant and polygenic score analyses in UK Biobank provide strong evidence that the SLC25A48 causal effects on human disease may in part be mediated by the effects of choline. Altogether, our study provides a discovery platform for metabolic gene function and proposes SLC25A48 as a mitochondrial choline transporter.
    DOI:  https://doi.org/10.1038/s41588-024-01827-2
  29. J Mol Cell Cardiol Plus. 2024 Jun;pii: 100076. [Epub ahead of print]8
    Dietary linoleic acid supplementation fails to rescue established cardiomyopathy in Barth syndrome.
    Siting Zhu, Jing Pang, Anh Nguyen, Helen Huynh, Sharon Lee, Yusu Gu, Frederic M Vaz, Xi Fang.
      Barth syndrome (BTHS) is a mitochondrial lipid disorder caused by mutations in TAFAZZIN (TAZ), required for cardiolipin (CL) remodeling. Cardiomyopathy is a major clinical feature, with no curative therapy. Linoleic acid (LA) supplementation is proposed to ameliorate BTHS cardiomyopathy by enhancing linoleoyl group incorporation into CL. While the beneficial effect of dietary LA supplementation in delaying the development of BTHS cardiomyopathy has been recently tested, its potential to reverse established BTHS cardiomyopathy remains unclear. Our study revealed that LA supplementation cannot rescue established BTHS cardiomyopathy in mice, highlighting the importance of early initiation of LA supplementation for maximum benefits.
    Keywords:  Barth syndrome; Cardiomyopathies; Dietary supplements; Linoleic acid
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100076
  30. Eur J Neurol. 2024 Jul 08. e16405
    Adult presentation of a rare mitochondrial tRNA Val gene mutation-an expanding clinical phenotype.
    Eimear Joyce, Mohib Ali, Georgia Richard, Siobhan Kelly, Fiachra Martin, Peter J Conlon, Anna Whelehan, Yi Shiau Ng, Stela Lefter.
      BACKGROUND AND PURPOSE: Late-onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67-year-old gentleman who presented with a 3-month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end-stage chronic kidney disease.METHODS: Extensive work-up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis.
    RESULTS: Magnetic resonance imaging brain demonstrated a single non-enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT-TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co-enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight.
    CONCLUSION: An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT-TV variant, previously reported once in a child who displayed a different clinical phenotype.
    Keywords:  MT‐TV gene variant; late onset mitochondrial disorder; m.1659T>C
    DOI:  https://doi.org/10.1111/ene.16405
  31. Vascul Pharmacol. 2024 Jun;pii: S1537-1891(24)00057-0. [Epub ahead of print]155 107332
    Investigating mitochondrial remodelling in Arrhythmogenic Cardiomyopathy.
    Andrea Medici, Chiara Volani, Reginald Philippe, Alexandros Lavdas, Michael Blumer, Elena Sommariva, Giulio Pompilio, Jakob Troppmair, Alessandra Rossini.
      
    DOI:  https://doi.org/10.1016/j.vph.2024.107332
  32. Mol Cell Biochem. 2024 Jul 13.
    Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.
    Haixia Fan, Minghao Yuan, Shenyuan Wang, Xu Yang, Liu Shu, Yinshuang Pu, Qian Zou, Xiaogang Zhang, Chuanling Wang, Zhiyou Cai.
      Dietary salt is increasingly recognized as an independent risk factor for cognitive impairment. However, the exact mechanisms are not yet fully understood. Mitochondria, which play a crucial role in energy metabolism, are implicated in cognitive function through processes such as mitochondrial dynamics and mitophagy. While mitochondrial dysfunction is acknowledged as a significant determinant of cognitive function, the specific relationship between salt-induced cognitive impairment and mitochondrial health has yet to be fully elucidated. Here, we explored the underlying mechanism of cognitive impairment of mice and N2a cells treated with high-salt focusing on the mitochondrial homeostasis with western blotting, immunofluorescence, electron microscopy, RNA sequencing, and more. We further explored the potential role of SIRT3 in salt-induced mitochondrial dysfunction and synaptic alteration through plasmid transfection and siRNA. High salt diet significantly inhibited mitochondrial fission and blocked mitophagy, leading to dysfunctional mitochondria and impaired synaptic plasticity. Our findings demonstrated that SIRT3 not only promote mitochondrial fission by modulating phosphorylated DRP1, but also rescue mitophagy through promoting PINK1/Parkin-dependent pathway. Overall, our data for the first time indicate that mitochondrial homeostasis imbalance is a driver of impaired synaptic plasticity in a cognitive impairment phenotype that is exacerbated by a long-term high-salt diet, and highlight the protective role of SIRT3 in this process.
    Keywords:  Cognitive impairment; Dietary salt; Mitochondrial homeostasis; Synaptic plasticity
    DOI:  https://doi.org/10.1007/s11010-024-05069-y
  33. Int J Mol Sci. 2024 Jun 22. pii: 6878. [Epub ahead of print]25(13):
    Lipid Droplet-Mitochondria Contacts in Health and Disease.
    Hongjun Fan, Yanjie Tan.
      The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.
    Keywords:  disease; lipid droplet; metabolism; mitochondria; redox
    DOI:  https://doi.org/10.3390/ijms25136878
  34. Am J Physiol Cell Physiol. 2024 Jul 09.
    Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.
    Soi-Yi Park, Su-Ryun Jung, Jong-Yeon Kim, Yong-Woon Kim, Hoon-Ki Sung, So-Young Park, Kyung-Oh Doh, Jin-Ho Koh.
      Lower oxidative capacity in skeletal muscles (SKMs) is a prevailing cause of metabolic diseases. Exercise not only enhances the fatty acid oxidation (FAO) capacity of SKMs but also increases lactate levels. Given that lactate may contribute to tricarboxylic acid cycle (TCA) flux and impact monocarboxylate transporter 1 in the SKMs, we hypothesize that lactate can influence glucose and fatty acid (FA) metabolism. To test this hypothesis, we investigated the mechanism underlying lactate-driven FAO regulation in the SKM of mice with diet-induced obesity (DIO). Lactate was administered to DIO mice immediately after exercise over three weeks. We found that increased lactate levels enhanced energy expenditure mediated by fat metabolism during exercise recovery and decreased triglyceride levels in DIO mice SKMs. To determine the lactate-specific effects without exercise, we administered lactate to mice on a high-fat diet (HFD) for eight weeks. Similar to our exercise conditions, lactate increased FAO, TCA cycle activity, and mitochondrial respiration in the SKMs of HFD-fed mice. Additionally, under sufficient FA conditions, lactate increased uncoupling protein-3 abundance via the NADH/NAD+ shuttle. Conversely ATP synthase abundance decreased in the SKMs of HFD mice. Taken together, our results suggest that lactate amplifies the adaptive increase in FAO capacity mediated by the TCA cycle and mitochondrial respiration in SKMs under sufficient FA abundance.
    Keywords:  Exercise; Fatty acid oxidation; Lactate; Mitochondrial respiration; TCA cycle
    DOI:  https://doi.org/10.1152/ajpcell.00060.2024
  35. Int J Mol Sci. 2024 Jul 03. pii: 7305. [Epub ahead of print]25(13):
    Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.
    Emanuele Marzetti, Riccardo Calvani, Francesco Landi, Helio José Coelho-Júnior, Anna Picca.
      Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity.
    Keywords:  DAMPs; SASP; cell death; extracellular vesicles; inflammaging; interleukin; mitochondrial quality control; mitochondrial-derived vesicles; mtDNA; pyroptosis
    DOI:  https://doi.org/10.3390/ijms25137305
  36. JIMD Rep. 2024 Jul;65(4): 212-225
    Transient response to high-dose niacin therapy in a patient with NAXE deficiency.
    Fatema Al-Amrani, Khalid Al-Thihli, Eiman Al-Ajmi, Amna Al-Futaisi, Fathiya Al-Murshedi.
      Background: NAXE-encephalopathy or early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL-1) and NAXD-encephalopathy (PEBEL-2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation.Methods: We describe a patient with a confirmed PEBEL-1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL-1 and PEBEL-2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off-label use of a COX2 inhibitor to treat niacin-related urticaria in NAXE-encephalopathy.
    Results: So far, seven patients with PEBEL-1 and PEBEL-2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL-1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient.
    Conclusion: Despite previous positive results for niacin supplementation in patients with PEBEL-1 and PEBEL-2, this is the first report of a patient with PEBEL-1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date.
    Keywords:  COX2 inhibitors; NAXD‐encephalopathy; NAXE‐encephalopathy; PEBEL‐2; early onset progressive encephalopathy with brain edema and/or leukoencephalopathy −1 (PEBEL‐1); niacin; vitamin B3
    DOI:  https://doi.org/10.1002/jmd2.12425
  37. Neurol Genet. 2024 Aug;10(4): e200167
    Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency.
    Agnès Rötig, Pauline Gaignard, Giulia Barcia, Zahra Assouline, Claire-Marine Berat, Magalie Barth, Léna Damaj, Nolwenn Laborde, Marie-Thérèse Abi-Warde, Brigitte Chabrol, Pascale De Lonlay, Isabelle Desguerre, Alice Goldenberg, Emmanuel Gonzales, Emmanuel Jacquemin, Patrizia Amati-Bonneau, Dominique Bonneau, Véronique Abadie, Chrystèle Bonnemains, Pierre Broue, Anne De Saint-Martin, Philippe Durand, Alain Fouilhoux, Bertrand Isidor, Marianne Jaroussie, Guillaume Jedraszak, Hélène Maurey, Karine Mention, Sylvie S Odent, Laurent Pasquier, Christelle Rougeot-Jung, Cyril Gitiaux, Charles-Joris Roux, Nathalie Boddaert, Arnold Munnich, Manuel Schiff.
      Background and Objectives: DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants.Methods: The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency.
    Results: Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types.
    Discussion: The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.
    DOI:  https://doi.org/10.1212/NXG.0000000000200167
  38. Biochemistry (Mosc). 2024 Jun;89(6): 1061-1078
    Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role.
    Natalia V Belosludtseva, Mikhail V Dubinin, Konstantin N Belosludtsev.
      Voltage-dependent anion channels (VDAC1-3) of the outer mitochondrial membrane are a family of pore-forming β-barrel proteins that carry out controlled "filtration" of small molecules and ions between the cytoplasm and mitochondria. Due to the conformational transitions between the closed and open states and interaction with cytoplasmic and mitochondrial proteins, VDACs not only regulate the mitochondrial membrane permeability for major metabolites and ions, but also participate in the control of essential intracellular processes and pathological conditions. This review discusses novel data on the molecular structure, regulatory mechanisms, and pathophysiological role of VDAC proteins, as well as future directions in this area of research.
    Keywords:  VDAC; cancer; cell death; diabetes mellitus; membrane transport; mitochondria; neurodegenerative diseases
    DOI:  https://doi.org/10.1134/S0006297924060075
  39. Nat Genet. 2024 Jul 08.
    Unsupervised representation learning on high-dimensional clinical data improves genomic discovery and prediction.
    Taedong Yun, Justin Cosentino, Babak Behsaz, Zachary R McCaw, Davin Hill, Robert Luben, Dongbing Lai, John Bates, Howard Yang, Tae-Hwi Schwantes-An, Yuchen Zhou, Anthony P Khawaja, Andrew Carroll, Brian D Hobbs, Michael H Cho, Cory Y McLean, Farhad Hormozdiari.
      Although high-dimensional clinical data (HDCD) are increasingly available in biobank-scale datasets, their use for genetic discovery remains challenging. Here we introduce an unsupervised deep learning model, Representation Learning for Genetic Discovery on Low-Dimensional Embeddings (REGLE), for discovering associations between genetic variants and HDCD. REGLE leverages variational autoencoders to compute nonlinear disentangled embeddings of HDCD, which become the inputs to genome-wide association studies (GWAS). REGLE can uncover features not captured by existing expert-defined features and enables the creation of accurate disease-specific polygenic risk scores (PRSs) in datasets with very few labeled data. We apply REGLE to perform GWAS on respiratory and circulatory HDCD-spirograms measuring lung function and photoplethysmograms measuring blood volume changes. REGLE replicates known loci while identifying others not previously detected. REGLE are predictive of overall survival, and PRSs constructed from REGLE loci improve disease prediction across multiple biobanks. Overall, REGLE contain clinically relevant information beyond that captured by existing expert-defined features, leading to improved genetic discovery and disease prediction.
    DOI:  https://doi.org/10.1038/s41588-024-01831-6
  40. Protein Sci. 2024 Aug;33(8): e5108
    MRS2 missense variation at Asp216 abrogates inhibitory Mg2+ binding, potentiating cell migration and apoptosis resistance.
    Sukanthathulse Uthayabalan, Taylor Lake, Peter B Stathopulos.
      Mitochondrial magnesium (Mg2+) is a crucial modulator of protein stability, enzymatic activity, ATP synthesis, and cell death. Mitochondrial RNA splicing protein 2 (MRS2) is the main Mg2+ channel in the inner mitochondrial membrane that mediates influx into the matrix. Recent cryo-electron microscopy (cryo-EM) human MRS2 structures exhibit minimal conformational changes at high and low Mg2+, yet the regulation of human MRS2 and orthologues by Mg2+ binding to analogous matrix domains has been well established. Further, a missense variation at D216 has been identified associated with malignant melanoma and MRS2 expression and activity is implicated in gastric cancer. Thus, to gain more mechanistic and functional insight into Mg2+ sensing by the human MRS2 matrix domain and the association with proliferative disease, we assessed the structural, biophysical, and functional effects of a D216Q mutant. We show that the D216Q mutation is sufficient to abrogate Mg2+-binding and associated conformational changes including increased α-helicity, stability, and monomerization. Further, we reveal that the MRS2 matrix domains interact with ~μM affinity, which is weakened by up to two orders of magnitude in the presence of Mg2+ for wild-type but unaffected for D216Q. Finally, we demonstrate the importance of Mg2+ sensing by MRS2 to prevent matrix Mg2+ overload as HeLa cells overexpressing MRS2 show enhanced Mg2+ uptake, cell migration, and resistance to apoptosis while MRS2 D216Q robustly potentiates these cancer phenotypes. Collectively, our findings further define the MRS2 matrix domain as a critical Mg2+ sensor that undergoes conformational and assembly changes upon Mg2+ interactions dependent on D216 to temper matrix Mg2+ overload.
    Keywords:  Mg2+ sensor; apoptosis; feedback inhibition; gastric cancer; ion channels; magnesium ions (Mg2+); mitochondria; mitochondrial RNA splicing protein 2 (MRS2); signal transduction
    DOI:  https://doi.org/10.1002/pro.5108
  41. Lancet Digit Health. 2024 Jul 09. pii: S2589-7500(24)00114-6. [Epub ahead of print]
    ChatGPT for digital pathology research.
    Mohamed Omar, Varun Ullanat, Massimo Loda, Luigi Marchionni, Renato Umeton.
      The rapid evolution of generative artificial intelligence (AI) models including OpenAI's ChatGPT signals a promising era for medical research. In this Viewpoint, we explore the integration and challenges of large language models (LLMs) in digital pathology, a rapidly evolving domain demanding intricate contextual understanding. The restricted domain-specific efficiency of LLMs necessitates the advent of tailored AI tools, as illustrated by advancements seen in the last few years including FrugalGPT and BioBERT. Our initiative in digital pathology emphasises the potential of domain-specific AI tools, where a curated literature database coupled with a user-interactive web application facilitates precise, referenced information retrieval. Motivated by the success of this initiative, we discuss how domain-specific approaches substantially minimise the risk of inaccurate responses, enhancing the reliability and accuracy of information extraction. We also highlight the broader implications of such tools, particularly in streamlining access to scientific research and democratising access to computational pathology techniques for scientists with little coding experience. This Viewpoint calls for an enhanced integration of domain-specific text-generation AI tools in academic settings to facilitate continuous learning and adaptation to the dynamically evolving landscape of medical research.
    DOI:  https://doi.org/10.1016/S2589-7500(24)00114-6
  42. bioRxiv. 2024 Jun 25. pii: 2024.06.24.600538. [Epub ahead of print]
    Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.
    Jeffrey T Mindrebo, Gabriel C Lander.
      AAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryo-electron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding allosterically regulates proteolytic activity, and that LONP1 can adopt a configuration conducive to substrate translocation even when the ATPases are bound to ADP. These results challenge the conventional understanding of the hand-over-hand translocation mechanism, giving rise to an alternative model that aligns more closely with biochemical and biophysical data on related enzymes like ClpX, ClpA, the 26S proteasome, and Lon protease.
    DOI:  https://doi.org/10.1101/2024.06.24.600538
  43. Nat Commun. 2024 Jul 10. 15(1): 5796
    A diverse proteome is present and enzymatically active in metabolite extracts.
    Rachel Rae J House, Molly T Soper-Hopper, Michael P Vincent, Abigail E Ellis, Colt D Capan, Zachary B Madaj, Emily Wolfrum, Christine N Isaguirre, Carlos D Castello, Amy B Johnson, Martha L Escobar Galvis, Kelsey S Williams, Hyoungjoo Lee, Ryan D Sheldon.
      Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-50128-z
  44. Annu Rev Cell Dev Biol. 2024 Jul 08.
    Mitochondrial Structure, Dynamics, and Physiology: Light Microscopy to Disentangle the Network.
    Juan C Landoni, Tatjana Kleele, Julius Winter, Willi Stepp, Suliana Manley.
      Mitochondria serve as energetic and signaling hubs of the cell: This function results from the complex interplay between their structure, function, dynamics, interactions, and molecular organization. The ability to observe and quantify these properties often represents the puzzle piece critical for deciphering the mechanisms behind mitochondrial function and dysfunction. Fluorescence microscopy addresses this critical need and has become increasingly powerful with the advent of superresolution methods and context-sensitive fluorescent probes. In this review, we delve into advanced light microscopy methods and analyses for studying mitochondrial ultrastructure, dynamics, and physiology, and highlight notable discoveries they enabled.
    DOI:  https://doi.org/10.1146/annurev-cellbio-111822-114733
  45. NPJ Aging. 2024 Jul 10. 10(1): 32
    Strategies for modeling aging and age-related diseases.
    D Jothi, Linda Anna Michelle Kulka.
      The ability to reprogram patient-derived-somatic cells to IPSCs (Induced Pluripotent Stem Cells) has led to a better understanding of aging and age-related diseases like Parkinson's, and Alzheimer's. The established patient-derived disease models mimic disease pathology and can be used to design drugs for aging and age-related diseases. However, the age and genetic mutations of the donor cells, the employed reprogramming, and the differentiation protocol might often pose challenges in establishing an appropriate disease model. In this review, we will focus on the various strategies for the successful reprogramming and differentiation of patient-derived cells to disease models for aging and age-related diseases, emphasizing the accuracy in the recapitulation of disease pathology and ways to overcome the limitations of its potential application in cell replacement therapy and drug development.
    DOI:  https://doi.org/10.1038/s41514-024-00161-5
  46. Neural Regen Res. 2025 Apr 01. 20(4): 1124-1134
    Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.
    Yanting Liu, Wei Huang, Jiayi Wen, Xin Xiong, Ting Xu, Qi Wang, Xiusheng Chen, Xianxian Zhao, Shihua Li, Xiaojiang Li, Weili Yang.
      JOURNAL/nrgr/04.03/01300535-202504000-00028/figure1/v/2024-07-06T104127Z/r/image-tiff The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration. However, it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains. This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals. Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin. Recently, we showed that the PINK1 kinase is selectively expressed as a truncated form (PINK1-55) in the primate brain. In the present study, we used multiple antibodies, including our recently developed monoclonal anti-PINK1, to validate the selective expression of PINK1 in the primate brain. We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages, which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains. PINK1 was enriched in the membrane-bound fractionations, whereas Parkin was soluble with a distinguishable distribution. Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes, though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress. These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-01140
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